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c48cfa5bbedd29f4434e9586b60ec7ce

Growth inhibition of cloned promastigotes showed that the films have enough releasing capacity and in vivo system , the films containing paromomycin and gentamicin was able to reduce the lesion size and induced complete cure in 80 % of the mice but relapse was seen in 60 % of the cured mice and overall 50 % cure rate was seen during 20 weeks period of the study .

Leishmanicidal Activity of Films Containing Paromomycin and Gentamicin Sulfate both In Vitro and In Vivo. Based on the efficacy of paromomycin ointment and recent ongoing clinical trials of combination of paromomycin and gentamicin, a new physical form of films of the paromomycin and gentamicin was prepared and anti-Leishmania activities of the prepared films were assessed in vitro and in vivo. ### methods paromomycin 15% and gentamicin 0.5% was incorporated in a film using ethyl cellulose and HPMC (Hydroxyl Propyl Methyl Cellulose). In order to assess the drug release and anti-Leishmania activities of the preparation, a clone L. major parasite was established using a set of modified NNN medium without overlay liquid layer. Therapeutic effects of the films were evaluated using Balb/c mice model. The mice were inoculated with 2×10(6)L. major promastigotes (MRHO/IR/75/ER) and then when the lesions developed the mice were randomly divided in 3 groups, 10 mice per group, and treated with either perpetrated films or placebo for 28 days or left untreated. ### results Growth inhibition of cloned promastigotes showed that the films have enough releasing capacity and in vivo system , the films containing paromomycin and gentamicin was able to reduce the lesion size and induced complete cure in 80 % of the mice but relapse was seen in 60 % of the cured mice and overall 50 % cure rate was seen during 20 weeks period of the study . ### conclusion It seems that the prepared films might be further used in human clinical trials.

https://pubmed.ncbi.nlm.nih.gov/22347298/

084c0fc7d39df4df24e947ba414c6e06

Management and outcome : The patient was initially treated with bortezomib and dexamethasone for the myeloma .

Synchronous detection of multiple myeloma and acute myeloid leukemia: A diagnostic and therapeutic challenge. Synchronous detection of multiple myeloma and acute myeloid leukemia in a single patient is a rare coincidence. Treatment of these patients is still unclear, mostly based on acute myeloid leukemia strategies combined with bortezomib. ### Case Report A 72-year-old male with no medical history was investigated for pancytopenia. On medical examination, he was complicated with a wide and severe skin infection on arm. On examination of bone marrow aspirate, 25% myeloblasts infiltration and additional 10% plasma cells were seen. Acute myeloid leukemia was diagnosed and plasma cell proliferation was attributed to reactive plasmacytosis due to skin infection. However, flowcytometric studies and immunohistochemical examination revealed two different cell populations with 30-40% atypical plasma cells and >20% myeloblasts. Serum M-protein detected by serum electrophoresis test and immunofixation test revealed a monoclonal IgG lambda band. He was diagnosed with concurrent acute myeloid leukemia and multiple myeloma without history of chemotherapy. Management and outcome : The patient was initially treated with bortezomib and dexamethasone for the myeloma . Subsequently, azacitidine was administered subcutaneously for the acute myeloid leukemia treatment. The tru-cut biopsy of the lesion on his arm revealed suppurative inflammatory findings and no malign cells detected. Antibiotherapy was started according to susceptibility. He expired after three months of survival. ### discussion The synchronous occurrence of these two different clonal hematological malignancies is rare in hematology practice. Patient-based prospective studies and case series are needed to guide diagnosis and treatment strategies. Furthermore, this report highlights the importance of ruling out reactive plasmacytosis in patients with hematological malignancy who developed severe infections.

https://pubmed.ncbi.nlm.nih.gov/33620259/

a8dd8920926a20064069044a6f415a1c

Majority of the interventions were to stop the antimicrobial therapy ( 30.3 % ) , and the most common audited antimicrobials was Piperacillin/Tazobactam ( 25.5 % ) , followed by Meropenem ( 11.82 % ) , Amoxicillin/Clavulanate and Vancomycin ( 8.18 % ) respectively .

Antimicrobial stewardship program in a Malaysian district hospital: First year experience. Antimicrobial resistance is an alarming public health threat that requires urgent global solution. Implementation of antimicrobial stewardship program (ASP) is an essential practice element for healthcare institutions in gate-keeping judicious antimicrobial use. This study highlighted the development, first year experience, and result of the implementation of ASP utilizing persuasive and restrictive approaches in a Malaysian district hospital. ### methods An observational study was conducted between January 2015 to December 2015 on implementation of ASP among hospitalized inpatients age 12 years old and above. ### results Recommendations were provided for 60% of cases (110 patients) with the average acceptance rate of 83.33%. Majority of the interventions were to stop the antimicrobial therapy ( 30.3 % ) , and the most common audited antimicrobials was Piperacillin/Tazobactam ( 25.5 % ) , followed by Meropenem ( 11.82 % ) , Amoxicillin/Clavulanate and Vancomycin ( 8.18 % ) respectively . The concordance rate towards authorization policy was increased in 2015 (71.59% of cases) as compared before the implementation of ASP in 2014 (60.6% of cases). Restrictive enforcement under ASP had been shown to improve significantly adherence rate towards antimicrobials authorization policy (p-value: 0.004). ### conclusion ASP was successfully implemented in a district hospital. Future studies on its clinical outcomes are important to evaluate its effectiveness as well as focus on the improvement to the pre-existing strategies and measures.

https://pubmed.ncbi.nlm.nih.gov/27648056/

5e8cfd3f800bb3e3855a1c5a47bfbd12

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer .

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer . Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

https://pubmed.ncbi.nlm.nih.gov/27493615/

42a09be85103a5958ec546ff014eb697

We retrospectively evaluated 52 metastatic renal cell carcinoma patients who were treated with nivolumab plus ipilimumab between August 2015 and January 2020 .

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. To investigate the efficacy and safety of first-line nivolumab plus ipilimumab for patients treated with metastatic renal cell carcinoma. ### methods We retrospectively evaluated 52 metastatic renal cell carcinoma patients who were treated with nivolumab plus ipilimumab between August 2015 and January 2020 . Data on patient characteristics, treatment parameters and adverse events were obtained. Oncological outcomes were assessed according to the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model. Furthermore, differences in treatment parameters between patients with objective response (responders) and non-responders were compared. ### results The median age and follow-up periods were 69 years and 8.2 months, respectively. The 1-year progression-free survival and overall survival rates were 55% and 75%, respectively. The objective response rate was 39%, and it was significantly different between the International Metastatic Renal Cell Carcinoma Database Consortium intermediate- and poor-risk groups (52% vs 24%). We observed 36 (69%) any immune-related adverse events, and 19 (37%) severe immune-related adverse events (grades III-V). The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and higher value of initial C-reactive protein (≥1.0 mg/dL) were significantly associated with non-responders. Patients with two factors (the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group plus C-reactive protein ≥1.0 mg/dL) had a significantly poor overall survival than those with none or a single factor. ### conclusions In our experience, treatment response to nivolumab plus ipilimumab is comparable with that of the CheckMate 214 clinical trial, but the incidence of treatment-related adverse events is lower. The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and initial C-reactive protein value might have a prognostic value for poor survival.

https://pubmed.ncbi.nlm.nih.gov/32893401/

5059821f165b54b741fff5d949937c46

Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat , thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier ( BBB ) in vivo .

P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents. Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat , thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier ( BBB ) in vivo . The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

https://pubmed.ncbi.nlm.nih.gov/23670590/

43e5febf8c327a283f09cb768dda4713

The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside .

Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins. Synergistic activity between both azlocillin and mezlocillin and aminoglycosides or cefazolin could be demonstrated by checkerboard dilution, isobologram, and killing curve techniques. azlocillin and mezlocillin combined with gentamicin, netilmicin, or amikacin were synergistic against Escherichia coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and indole-positive Proteus. Synergy was observed with isolates that were susceptible or resistant to azlocillin or mezlocillin. Synergy was seen most often when azlocillin or mezlocillin were combined with amikacin, gentamicin, or netilmicin against Pseudomonas aeruginosa. The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside . No antagonism was seen when aminoglycoside antibiotics were combined with azlocillin or mezlocillin. cefazolin was synergistic against Pseudomonas, Providencia, P. mirabilis, indole-positive Proteus, Citrobacter, Klebsiella, and Escherichia coli, when combined with azlocillin or mezlocillin. However, the combination of either agent with cefazolin was antagonistic when tested against selected indole-positive Proteus and Enterobacter isolates.

https://pubmed.ncbi.nlm.nih.gov/666302/

6d09f2725d4b0e2d4cf4b2c255f6dec9

Eligible patients ( n = 17 ) were divided into 2 groups receiving a combined chemotherapy of intravenous cisplatinum ( 70 mg/m2 ) and cyclophosphamide ( 700 mg/m2 ) with or without the addition of Lenograstim .

The use of lenograstim (Granocyte) in chemotherapy for ovarian cancer. We have conducted an open, controlled study on the febrile neutropenia effects by lenograstim (Granocyte) therapy following cytotoxic chemotherapy of cisplatinum and cyclophosphamide in patients with primary advanced epithelial ovarian cancer. Eligible patients ( n = 17 ) were divided into 2 groups receiving a combined chemotherapy of intravenous cisplatinum ( 70 mg/m2 ) and cyclophosphamide ( 700 mg/m2 ) with or without the addition of Lenograstim . Subcutaneous administration of lenograstim (100 micrograms/day) for 7 consecutive days was given from day 8 to day 14 of the 3rd to the 5th cycle of chemotherapy in lenograstim treated patients. After 3 cycles of treatment, lenograstim treated patients (group 1, n = 10) showed a significant improvement in white blood cell (WBC) count as compared with group 2 (control) of 7 patients (p = 0.00002). Group 1 patients also showed an increased C-reactive protein, though of no significance. There were no significant differences among the 2 groups regarding ESR, hematocrit, platelet counts and blood chemistry profiles. This preliminary data encourages more study of the benefits of lenograstim in the treatment of ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/9681128/

b3163af31193b27f97a8a16973bd30c2

In particular , caspofungin for invasive candidiasis and voriconazole for invasive aspergillosis seem at least equivalent to amphotericin B. A clear advantage is the advent of lipid formulations of amphotericin B.

[Therapy of severe fungal infections]. Severe fungal infections increase in numbers in the Western world. This is due to more intensive therapies against cancers leading to severe and prolonged immunosuppression. For many years treatment of severe fungal infections had to be done solely with amphothericin B desoxycholate and 5-fluorocytosine. With the advent of triazoles such as fluconazole, lipid formulations of amphotericin B and the development of echinocandines such as caspofungin also severe candidiasis and invasive aspergillosis has become treatable. In particular , caspofungin for invasive candidiasis and voriconazole for invasive aspergillosis seem at least equivalent to amphotericin B. A clear advantage is the advent of lipid formulations of amphotericin B. This regards especially side effects which are reduced with these newer formulations, i.e. nephrotoxicity. Due to the fact that prospective trials are difficult to conduct because patient populations may vary considerably (especially the underlying disease) many comparisons were not yet performed. Nevertheless, promising results indicate that certain combinations of antifungals may enhance prognosis of refractory fungal infections with a so far very serious prognosis.

https://pubmed.ncbi.nlm.nih.gov/14689198/

9d63911361295300c7b4ea4df9aa7984

Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days , and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1 .

Continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for recurrent or refractory osteosarcoma patients in China: a retrospective study. The aim of this retrospective study was to evaluate the feasibility and efficacy of response to continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for patients with recurrent or refractory osteosarcoma. ### Materials And Methods Eighteen recurrent or refractory osteosarcoma patients who were treated with continuous-infusion ifosfamide and doxorubicin combination between May 1999 and April 2011 were included in the analysis. Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days , and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1 . The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. ### results The patients (ages 7-53 years) received a total of 42 cycles of chemotherapy (median: 2 courses; range: 2-5 courses). The overall response rate was 0% and the disease control rate was 22.3%, with four patients having stable disease. The median time to progression and overall survival time were 2 months (range: 2-5 months) and 9 months (range: 3-29 months), respectively. Major severe toxicities were leucopenia 7 (38.9%), nausea and vomiting 3 (16.7%) and alopecia 9 (50%). There were no treatment-related deaths. ### conclusions In our experience, continuous-infusion ifosfamide and doxorubicin combination therapy at this dosage and schedule was found to be well tolerated and moderate effective, which could be considered as salvage therapy for patients with recurrent or refractory osteosarcoma. Further assessment is necessary to confirm the safety and efficacy of this treatment.

https://pubmed.ncbi.nlm.nih.gov/25824770/

269cf8a7f7d3ae688bf0187afe5819b6

A Randomized , Double-blind , Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-naive Depressed Women : A Pilot Study .

A Randomized , Double-blind , Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-naive Depressed Women : A Pilot Study . This study was designed to examine the antidepressant effect of celecoxib (200 mg/day) augmentation of sertraline in the treatment of female patients with first episode of major depression over 8 weeks of therapy. Thirty female outpatients diagnosed with first episode of major depression, were recruited for this study. Participants were randomly assigned into two equal groups receiving either sertraline plus celecoxib 100 mg twice daily or sertraline plus placebo twice daily. Patients were assessed by Hamilton Depression and Anxiety Rating Scale at baseline, week 4 and week 8 of treatment. Both treatment groups showed notable improvement in their symptoms from baseline; however, celecoxib group showed greater decrease in Hamilton Depression Scores compared to the placebo group after four weeks of treatment. Response rates were also found to be significantly higher in the celecoxib group compared to the placebo group over 4 weeks. Nevertheless, the mentioned differences between two groups were not significant at the end of week 8. Also, remission rate was remarkably higher in celecoxib group in comparison with placebo at the end point. The results suggested that celecoxib may hasten the onset of therapeutic action of sertraline and increase response and remission rate in depressive disorders.

https://pubmed.ncbi.nlm.nih.gov/26330878/

33ceaf2ec6a03465860d3825e935bddb

The aim of this retrospective study was to investigate susceptibility rates of Mycobacterium tuberculosis complex ( MTBC ) isolates against streptomycin , rifampicin , isoniazid , and ethambutol between January 1998 and December 2000 in the Turkish Army .

Resistance patterns of Mycobacterium tuberculosis complex isolates in the Turkish Army from 1998 to 2000. The aim of this retrospective study was to investigate susceptibility rates of Mycobacterium tuberculosis complex ( MTBC ) isolates against streptomycin , rifampicin , isoniazid , and ethambutol between January 1998 and December 2000 in the Turkish Army . Specimens collected from patients were cultured both conventionally and radiometrically. Differentiation of MTBC bacteria from Mycobacteria other than tuberculosis bacilli was made by the BACTEC p-nitro-alpha-acetyl-amino-beta-hydroxypropiophenone test. Susceptibility testing of MTBC isolates was performed using the BACTEC radiometric susceptibility assay for mycobacteria. Most of the specimens originated from respiratory system. A total of 98 isolates in 1998, 123 isolates in 1999, and 84 isolates in 2000 were obtained and identified as MTBC using the radiometric BACTEC TB460 system. Initial resistance was most frequent to isoniazid followed by ethambutol, streptomycin , and rifampicin in this study period. The differences between resistance rates were not statistically significant on an annual basis. None of these isolates was resistant to all four antimycobacterial agents. Although resistance rates of our isolates were not as high as previously reported by some authors from Turkey and there was no significant difference between the annual susceptibility rates, routine screening of antituberculosis drug susceptibility should be continued to control the resistance development and its spread.

https://pubmed.ncbi.nlm.nih.gov/12546241/

f3511ea384b9ad10337cbf06d03a2514

JAK2 ATP competitive inhibitors ( ruxolitinib , lestaurtinib , SAR302503 , SB1518 and CYT387 ) or drugs that indirectly inhibit the JAK-STAT pathway ( everolimus ) have documented major effects on splenomegaly and its constitutional symptoms .

Emerging targeted therapies in myelofibrosis. Conventional drugs for myelofibrosis are driven by clinical needs, primarily anemia and splenomegaly. With these therapies, stem cell transplantation remains the only potentially curative approach. The discovery that mutations affecting JAK2 or MPL lead to activation of the intracellular JAK-STAT signaling pathway, and that other mutations (TET2, EZH2, ASXL1, IDH1 and IDH2) interfere with the normal machinery of epigenetics, has prompted to the development of therapies targeted at controling the major disease mechanisms. JAK2 ATP competitive inhibitors ( ruxolitinib , lestaurtinib , SAR302503 , SB1518 and CYT387 ) or drugs that indirectly inhibit the JAK-STAT pathway ( everolimus ) have documented major effects on splenomegaly and its constitutional symptoms . Epigenetic drugs (demethylating agents and histone deacetylase inhibitors) have displayed only minor effects on the disease symptoms. Relenting disease progression remains an unmet clinical need.

https://pubmed.ncbi.nlm.nih.gov/22780211/

dfc119d182b2ca831617594789da1242

We therefore tested second-generation inhibitors of the 20S proteasome ( delanzomib , carfilzomib and ixazomib ) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination ( b-AP15 , MLN4924 ) for their effectiveness and mechanism of action in GIST .

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells. The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome ( delanzomib , carfilzomib and ixazomib ) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination ( b-AP15 , MLN4924 ) for their effectiveness and mechanism of action in GIST . All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

https://pubmed.ncbi.nlm.nih.gov/32198455/

9991b6203110cd7b2d728fcfd1b25a75

In seven patients with type B insulin resistance , standardized treatment with rituximab , cyclophosphamide , and pulse steroids results in remission of the disease .

Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies. Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. ### methods We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. ### results All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. ### conclusions In seven patients with type B insulin resistance , standardized treatment with rituximab , cyclophosphamide , and pulse steroids results in remission of the disease . Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.

https://pubmed.ncbi.nlm.nih.gov/20484479/

44a992639d1a8ab6152baa1f9da60aed

The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen ( regular and escalated ) ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisone ) as compared to the ABVD regimen ( doxorubicin , vinblastine , dacarbazine , bleomycin ) in Hodgkin lymphoma patients under the age of 40 at the time of treatment .

Fertility in young patients following treatment for Hodgkin's lymphoma: a single center survey. The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen ( regular and escalated ) ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisone ) as compared to the ABVD regimen ( doxorubicin , vinblastine , dacarbazine , bleomycin ) in Hodgkin lymphoma patients under the age of 40 at the time of treatment . ### methods A questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012. ### results In comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2% of patients in the ABVD female group, 34.6% in the BEACOPP female group, 52.6% in the ABVD male group, and 33.3% in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy. ### conclusions Based on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.

https://pubmed.ncbi.nlm.nih.gov/26678493/

91b767ae52b2ae4a4f7e75bd7b793361

The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol , CGRP(8 - 37 ) , or combined propranolol+CGRP(8 - 37 ) .

Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling. Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist dpdpe (100 μg/kg) with or without 10-min pretreatment with either β-adrenergic receptor (β-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 μg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after dpdpe infusion. At 5-min dpdpe induced a 36 ± 18% (p<0.001) increase of the LVFS, which continues to increase to 51 ± 24% (p<0.0001) by 10 min, and 68 ± 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11 ± 6% (p<0.001) by 15 min post dpdpe infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 ± 8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post dpdpe administration, respectively. There was a modest (9 ± 9%, p=0.03) decrease in SBP that was not apparent until 20 min post dpdpe infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol , CGRP(8 - 37 ) , or combined propranolol+CGRP(8 - 37 ) . Furthermore, in whole animal and cardiomyocyte cell culture preparations, dpdpe induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced β-AR and CGRPR co-signaling.

https://pubmed.ncbi.nlm.nih.gov/22108711/

4e423fff47565b3915ebb416a65e38ed

A case of Scedosporium apiospermum infection after BMT , treated initially with amphotericin B ( total dose of 2.5 g ) and then with itraconazole ( for 25 days ) , is reported here .

Scedosporium apiospermum pneumonia after autologous bone marrow transplantation. Although opportunistic infections after bone marrow transplantation (BMT) are very common, only five cases of Pseudallescheria boydii infection have been reported in the literature, two of which were autopsy findings. A case of Scedosporium apiospermum infection after BMT , treated initially with amphotericin B ( total dose of 2.5 g ) and then with itraconazole ( for 25 days ) , is reported here . When the patient failed to improve, Scedosporium apiospermum pneumonia was diagnosed and therapy was changed. The patient was treated successfully with miconazole (600 mg/8h for 32 days) and ketoconazole (200 mg/8h for 7 days) plus surgery.

https://pubmed.ncbi.nlm.nih.gov/8874080/

a61f2a1bdd946f81943993a86ee40960

Thymidine Phosphorylase/β-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel .

Thymidine Phosphorylase/β-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel . To assess the role of Thymidine Phosphorylase and β-tubulin III in clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. ### methods The clinical data and tumor biopsies prior treatment from 33 advanced gastric cancer patients receiving capecitabine plus paclitaxel (cohort 1, experimental group) and 18 patients receiving capecitabine plus cisplatin (cohort 2, control group) in Beijing Cancer Hospital from July 2003 to December 2008 were retrospectively collected and analyzed for Thymidine Phosphorylase and β-tubulin III expressions by immunohistochemistry. The relationships between expressions of biomarkers and response or survival were determined by statistical analysis. ### results The median age of 51 patients was 57 years (range, 27-75) with male 34 and female 17, and the response rate, median progression-free survival and overall survival were 43.1%, 120d and 265d. Among cohort 1, the response rate, median progression-free survival and overall survival in β-tubulin III positive (n = 22) and negative patients (n = 11) were 36.4%/72.7% (positive vs negative, P = 0.049), 86d/237d (P = 0.046) and 201d/388d (P = 0.029), respectively; the response rate (87.5% vs 14.3%, P = 0.01) and median progression-free survival (251d vs 84d, P = 0.003) in Thymidine Phosphorylase positive & β-tubulin III negative patients (n = 8) were also significantly higher than those in Thymidine Phosphorylase negative & β-tubulin III positive patients (n = 7). There was no correlation between β-tubulin III expression and response or survival among cohort 2 (n = 18). ### conclusions In Chinese advanced gastric cancer, Thymidine Phosphorylase positive & β-tubulin III negative might predict response and prognosis to capecitabine plus paclitaxel chemotherapy. Further prospective evaluation in large samples should be performed to confirm these preliminary findings.

https://pubmed.ncbi.nlm.nih.gov/21586171/

ab09d23f3137b7dee2757d07895c695b

An equihypotensive dose of the calcium antagonist nifedipine had no significant effect ; however , EMD 52692 produced the same reduction in infarct size as had nicorandil .

Cardioprotective effects of nicorandil. The effects of nicorandil, a nicotinamide nitrate with K(+)-channel-opening activity, was investigated in several models of ischemia-reperfusion injury in conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In several models of reversible ischemic injury (stunned myocardium) in dogs, nicorandil resulted in an enhanced recovery of regional systolic shortening during reperfusion after a single episode of coronary artery occlusion (10-15 min). These beneficial actions of nicorandil were not shared by the nitrovasodilator sodium nitroprusside but were mimicked by the selective K(+)-channel opener EMD 52692. In a model of irreversible ischemia-reperfusion injury (i.e., 2 h of coronary occlusion followed by reperfusion) in anesthetized dogs, nicorandil produced a marked reduction of myocardial infarct size. An equihypotensive dose of the calcium antagonist nifedipine had no significant effect ; however , EMD 52692 produced the same reduction in infarct size as had nicorandil . In isolated, perfused rat hearts subjected to 20 min of low-flow (1.0 ml/min) global ischemia followed by 30 min of reperfusion, nicorandil (7 microM) resulted in a significant improvement in the recovery of isovolumic left ventricular minute work during reperfusion compared with untreated hearts. Finally, the results of in vitro experiments indicated that nicorandil (10(-6) to 10(-3) M) produced a concentration-dependent inhibition of superoxide anion free radical production by human and canine neutrophils. The K(+)-channel opener EMD 52692 also inhibited superoxide production in canine neutrophils. These results indicate that nicorandil is a highly efficacious myocardial protective agent in several animal models of reversible or irreversible ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1282172/

f92a7d9296c1377c90cc43814c1eb6b0

Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial .

Epirubicin: a review of its intravesical use in superficial bladder cancer. The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-alpha-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification. Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in many trials of intravesical epirubicin, and when reported generally occurred in < or =5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial . The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG. ### conclusions Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.

https://pubmed.ncbi.nlm.nih.gov/10582777/

49c8d4c6aa6ad992443539db2ba18d2c

Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects .

Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects . To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects. ### methods A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared. ### results The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 . ### conclusion A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610)

https://pubmed.ncbi.nlm.nih.gov/25545238/

4f83a84ae42010b73e8bd3862738df14

We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine ( F-ara-A ) and hydroxyurea ( HU ) enhanced ara-CTP levels in two human myeloid ( HL-60 , CMK ) and two lymphoblastic leukemia cell lines ( MOLT-4 , BLIN-1 ) and also in blasts from 28 children with acute leukemia ( AML : 14 , ALL : 14 ) .

Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells. The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine ( F-ara-A ) and hydroxyurea ( HU ) enhanced ara-CTP levels in two human myeloid ( HL-60 , CMK ) and two lymphoblastic leukemia cell lines ( MOLT-4 , BLIN-1 ) and also in blasts from 28 children with acute leukemia ( AML : 14 , ALL : 14 ) . Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.

https://pubmed.ncbi.nlm.nih.gov/11243402/

078b4247228f2bac344b5add11ee697a

In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine .

The effect of olprinone compared with milrinone on diaphragmatic muscle function in dogs. We compared the effect of olprinone with milrinone on the contractility of fatigued diaphragms in dogs. Animals were divided into four groups of 10 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, Group I received only maintenance fluids; Group II was given a bolus injection (50 microg/kg) followed by continuous infusion (0.5 microg x kg(-1) x min(-1)) of milrinone; Group III was infused with olprinone (10 microg/kg initial dose plus 0.3 microg x kg(-1) x min(-1) maintenance dose); Group IV was infused with nicardipine (5 microg x kg(-1) x min(-1)) during olprinone administration. After the fatigue-producing period in each group, transdiaphragmatic pressure (Pdi) at low-frequency (20 Hz) stimulation decreased from the prefatigued values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups II and III, during study drug infusion, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group III than in Group II (P < 0.05). In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine . We conclude that olprinone is more effective than milrinone for the improvement of contractility in he fatigued diaphragm and that the potentiating mechanism of olprinone may be closely related to the transmembrane calcium movement. ### implications Diaphragmatic fatigue may contribute to the development of respiratory failure. Compared with milrinone, olprinone improves the contractility in fatigued diaphragm in dogs.

https://pubmed.ncbi.nlm.nih.gov/10475325/

d37eb6b8bb8d8d15526161f2cfe27698

Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan .

Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. ### methods 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. ### results telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan . telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. ### conclusions The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.

https://pubmed.ncbi.nlm.nih.gov/23451083/

c1417edecd6a1bb79585910ff15c392b

A single 1-g dose of oral azithromycin is as effective as a seven-day course of oral doxycycline , 100 mg twice a day , for the treatment of chlamydial infection .

Drug treatment of common STDs: Part II. Vaginal infections, pelvic inflammatory disease and genital warts. The Centers for Disease Control and Prevention (CDC) released new guidelines for the treatment of sexually transmitted diseases (STDs) in 1998. Several treatment advances have been made since the previous guidelines were published. Part II of this two-part series on STDs describes recommendations for the treatment of diseases characterized by vaginal discharge, pelvic inflammatory disease, epididymitis, human papillomavirus infection, proctitis, proctocolitis, enteritis and ectoparasitic diseases. Single-dose therapies are recommended for the treatment of several of these diseases. A single 1-g dose of oral azithromycin is as effective as a seven-day course of oral doxycycline , 100 mg twice a day , for the treatment of chlamydial infection . erythromycin and ofloxacin are alternative agents. Four single-dose therapies are now recommended for the management of uncomplicated gonococcal infections, including 400 mg of cefixime, 500 mg of ciprofloxacin, 125 mg of ceftriaxone or 400 mg of ofloxacin. Advances in the treatment of bacterial vaginosis also have been made. A seven-day course of oral metronidazole is still recommended for the treatment of bacterial vaginosis in pregnant women, but intravaginal clindamycin cream and metronidazole gel are now recommended in nonpregnant women. Single-dose therapy with 150 mg of oral fluconazole is a recommended treatment for vulvovaginal candidiasis. Two new topical treatments, podofilox and imiquimod, are available for patient self-administration to treat human papillomavirus infection. Permethrin cream is now the preferred agent for the treatment of pediculosis pubis and scabies.

https://pubmed.ncbi.nlm.nih.gov/10537386/

089f35f8fbaac65263cd437b70b772de

The side-effects of halofantrine and mefloquine were comparable and transient .

Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand. The antimalarial efficacy of halofantrine was compared with mefloquine in an open-label, randomized comparative trial in adult male patients with acute uncomplicated falciparum malaria. Twenty-eight patients received halofantrine and 27 received mefloquine. halofantrine was administered in 3 doses of 500 mg at 6 hour intervals and mefloquine was administered in divided doses of 1,250 mg or 1,500 mg depending on whether the patients weighed less than or more than 60 kg. The patients were followed for 42 days and observed for drug tolerance and evidence of recrudescence. Response to treatment was favorable with both drugs, but three patients (two treated with halofantrine and one with mefloquine) did not completely eliminate malaria parasites from peripheral blood films in seven days. The parasite and fever clearance times were 75.6 and 55.7 hours, and 80.1 and 61.3 hours, respectively for halofantrine and mefloquine. However, 12 patients recrudesced during the 42 day follow-up period. Nine of these had been treated with halofantrine and three with mefloquine. The 42-day cure rate for the two drugs was 56% and 84%, respectively. The side-effects of halofantrine and mefloquine were comparable and transient . These are diarrhea, dizziness, orthostatic hypotension and black out. However, vomiting was found to be more common in mefloquine group (41% vs 22%).

https://pubmed.ncbi.nlm.nih.gov/8362305/

fe77c57a1fc49e8755ef2c89b0c3538b

Significantly , green tea polyphenols , as well as several flavonoids such as genistein , curcumin and resveratrol , have also been shown to have chemo-sensitizing properties in prostate , breast , hepatic , and lung tumors .

The proteasome as a potential target for novel anticancer drugs and chemosensitizers. A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly , green tea polyphenols , as well as several flavonoids such as genistein , curcumin and resveratrol , have also been shown to have chemo-sensitizing properties in prostate , breast , hepatic , and lung tumors . Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.

https://pubmed.ncbi.nlm.nih.gov/17197231/

c40e8bcd51fa9cf5c9ba39f9135e357b

In a 71 years-old patient , a severe therapy-resistant depressive episode without psychotic symptoms was successfully treated by a combination of paroxetine and risperidone .

[Paroxetine augmentation with risperidone in therapy-resistant depression]. In a 71 years-old patient , a severe therapy-resistant depressive episode without psychotic symptoms was successfully treated by a combination of paroxetine and risperidone . Previously, several different antidepressants were not effective in ameliorating the depressive symptoms which occurred repeatedly over a period of more than ten years.

https://pubmed.ncbi.nlm.nih.gov/11721229/

2d78b663f4a80912c2ae2082c42ba522

While there is no standard of care for PBL , current recommendations include dose-adjusted EPOCH ( etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) , with or without bortezomib .

A Rare Presentation of HIV-Negative Plasmablastic Lymphoma: A Diagnostic Dilemma. Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL , current recommendations include dose-adjusted EPOCH ( etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) , with or without bortezomib . We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.

https://pubmed.ncbi.nlm.nih.gov/30906602/

89bbfb63ec14dde2805f31218f1ea77b

Our report of a patient with severe tardive dyskinesia ( TD ) who has been exposed to both typical antipsychotic and clozapine , olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD .

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report. Our report of a patient with severe tardive dyskinesia ( TD ) who has been exposed to both typical antipsychotic and clozapine , olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD . Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.

https://pubmed.ncbi.nlm.nih.gov/14571157/

9f7e34d9f7937382363be90a76a98bd1

Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer : a safety , feasibility , and efficacy study from the Hoosier Oncology Group .

Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer : a safety , feasibility , and efficacy study from the Hoosier Oncology Group . bevacizumab when combined with carboplatin and paclitaxel improves response rates (RRs) and overall survival in patients with advanced non-small cell lung cancer. paclitaxel has single-agent activity in relapsed small cell lung cancer (SCLC). Angiogenesis seems to play an important role in the pathogenesis of SCLC. This study evaluated the safety and efficacy of paclitaxel plus bevacizumab in patients with chemosensitive relapsed SCLC. ### methods Patients with relapsed chemosensitive SCLC with an Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. They received paclitaxel 90 mg/m intravenously on days 1, 8, and 15. bevacizumab was administered at 10 mg/kg intravenously on days 1 and 15. Cycles were every 28 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included RRs, toxicity, and overall survival. Correlative studies evaluated vascular endothelial growth factor polymorphisms. ### results Thirty-four patients were enrolled in the study. Median age was 66.5 (range, 38-88) years, male:female: 61.8%:38.2%, Eastern Cooperative Oncology Group performance status 0:1 47.1%:52.9%. Median progression-free survival was 14.7 weeks (equivalent to historical controls). Median survival time was 30 weeks. The overall RR was 18.1%. Stable disease rate was 39.3%, and 45.4% of patients had progressive disease. No unexpected toxicities were noted, and grade 3/4 toxicities were limited to neutropenia, fatigue, and dyspnea. None of the vascular endothelial growth factor polymorphisms evaluated were significantly associated with response. ### conclusions The addition of bevacizumab to paclitaxel does not improve outcomes in relapsed chemosensitive SCLC.

https://pubmed.ncbi.nlm.nih.gov/21102263/

0be07de2b909239dfdf4b4f903db6ef2

On day ten of admission , HIT panel was positive , and Dabigatran was changed to Lepirudin .

Heparin-Induced Thrombocytopenia in a Patient with Essential Thrombocythemia: A Case Based Update. Vascular thrombosis is a common clinical feature of both essential thrombocythemia (ET) and heparin-induced thrombocytopenia (HIT). The development of HIT in a patient with ET is rare and underrecognized. We report the case of a 77-year-old woman with preexisting ET, who was admitted with acute coronary syndrome, and IV heparin was started. She was exposed to unfractionated heparin (UFH) 5 days prior to this admission. Decrease in platelet count was noted, and HIT panel was sent. heparin was discontinued. Patient developed atrial fibrillation, and dabigatran was started. On day three, patient also developed multiple tiny cerebral infarctions and acute right popliteal DVT. On day ten of admission , HIT panel was positive , and Dabigatran was changed to Lepirudin . Two days later, lepirudin was also discontinued because patient developed pseudoaneurysm on the right common femoral artery at the site of cardiac catheterization access. A progressive increase in the platelet count was noted after discontinuing heparin. Physicians should be aware of the coexistence of HIT and ET, accompanied challenges of the prompt diagnosis, and initiation of appropriate treatment.

https://pubmed.ncbi.nlm.nih.gov/26579318/

87a5b7601669048d416f0bda0058f733

If in vivo testing confirms the in vitro effectiveness of azithromycin , it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women , who should not take doxycycline , and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found .

In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. In an effort to find a potential alternative treatment for scrub typhus, we evaluated the effectiveness of the standard drug doxycycline and the new macrolide azithromycin against a doxycycline-susceptible strain (Karp) and a doxycycline-resistant strain (AFSC-4) of Rickettsia tsutsugamushi. The antibiotics were tested in an in vitro assay system in which infected mouse fibroblast cells (L929) were incubated for 3 days in various concentrations of the drugs. Rickettsial growth was evaluated by direct visual counts of rickettsiae in Giemsastained cells or by flow cytometry. Initial tests were conducted at the concentration of each antibiotic considered to be the upper breakpoint for susceptibility (16 micrograms/ml for doxycycline and 8 micrograms/ml for azithromycin). Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics, as measured by visual counts, although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60% as great as the percentage of cells infected with Karp in the presence of azithromycin. Flow cytometry confirmed that rickettsial growth occurred in the absence of antibiotics, but it failed to detect it in the presence of high concentrations of either drug. Visual counts of rickettsial growth at lower concentrations of the antibiotics (0.25 to 0.0078 microgram/ml) showed that the Karp strain was 16 times more susceptible that the AFSC-4 strain to doxycycline. azithromycin was much more effective than doxycycline against AFSC-4, inhibiting rickettsial growth at 0.0156 microgram/ml to levels below that achieved by 0.25 microgram of doxycycline per ml. azithromycin was also more effective than doxycycline against the Karp strain, causing greater reductions in the number of rickettsiae per cell at lower concentrations. If in vivo testing confirms the in vitro effectiveness of azithromycin , it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women , who should not take doxycycline , and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found . When tested in an in vitro assay system, azithromycin was more effective than doxycycline against doxycycline-susceptible and -resistant strains of R. tsutsugamushi.

https://pubmed.ncbi.nlm.nih.gov/8585717/

febbf2b27d4e13039a1618260b55b41a

Significantly , genes regulated by both formoterol and budesonide were overrepresented in the genome ; moreover , budesonide-plus-formoterol induced and repressed 609 and 577 mRNAs , respectively , of which ~1/3 failed the cut-off criterion for either treatment alone .

Transcriptome-level interactions between budesonide and formoterol provide insight into the mechanism of action of ICS/LABA combination therapy in asthma. In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy should be a first-in-line treatment option for asthma. Although clinically superior to ICS, mechanisms underlying the efficacy of this combination therapy remain unclear. We hypothesised the existence of transcriptomic interactions, an effect that was tested in BEAS-2B and primary human bronchial epithelial cells (pHBECs) using formoterol and budesonide as representative LABA and ICS, respectively. In BEAS-2B cells, formoterol produced 267 (212 induced; 55 repressed) gene expression changes (>=2/<=0.5-fold) that were dominated by rapidly (1-2h) upregulated transcripts. Conversely, budesonide induced 370 and repressed 413 mRNAs, which occurred predominantly at 6-18h and were preceded by transcripts enriched in transcriptional regulators. Significantly , genes regulated by both formoterol and budesonide were overrepresented in the genome ; moreover , budesonide-plus-formoterol induced and repressed 609 and 577 mRNAs , respectively , of which ~1/3 failed the cut-off criterion for either treatment alone . While induction of many mRNAs by budesonide-plus-formoterol was supra-additive, the dominant (and potentially beneficial) effect of budesonide on formoterol-induced transcripts, including those encoding many pro-inflammatory proteins, was repression. Gene ontology analysis of the budesonide-modulated transcriptome returned enriched terms for transcription, apoptosis, proliferation, differentiation, development and migration. This "functional" ICS signature was augmented in presence of formoterol. Thus, LABAs modulate glucocorticoid action and comparable transcriptome-wide interactions in pHBECs imply that such effects may be extrapolated to asthmatics taking combination therapy. While repression of formoterol-induced pro-inflammatory mRNAs should be beneficial, the pathophysiological consequences of other interactions require investigation.

https://pubmed.ncbi.nlm.nih.gov/33376135/

09edda12a9b4dd6af65d9697d8404aae

This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 ( gefitinib sensitive ) and HCC827R ( gefitinib resistant ) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced ( DCE ) and diffusion-weighted MRI .

Functional evaluation of therapeutic response of HCC827 lung cancer to bevacizumab and erlotinib targeted therapy using dynamic contrast-enhanced and diffusion-weighted MRI. This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 ( gefitinib sensitive ) and HCC827R ( gefitinib resistant ) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced ( DCE ) and diffusion-weighted MRI . In the HCC827 model, temporal changes in DCE-MRI derived parameters (Ktrans, kep, and iAUC90) and apparent diffusion coefficient (ADC) were significantly correlated with tumor size. Ktrans and iAUC90 significantly decreased at week 2 in the groups receiving erlotinib alone and in combination with bevacizumab, whereas kep decreased at week 1 and 2 in both treatment groups. In addition, there was a significant difference in iAUC90 between the treatment groups at week 1. Compared to the control group of HCC827, there was a significant reduction in microvessel density and increased tumor apoptosis in the two treatment group. ADC value increased in the erlotinib alone group at week 1 and week 2, and in the erlotinib combined with bevacizumab group at week 2. Enlarged areas of central tumor necrosis were associated with a higher ADC value. However, progressive enlargement of the tumors but no significant differences in DCE parameters or ADC were noted in the HCC827R model. These results showed that both erlotinib alone and in combination with bevacizumab could effectively inhibit tumor growth in the gefitinib-sensitive lung cancer mice model, and that this was associated with decreased vascular perfusion, increased ADC percentage, decreased microvessel density, and increased tumor apoptosis with a two-week treatment cycle.

https://pubmed.ncbi.nlm.nih.gov/29121075/

2581d924556a6f63227c9ff8e08e605a

, olmesartan medoxomil + amlodipine + HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies , irrespective of hypertension severity , age , sex , race or diabetes mellitus status .

Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension. The antihypertensive agents olmesartan medoxomil, amlodipine and hydrochlorothiazide (HCTZ) are now available as a fixed-dose combination tablet (olmesartan medoxomil/amlodipine/HCTZ). In a 12-week, randomized, double-blind, multicentre trial (TRINITY) in adults with moderate to severe hypertension, olmesartan medoxomil + amlodipine + HCTZ triple combination therapy produced significantly greater least squares mean reductions from baseline in seated diastolic blood pressure (BP) [primary endpoint] and seated systolic BP than olmesartan medoxomil/amlodipine, olmesartan medoxomil/HCTZ or amlodipine + HCTZ. Furthermore, significantly more patients achieved BP goals and targets with the triple combination regimen than with any of the dual combination regimens at week 12, with olmesartan medoxomil + amlodipine + HCTZ also demonstrating benefit over the dual regimens in terms of ambulatory BP control. According to subgroup analyses of the TRINITY trial , olmesartan medoxomil + amlodipine + HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies , irrespective of hypertension severity , age , sex , race or diabetes mellitus status . Data from a number of smaller clinical studies indicated that olmesartan medoxomil + amlodipine + HCTZ triple combination therapy provides antihypertensive efficacy in patients whose BP is not adequately controlled with olmesartan medoxomil + amlodipine. olmesartan medoxomil + amlodipine + HCTZ was generally well tolerated in the TRINITY study, with adverse events usually being mild or moderate in severity.

https://pubmed.ncbi.nlm.nih.gov/21275446/

a59d85a5e7f76dbd749b45c864dfdb7c

Multiple-dose pharmacokinetics of telmisartan and of hydrochlorothiazide following concurrent administration in healthy subjects .

Multiple-dose pharmacokinetics of telmisartan and of hydrochlorothiazide following concurrent administration in healthy subjects . This open-label, crossover study had two objectives: to compare the steady-state pharmacokinetics of high-dose telmisartan with and without coadministered high-dose hydrochlorothiazide and to compare the steady-state pharmacokinetics of hydrochlorothiazide with and without coadministered telmisartan. A total of 13 healthy males and females of nonchildbearing potential received the following oral, once-daily medications, each for 7 days: telmisartan 160 mg, hydrochlorothiazide 25 mg, and telmisartan 160 mg plus hydrochlorothiazide 25 mg. Between medication periods, there was a 14-day washout. Blood was collected at intervals over 48 and 84 hours, respectively, at the end of the 7-day dosing period for the determination of plasma telmisartan and hydrochlorothiazide concentrations by high-performance liquid chromatography. Predose blood samples were also collected on days 1, 6, and 7. Tolerability of single-agent and combination medication was monitored. For hydrochlorothiazide and telmisartan, given alone or in combination, there were no appreciable differences in trough plasma concentrations between days 6, 7, and 8; thus, at day 7, both agents had achieved steady state. Mean values of the primary end points (Cmax and AUC0-24) and secondary end points (Cmin and t1/2) for both telmisartan and hyrochlorothiazide were unaffected when administered simultaneously. Moreover, concurrent telmisartan had no effect on urinary excretion of hydrochlorothiazide. Transient lightheadedness, associated with postural hypotension, was the most common adverse event. The absence of any significant effects on the pharmacokinetics of either hydrochlorothiazide or telmisartan shows that no dose adjustment is required if the two agents are given concurrently for the management of hypertension.

https://pubmed.ncbi.nlm.nih.gov/11185630/

415bbe9c2f11592ae2af241a79743f8f

The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results .

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results . ### methods In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. ### results The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. ### conclusions sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.

https://pubmed.ncbi.nlm.nih.gov/28662274/

64f63b536073641af3534f1feda74dcd

The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma ( NB ) , who had been treated with 6 cycles of cyclophosphamide , doxorubicin , cisplatin , and etoposide for 12 months .

Simultaneous occurrence of advanced neuroblastoma and acute myeloid leukemia. The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma ( NB ) , who had been treated with 6 cycles of cyclophosphamide , doxorubicin , cisplatin , and etoposide for 12 months . The patient reached partial remission and presented a diagnosis of acute myelomonocytic leukemia (M4 AML), confirmed by immunophenotyping. After 2 months of therapy for leukemia, the child died with both malignancies in activity. A necropsy histologically confirmed the simultaneity of the two diseases. The authors review the possibilities of this association. The review leads to the conclusion that AML can occur as a secondary malignancy after the onset of the neuroblastoma, or be suggested by a misdiagnosis. The simultaneous occurrence of both as described here is not, however, found in the literature, to the best of the authors' knowledge.

https://pubmed.ncbi.nlm.nih.gov/11255731/

81f6f0d6eaf34525aa979c4077fde7b5

Days of utilization , adherence ( proportion of days covered ≥0.8 ) , and discontinuation ( non-use for ≥30 days immediately prior to BP measurement ) of three statins ( atorvastatin , pravastatin , and simvastatin ) over a period of up to 2 years was monitored retrospectively from electronic databases .

Statin utilisation in a real-world setting: a retrospective analysis in relation to arterial and cardiovascular autonomic function. Randomized trials suggest that statin treatment may lower blood pressure and influence cardiovascular autonomic function (CVAF), but the impact of duration of usage, discontinuation, and adherence to this therapy is unknown. We examined these issues with regard to blood pressure (BP)-related variables in a large, population-based study. Participants were 4942 adults (58% male; aged 50-84 years): 2179 on statin treatment and 2763 untreated. Days of utilization , adherence ( proportion of days covered ≥0.8 ) , and discontinuation ( non-use for ≥30 days immediately prior to BP measurement ) of three statins ( atorvastatin , pravastatin , and simvastatin ) over a period of up to 2 years was monitored retrospectively from electronic databases . Systolic BP (SBP), diastolic BP (DBP), augmentation index, excess pressure, reservoir pressure, and CVAF (pulse rate and BP variability) parameters were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. Days of statin treatment had inverse relationships with pulse rate variability parameters in cardiac arrhythmic participants (20-25% lower than in statin non-users) and with most arterial function parameters in everyone. For example, compared to untreated participants, those treated for ≥659 days had 3.0 mmHg lower aortic SBP (

https://pubmed.ncbi.nlm.nih.gov/28097009/

0b38299d34d4d410042ee85945da2432

Due to dose-limiting toxicity ( DLT ) in both patients ( elevated transaminases and thrombocytopenia ) , an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2 .

Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG). Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. ### methods We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. ### results Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity ( DLT ) in both patients ( elevated transaminases and thrombocytopenia ) , an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2 . Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. ### conclusion The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.

https://pubmed.ncbi.nlm.nih.gov/25591040/

1e94c488f0f6c6510be68295b36d7a0a

Compared with alemtuzumab , bendamustine was considered to be a dominant treatment providing greater benefit ( 6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs ) at lower cost ( $ 78,776 versus $ 121,441 ) .

Economic implications of using bendamustine, alemtuzumab, or chlorambucil as a first-line therapy for chronic lymphocytic leukemia in the US: a cost-effectiveness analysis. The objective of this analysis was to evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C chronic lymphocytic leukemia (CLL) in the US. ### methods A discrete event simulation of the disease course of CLL was developed to evaluate the economic implications of single-agent treatment with bendamustine, alemtuzumab, or chlorambucil, which are indicated for a treatment-naïve patient population with Binet stage B or C CLL. Data from clinical trials were used to create a simulated patient population, risk equations for progression-free survival and survival post disease progression, response rates, and rates of adverse events. Costs from a US health care payer perspective in 2012 US dollars, survival (life years), and quality-adjusted life years (QALYs) were estimated over a patient's lifetime; all were discounted at 3% per year. ### results Compared with alemtuzumab , bendamustine was considered to be a dominant treatment providing greater benefit ( 6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs ) at lower cost ( $ 78,776 versus $ 121,441 ) . Compared with chlorambucil, bendamustine was associated with higher costs ($78,776 versus $42,337) but with improved health outcomes (6.10 versus 5.21 life years and 4.02 versus 3.30 QALYs), resulting in incremental cost-effectiveness ratios of $40,971 per life year gained and $50,619 per QALY gained. ### conclusion bendamustine is expected to provide cost savings and greater health benefit than alemtuzumab in treatment-naïve patients with CLL. Furthermore, it can be considered as a cost-effective treatment providing health benefits at an acceptable cost versus chlorambucil in the US.

https://pubmed.ncbi.nlm.nih.gov/24729719/

3a30e0b4d614f6d5d5f93bc0236ded4c

He accepted surgical resection with followed multi-agent chemotherapy , containing vincristine , doxorubicin , ifosfamide and etoposide .

Primary desmoplastic small round cell tumor of the tibia: PET/CT and MRI presentation of a rare case and review of the literature. Desmoplastic small round cell tumor (DSRCT) was a soft tissue sarcoma of mesenchymal cell origin that typically exhibited a multi-phenotypic pattern of immunohistochemical staining. DSRCT mainly presented in the abdomen sites and primary occurrence in bone was exceptional. In this study, we reported a new case of primary DSRCT of the tibia in a 33-year-old man who had intermittent pain in the left tibia. Radiographs showed transparent lesions in the left upper tibial. MRI revealed a lobular, lytic and ill-identified lesion with adjacent soft tissues swelling of the upper left tibia. CT confirmed notable destruction and wormlike osteolysis of the bone cortex. PET/CT showed a mass of high uptakes, indicating the malignance. He accepted surgical resection with followed multi-agent chemotherapy , containing vincristine , doxorubicin , ifosfamide and etoposide . Clinically and radiologically, the patient did not show any evidence of recurrence or metastasis at 30 months after surgical treatment. Primary osteogenic DSRCT was extremely rare and should be considered in differential diagnosis of bone tumors.

https://pubmed.ncbi.nlm.nih.gov/31871884/

042530ad82d750063f600c5c6c9b69f9

The gemcitabine and mitoxantrone regimen was feasible to administer even in heavily pre-treated patients .

Mitoxantrone and prolonged infusion gemcitabine as salvage therapy in patients with acute myelogenous leukemia. In a recent phase I study, a combination of gemcitabine at 10 mg/(m(2)min) for 12 h and mitoxantrone 12 mg/m(2) daily for 3 days, achieved a complete remission (CR) in 3 of 12 (25%) patients with refractory leukemia. A pilot assessment of this regimen was conducted to determine its tolerability in patients with refractory acute myeloid leukemia (AML). In a cohort of 18 patients with very refractory disease (6 primary refractory, 12 relapsed, mean initial CR duration 3.5 months), one patient achieved a CR, a second CR with incomplete platelet recovery (CRp). Sepsis and mucositis were significant extramedullary toxicities. The gemcitabine and mitoxantrone regimen was feasible to administer even in heavily pre-treated patients . It was not active in patients who had failed a prior salvage regimen. It may warrant further study in patients with primary resistant AML.

https://pubmed.ncbi.nlm.nih.gov/12531220/

3abf5b8dae64e23003a5ae9522e0ead1

The aim of this study was to evaluate four phytocompounds ( cinnamaldehyde , citral , eugenol and geraniol ) for their in vitro inhibitory activity against pre-formed biofilms of Candida albicans alone or in combination with fluconazole and amphotericin B. These compounds were also tested at subinhibitory concentrations for their ability to inhibit biofilm formation .

Antibiofilm activity of certain phytocompounds and their synergy with fluconazole against Candida albicans biofilms. The aim of this study was to evaluate four phytocompounds ( cinnamaldehyde , citral , eugenol and geraniol ) for their in vitro inhibitory activity against pre-formed biofilms of Candida albicans alone or in combination with fluconazole and amphotericin B. These compounds were also tested at subinhibitory concentrations for their ability to inhibit biofilm formation . ### methods The XTT reduction assay, light microscopy and scanning electron microscopy (SEM) were employed to determine the inhibitory effect of the test compounds on biofilms. A chequerboard method was used for combination studies. ### results Both clinical and reference strains of C. albicans (C. albicans 04 and C. albicans SC5314, respectively) displayed formation of strong biofilms. Pre-formed Candida biofilms showed ≥1024× increased resistance to antifungal drugs and 2× increased resistance to cinnamaldehyde and geraniol, but no increased tolerance of eugenol. The test compounds were more active against pre-formed biofilms than amphotericin B and fluconazole. At 0.5× MIC, eugenol and cinnamaldehyde were the most inhibitory compounds against biofilm formation. Light and electron microscopic studies revealed the deformity of three-dimensional structures of biofilms formed in the presence of sub-MICs of eugenol and cinnamaldehyde. The cell membrane appeared to be the target site of compounds in both planktonic and sessile C. albicans cells, as observed by SEM. Combination studies showed that synergy was highest between eugenol and fluconazole (fractional inhibitory concentration index = 0.14) against pre-formed biofilms of C. albicans SC5314. ### conclusions Promising antibiofilm activity was displayed by eugenol and cinnamaldehyde, which also showed synergy with fluconazole in vitro. Further evaluation in in vivo systems is required to determine whether these findings can be exploited in treating biofilm-associated candidiasis.

https://pubmed.ncbi.nlm.nih.gov/22167241/

b1e132fb73f96e11922acfd78c2ac03d

Neoadjuvant trastuzumab , pertuzumab , and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer ( KRISTINE ): a randomised , open-label , multicentre , phase 3 trial .

Neoadjuvant trastuzumab , pertuzumab , and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer ( KRISTINE ): a randomised , open-label , multicentre , phase 3 trial . HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. ### methods We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m ### findings Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment. ### interpretation Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. ### funding F Hoffmann-La Roche and Genentech.

https://pubmed.ncbi.nlm.nih.gov/29175149/

8fc577a14f80c50cfbb664588f852a56

≥ 3 adverse events ( AE ) than cetuximab and conatumumab , neutropenia than conatumumab , and fatigue than cetuximab .

Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review. Although various therapies are available for the treatment of metastatic colorectal cancer (mCRC), there is lack of head-to-head evidence. Recent studies have demonstrated the efficacy of chemotherapy in combination with different biological agents including regorafenib in second-line therapy in patients with mCRC. We conducted a network meta-analysis (NMA) to estimate the relative efficacy and safety of regorafenib in combination with chemotherapy compared to other biological agents with chemotherapy combinations. ### methods A literature search was conducted in PubMed, Embase, and Cochrane databases to identify all randomized controlled trials (RCTs) evaluating the efficacy and safety of bevacizumab, regorafenib, panitumumab, cetuximab, ramucirumab, conatumumab, ganitumab, and aflibercept in combination with chemotherapy against chemotherapy alone as second-line setting from inception to 7 February 2019 in patients with mCRC. The survival outcomes were analyzed by the frequentist statistical approach (R software, netmeta package) while the level of individual treatment arms was assessed using the Bayesian method (R software, gemtc package). ### results We identified 12 articles involving eight RCTs studies analyzing 6805 patients. The studies compared bevacizumab (3), regorafenib (1), panitumumab (2), cetuximab (3), ramucirumab (1), conatumumab (1), ganitumab (1), and aflibercept (1) against chemotherapy alone as comparator. The progression-free survival (PFS) revealed that regorafenib performed better than aflibercept (HR 0.9631, 95% CI 0.6785-1.367), ganitumab (HR 0.7228, 95% CI 0.3985-1.3109), panitumumab (HR 0.9653, 95% CI 0.6781-1.3742), and ramucirumab (HR 0.9206, 95% CI 0.6504-1.303). regorafenib performed better than bevacizumab (OR 0.797, 95% CI 0.328-1.88) in terms of tumor response. Safety analysis showed that regorafenib performed better in reducing grade ≥ 3 adverse events ( AE ) than cetuximab and conatumumab , neutropenia than conatumumab , and fatigue than cetuximab . ### conclusions regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results.

https://pubmed.ncbi.nlm.nih.gov/32770529/

dbd1477b1210b870d5f317aa732a145d

Ultimately , the patient was successfully treated with combination therapy of Liposomal amphotericin B and Miltefosine without any relapse .

A rare case of Visceral leishmaniasis with multiple relapse and multi-drug unresponsive: successfully treated with combination therapy. We report a 32-year old relapse case of Visceral leishmaniasis, treated with paromomycin who belonged from a endemic zone of Bihar state, India. After confirmation, he was treated with amphotericin B, followed by Liposomal amphotericin B in full course and even in higher dose. But after each therapy, the patient either did not responded or relapsed after treatment. Ultimately , the patient was successfully treated with combination therapy of Liposomal amphotericin B and Miltefosine without any relapse . ### conclusion The multi-drug unresponsive Visceral leishmaniasis cases could pose a major threat to treatment strategy in the elimination program. In such situation, combination therapy seems to be a better approach that needs to be explored.

https://pubmed.ncbi.nlm.nih.gov/21833710/

4644446d0aa8617bcb774da8032011f6

However , verapamil significantly increased the sensitivity to etoposide , doxorubicin and vincristine in cells highly expressing MRP gene .

The multidrug resistance-associated protein gene confers drug resistance in human gastric and colon cancers. To determine the expression of multidrug resistance-associated protein (MRP) gene and its role in gastric and colon cancers, we analyzed 10 gastric and 10 colon non-drug-selected cell lines and a similar number of tissue samples of these cancers. We compared the expression of MRP and mdrl mRNA in cell lines and tissues using reverse-transcriptase polymerase chain reaction. In mdrl-negative cells, the relationship between the level of MRP gene expression and sensitivity to anticancer drugs was examined. The effect of verapamil, an MRP-modulating agent, was also examined in these cells. The expression of MRP gene in gastric cancer cell lines varied from a low to a high level, but mdrl was not detected in any of these cell lines. Colon cancer cell lines expressed low to intermediate levels of MRP gene, and half of the cells co-expressed low to high levels of mdrl. In tissue samples, the expression pattern of the two multidrug resistance (MDR) genes was broadly similar to that described for the cell lines, except that most of the gastric cancer tissue samples did express low levels of mdrl. No significant correlation was observed between the level of MRP gene expression and sensitivity to anticancer drugs in gastric and colon cell lines. However , verapamil significantly increased the sensitivity to etoposide , doxorubicin and vincristine in cells highly expressing MRP gene . Our results indicate that MRP gene may be important in conferring MDR in gastric and colon cancer cells.

https://pubmed.ncbi.nlm.nih.gov/9045962/

6fd826d6cc886ea9bdc4d4f22b40c1f0

Based on available phase III randomized trials , anti-VEGF agents such as sunitinib , sorafenib , bevacizumab-based therapy , and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease .

Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials , anti-VEGF agents such as sunitinib , sorafenib , bevacizumab-based therapy , and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease . Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.

https://pubmed.ncbi.nlm.nih.gov/21789125/

5e0548f00dcd95ab82e9f43765a7ea76

Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib .

Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6. The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. ### Experimental Design Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration. ### results Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib . Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model. ### conclusions Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.

https://pubmed.ncbi.nlm.nih.gov/26369631/

c7b449ddcf06a1a101b77f14c026b7f1

Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine .

Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine . A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.

https://pubmed.ncbi.nlm.nih.gov/512885/

80278bd2e6c19140fe092fa4726b25da

Background Epidemiological evidence is insufficient to draw conclusions on the impact of low-dose aspirin use on breast cancer risk , and the potential impact of other antiplatelet drugs such as clopidogrel needs to be explored .

Antiplatelet drug use and breast cancer risk in a prospective cohort of postmenopausal women. Background Epidemiological evidence is insufficient to draw conclusions on the impact of low-dose aspirin use on breast cancer risk , and the potential impact of other antiplatelet drugs such as clopidogrel needs to be explored . Methods We investigated the association between breast cancer risk and low-dose aspirin or clopidogrel use in the E3N cohort, which includes 98,995 women, with information on breast cancer risk factors collected from biennial questionnaires matched with drug reimbursement data available from 2004. Women with at least two reimbursements of the drug of interest in any previous three-month period were considered "ever" exposed. Exposure was considered as time-varying and multivariable Cox regression models were used to estimate hazard ratios (HRs) of breast cancer. Results Among 62,512 postmenopausal women followed during nine years on average, 2,864 breast cancer cases were identified. Compared with never use, a transient higher breast cancer risk was observed during the 3rd year of low-dose aspirin use [HR2-{less than or equal to}3 years of use= 1.49 (1.08-2.07)], followed by a lower risk [HR4+ years of use= 0.72 (0.52-0.99)]. clopidogrel ever use was associated with a higher breast cancer risk [HR= 1.30 (1.02-1.68)], restricted to estrogen receptor negative (ER-) tumors [HRER+= 1.14 (0.83-1.57), HRER-= 3.07 (1.64-5.76), Phomogeneity= 0.01]. Conclusions Low-dose aspirin was associated with a lower breast cancer risk only after several years of use, while ever use of clopidogrel was associated with a higher ER- breast cancer risk. Impact Antiplatelet drugs are not good pharmacological candidates for breast cancer prevention.

https://pubmed.ncbi.nlm.nih.gov/33531438/

6217aaf92cbd6304f2ccffe4ac3e0acb

Using a FOLFOXIRI ( 5-fluorouracil [ 5-FU ] , irinotecan , and oxaliplatin ) combination regimen , patients with metastatic colorectal cancer now have the possibility of longer survival , but disappointingly , with increased toxicities .

Triplet chemotherapy in patients with metastatic colorectal cancer: toward the best way to safely administer a highly active regimen in clinical practice. A major problem concerning the addition of more drugs in a chemotherapy combination is designing a proper schedule assuring the balance between dose intensity of each drug, efficacy of the combination, and tolerability lessening the burden of drug toxicity. We evaluated triplet chemotherapy-based intensive regimens proposed as first-line treatment in patients with metastatic colorectal cancer. Using a FOLFOXIRI ( 5-fluorouracil [ 5-FU ] , irinotecan , and oxaliplatin ) combination regimen , patients with metastatic colorectal cancer now have the possibility of longer survival , but disappointingly , with increased toxicities . Triplet chemotherapy regimen according to 5-fluorouracil, irinotecan /5-fluorouracil, oxaliplatin, characterized by timed flat-infusion 5-FU administration, without leucovorin, obtained efficacy equivalent to other reported similar combination regimens (5-FU, irinotecan, and oxaliplatin), with increased received 5-FU dose intensity and lower grade 3 to 4 neutropenia. To guarantee the proper balance between dose intensities, efficacy, and toxicity, triplet chemotherapy schedules could be further improved by abrogation of folinic acid and bolus 5-FU, a new and easy modality of 5-FU administration, such as timed flat-infusion 5-FU, associated with alternating irinotecan and oxaliplatin; this could favor diffusion of this intensive treatment in clinical practice.

https://pubmed.ncbi.nlm.nih.gov/22694897/

4510363c81a8ffc6245472b6466c935e

Combinations of antibodies with targeted drugs like ibrutinib , idelalisib , or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future .

Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia. The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib , idelalisib , or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future . However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL.

https://pubmed.ncbi.nlm.nih.gov/27040707/

55a6025065dfb1ee3c4e2b620a95e55a

The responses to quinine and mefloquine or halofantrine showed no correlation with each other .

In vitro activity of halofantrine and its relationship to other standard antimalarial drugs against African isolates and clones of Plasmodium falciparum. The in vitro activity of halofantrine was studied in chloroquine-susceptible and chloroquine-resistant African clones of Plasmodium falciparum over a period of six months. The susceptibility level remained stable in both clones. The chloroquine-susceptible clone (50% inhibitory concentration [IC50] 6.88 nM) was less susceptible to halofantrine than the chloroquine-resistant clone (IC50 2.98 nM). Using an isotopic semimicro drug susceptibility test, the in vitro activity of halofantrine was compared with the activities of chloroquine, quinine, and mefloquine to study the cross-resistance patterns against 76 African isolates of P. falciparum isolated from cases of malaria imported into France. chloroquine-resistant isolates (n = 47) were significantly less susceptible to quinine (IC50 234 nM), but were more susceptible to both mefloquine (IC50 3.20 nM) and halofantrine (IC50 1.14 nM) compared with the chloroquine-susceptible isolates (n = 29; IC50 147 nM for quinine, 7.16 nM for mefloquine, and 2.62 nM for halofantrine). A significant positive correlation was found between the activities of chloroquine and quinine and between those of mefloquine and halofantrine, indicating cross-resistance between these drugs, while a negative correlation was observed between chloroquine and mefloquine or halofantrine. The responses to quinine and mefloquine or halofantrine showed no correlation with each other . These results reinforce the importance of a cautious use of antimalarial drugs in Africa.

https://pubmed.ncbi.nlm.nih.gov/1443351/

796d6cd33fac087057506e5a6e1727e7

In a phase II study , we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy .

Treatment of advanced refractory sarcomas with ifosfamide and etoposide combination chemotherapy. Chemotherapy options for resistant advanced-stage sarcomas are limited and in most cases disappointing. In a phase II study , we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy . All patients had received prior doxorubicin- and/or cyclophosphamide-based chemotherapies. Seventeen patients were male and 9 were female. The patients' median age was 35 years (range: 19-67 years). A total of 24 patients were eligible for evaluation of responses. Seven patients had a complete response (CR) (29.1%), 3 had a partial response (PR) (12.5%), 3 had stable disease (SD) (12.5%), and 11 had progressive disease (PD) (45.9%). An overall 41.6% objective response was achieved. Median time to treatment failure was 13.3 months. A total of 108 cycles of therapy were evaluable for evaluation of toxicity. Myelosuppression, observed in 55.5% of the treatment courses, was the major dose-limiting toxicity. Nausea and vomiting, seen in 64% of the courses, were the most important nonhematological side effects. Alopecia was almost universal. Hemorrhagic cystitis was observed in only 1 patient. We have concluded that the combination of ifosfamide, mesna, and etoposide is effective in advanced refractory sarcomas, and has acceptable toxicity.

https://pubmed.ncbi.nlm.nih.gov/9627675/

aff9e9e3cfdf825cee175d0da197c451

A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy .

A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy . In September 2000, a 32-year-old woman presented to our hospital with a right breast mass. In September 2000, she underwent pectoral muscle-preserving mastectomy for the treatment of right breast cancer. Pathologyy results revealed a mucinous carcinoma 27 × 20 × 18 mm in size accompanied by an extensive intraductal component. The tumor was staged as T2 N1M0 stage IIB and found to be estrogen receptor-positive, and 6 cycles of postoperative adjuvant chemotherapy consisting of 5-fluorouracil, epirubicin, and cyclophosphamide were carried out. goserelin acetate plus tamoxifen was prescribed from April 2001 to March 2005. Since the patient received tamoxifen from April 2005 and eumenorrhea started in June 2006, goserelin acetate plus tamoxifen was started in August 2006. The patient was determined to be 25 weeks pregnant by abdominal ultrasonography in February 2007. This meant that she had been taking goserelin acetate plus tamoxifen for 6 months without realizing she was pregnant. She gave birth to a girl by cesarean section in May 2007. No abnormalities, including anomaly of the genitalia, were seen, and the subsequent growth of the infant was also satisfactory. We here report this case and a brief review of the literature.

https://pubmed.ncbi.nlm.nih.gov/23636905/

bd09951c809d28a0d257abf828fd1b19

Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) .

Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. ### Patients And Methods Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). ### results A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. ### conclusion IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.

https://pubmed.ncbi.nlm.nih.gov/25049329/

fe55806bbc6429c1b87f7ee28230d11a

A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry ( LC-MS/MS ) of five tyrosine kinase inhibitors ( afatinib , crizotinib , osimertinib , erlotinib and nintedanib ) used in the treatment of non-small cell lung cancer ( NSCLC ) was developed and validated in human plasma .

Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the EGFR inhibitors afatinib, erlotinib and osimertinib, the ALK inhibitor crizotinib and the VEGFR inhibitor nintedanib in human plasma from non-small cell lung cancer patients. A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry ( LC-MS/MS ) of five tyrosine kinase inhibitors ( afatinib , crizotinib , osimertinib , erlotinib and nintedanib ) used in the treatment of non-small cell lung cancer ( NSCLC ) was developed and validated in human plasma . Separation was performed on an Accucore

https://pubmed.ncbi.nlm.nih.gov/29883880/

9659b9335356195a3c706849721c878b

The objective of this study was to compare the effect of sildenafil alone and sildenafil with bosentan on severity of tricuspid regurgitation and duration of hospitalization in new-borns with persistent pulmonary hypertension .

Comparison Of The Efficacy Of Sildenafil Alone Versus Sildenafil Plus Bosentan In Newborns With Persistent Pulmonary Hypertension. Persistent pulmonary hypertension is a serious disease among new-borns. Inhaled nitric oxide is first line of therapy along with extracorporeal membrane oxygenation. Pulmonary vasodilators such as sildenafil, bosentan and milrinone are also used to treat persistent pulmonary hypertension especially in resource limited centres where inhaled nitric oxide is not available. The objective of this study was to compare the effect of sildenafil alone and sildenafil with bosentan on severity of tricuspid regurgitation and duration of hospitalization in new-borns with persistent pulmonary hypertension . ### methods This was single blinded clinical trial conducted at The Children's Hospital & the Institute of Child Health, Multan, Pakistan, from July 2016 to December 2016. New-borns with pulmonary hypertension were admitted and divided into two groups. Group A was treated with sildenafil (2mg per kg per dose three times a day) and group B with both sildenafil (2 mg per kg per dose three times a day) and bosentan (1 mg per kg per dose twice a day). ### results There were 50 new-borns in each group. The mean age, sex distribution and baseline TR measurement (mmHg) at the time of admission was similar in both the groups. Measurement of TR (mmHg) after 72 hours admission was significantly less in Group B as compared to group A (11±4.62 versus 23±4.78), p-value<0.0001. The mean duration of hospital stays (days) was 10.12±5.20 in group A and 7.56±3.77 in group B (p-value <0.0001). There was no mortality in any group and no case of hypotension in both groups. ### conclusions The combined use of sildenafil and bosentan is more effective than sildenafil alone for control of pulmonary hypertension in resource limited centres.

https://pubmed.ncbi.nlm.nih.gov/30465360/

63a1e75c482c440bda7c2429d0e862c2

In Crohn 's disease in remission after 6 months of azathioprine in combination with infliximab , 63.8 % of practitioners discontinued azathioprine .

Tumour necrosis factor antagonists and inflammatory bowel diseases: a national practice survey. Although the use of tumour necrosis factor (TNF) antagonists is increasingly codified, several unresolved issues remain. ### aim To conduct a French national survey on TNF antagonists use in inflammatory bowel disease (IBD). ### methods A postal questionnaire was sent to all French gastroenterologists among whom 450 prescribe TNF antagonists for IBD. Only anti-TNF prescribers were invited to respond. ### results A total of 333 questionnaires could be analysed, which represented a rate of survey completeness of 74%. Scheduled maintenance infliximab treatment was prescribed by 92% of gastroenterologists. In Crohn's disease in remission after 1 year of TNF antagonists, 77.4% of physicians continued treatment. In luminal Crohn's disease, 97% of hospital practitioners introduced infliximab as first-line anti-TNF therapy vs. 78% of physicians with nonhospital activity (P = 0.002); only 22.5% of gastroenterologists opted for adalimumab as first-line therapy. In Crohn 's disease in remission after 6 months of azathioprine in combination with infliximab , 63.8 % of practitioners discontinued azathioprine . In case of pregnancy during anti-TNF treatment, 35.1% of physicians discontinued therapy at the time of conception and did not administer anti-TNF therapy during pregnancy. ### conclusions The attitudes of French gastroenterologists generally reflect the recommendations regarding the use of anti-TNF and concomitant immunosuppressive therapy in IBD.

https://pubmed.ncbi.nlm.nih.gov/19764940/

d7309a2a214cb56ff2ccb1bf082db6cf

Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 ( Enzalutamide ) or Casodex ( Bicalutamide ) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling .

Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 ( Enzalutamide ) or Casodex ( Bicalutamide ) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling . Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

https://pubmed.ncbi.nlm.nih.gov/23928703/

41e58f3e0a78ae5a454f27fb445d0174

Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone .

Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone . The combination of high dose ketoconazole and hydrocortisone (HDK) is active against androgen independent prostate cancer (AIPC). Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses. Well characterized response and survival information, especially in the cohort of patients who experience these longer, more durable, responses has not been previously reported. Characterization of this subgroup is of particular interest since men with long-term responses derive the greatest benefit from HDK therapy. ### Materials And Methods The medical records of 78 patients with AIPC treated with HDK between March 1991 and February 1999 were retrospectively reviewed. Baseline clinical and laboratory factors predictive of prolonged response and survival were identified. ### results The median baseline prostate specific antigen (PSA) before the initiation of HDK was 25.1. The number of patients with zero, 1 to 3, and more than 3 lesions on bone scan were 25, 35 and 18, respectively. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. In a Cox proportional hazard regression, prolonged survival was predicted by percent PSA decrease, extent of disease on bone scan and baseline PSA. ### conclusions ketoconazole can induce prolonged responses, occasionally lasting for years. Long responses are more likely to occur in men initiating HDK earlier in the course of disease before the cancer burden becomes excessive.

https://pubmed.ncbi.nlm.nih.gov/15879788/

4bdf5d29e8c2dd9daefde62c6baaea1e

Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia .

Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia . Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT. ### methods VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed. ### results In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group ( ### conclusion These results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT.

https://pubmed.ncbi.nlm.nih.gov/29695895/

e5243e9e9c05ab3335f5b06ee025acee

Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer : a study of the Princess Margaret Hospital Phase II Consortium .

Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer : a study of the Princess Margaret Hospital Phase II Consortium . Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. ### methods Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. ### results Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. ### conclusion This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.

https://pubmed.ncbi.nlm.nih.gov/20847613/

c2e7991bf6a9c974641dbfcce66e7a7e

Pharmacological inhibition of p70S6 K using the PI3K/mTOR inhibitor NVP-BEZ235 , the specific mTOR inhibitor Rapamycin and the specific p70S6 K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells .

Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. selumetinib (AZD6244, ARRY-142886) is a MEK1/2 inhibitor that has gained interest as an anti-tumour agent. We have determined the degree of sensitivity/resistance to selumetinib in a panel of colorectal cancer cell lines using cell proliferation and soft agar assays. Sensitive cell lines underwent G1 arrest, whereas selumetinib had no effect on the cell cycle of resistant cells. Some of the resistant cell lines showed high levels of ERK1/2 phosphorylation in the absence of serum. selumetinib inhibited phosphorylation of ERK1/2 and RSK and had no effect on AKT phosphorylation in both sensitive and resistant cells. Furthermore, mutations in KRAS, BRAF, or PIK3CA were not clearly associated with selumetinib resistance. Surprisingly, selumetinib was able to inhibit phosphorylation of p70 S6 kinase (p70S6K) and its downstream target ribosomal protein S6 (RPS6) in sensitive cell lines. However, p70S6K and RPS6 phosphorylation remained unaffected or even increased in resistant cells. Moreover, in some of the resistant cell lines p70S6K and RPS6 were phosphorylated in the absence of serum. Interestingly, colorectal primary cultures derived from tumours excised to patients exhibited the same behaviour than established cell lines. Pharmacological inhibition of p70S6 K using the PI3K/mTOR inhibitor NVP-BEZ235 , the specific mTOR inhibitor Rapamycin and the specific p70S6 K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells . In addition, biological inhibition of p70S6K using siRNA rendered responsiveness to selumetinib in resistant cell lines. Furthermore, combination of p70S6K silencing and PF-47086714 was even more effective. We can conclude that p70S6K and its downstream target RPS6 are potential biomarkers of resistance to selumetinib in colorectal cancer.

https://pubmed.ncbi.nlm.nih.gov/25379021/

0f26c0de95da1e1eb1b43e59cfb69d93

Vinorelbine , ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer .

Vinorelbine , ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer . To assess, in a multicenter setting, the effectiveness of a combination of vinorelbine, ifosfamide and cisplatin in the treatment of non-small cell lung cancer, 123 patients (males=116) with a mean age of 60 years (range 27-75) with stage IIIb/IV non-small cell lung cancer (NSCLC) and performance status <or=2 were treated with vinorelbine (VNR; 25 mg/m(2)) on days 1 and 8; ifosfamide (IFO; 3 g/m(2)) on day 1; and cisplatin (CDDP; 80 mg/m(2)) on day 1, in repeated cycles of 21 days. Response rates, overall patient survival and toxicity profiles of the three-drug combination were assessed. The number of evaluable patients was 112, with a total of 441 cycles administered (mean=3.6 cycles/patient). Dose intensities (mg/m(2)/week; calculated in patients who concluded the proposed treatment and expressed as mean, median, and standard deviation) were: VNR 13.65, 13.32, 4.7; IFO 918.88, 868.97, 258.1; CDDP 23, 24.68, 6.98. Response rates were: complete response=3 (2.4%); partial response=58 (47.2%%); stable disease=20 (16.3%). The most frequent toxic events were nausea and vomiting (G1=33%, G2=31%, G3=8%). Neutropenia was the dose limiting toxicity (G1=6%, G2=11%, G3=10%, G4=7%). Alopecia G3 was a common undesirable effect in all the patients. Time to progression was 296 days (95% confidence interval 261-332) and the mean survival time was 338 days (95% CI 301-374). We conclude that the described therapeutic schedule is effective with good survival rates and response ratios together with a good tolerance and an acceptable toxicity level.

https://pubmed.ncbi.nlm.nih.gov/11679190/

660a7bcd6ef6ac8e461f7dbbcefb3758

Two large Phase III trials conducted in the Americas and across Europe , Australia , and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone ( DRSP ) 3 mg in combination with ethinyl estradiol ( EE ) 30 µg ( DRSP/EE ) groups but this difference was not statistically significant .

Nomegestrol acetate/17-beta estradiol: a review of efficacy, safety, and patient acceptability. Nomegestrol acetate (NOMAC) 2.5 mg with 17-beta estradiol (E2) 1.5 mg is a new combined oral contraceptive (COC) formulation and is the first monophasic E2 pill to be marketed, having been licensed for use in Europe in 2011. It is available to be taken daily in a regimen of 24 active pills followed by four placebo pills. NOMAC is a highly selective 19-nor progestogen derivative with specific binding to progesterone receptors, anti-estrogenic activity and no androgenic, mineralocorticoid nor glucocorticoid effects. E2 is an estrogen that is identical to endogenous estrogen. While it has been in use for only a short period of time, current evidence suggests that NOMAC/E2 is just as effective, safe, and acceptable as existing COC preparations. Two large Phase III trials conducted in the Americas and across Europe , Australia , and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone ( DRSP ) 3 mg in combination with ethinyl estradiol ( EE ) 30 µg ( DRSP/EE ) groups but this difference was not statistically significant . NOMAC/E2 exhibits a good safety profile and has less effects on cardiovascular risk, hemostatic, metabolic, and endocrine factors in comparison to COCs containing EE in combination with levonorgestrel (LNG) or DRSP. NOMAC/E2 has also been found to cause less breast cell proliferation when compared to E2 alone and has some anti-proliferative effect on human breast cancer cells. NOMAC/E2 is considered acceptable as its compliance, continuation rates, and bleeding patterns were similar to COCs containing DRSP/EE and LNG 150 µg combined with EE 30 µg or LNG 100 µg combined with EE 20 µg (LNG/EE). However, discontinuation was found to be slightly higher in the NOMAC/E2 groups in the two large Phase III trials comparing NOMAC/E2 use with DRSP/EE. As the scientific literature has limited information on NOMAC/E2, further experience with NOMAC/E2 is required.

https://pubmed.ncbi.nlm.nih.gov/29386925/

99921793a9d8f1905ea6c17410b4f174

Using 146 surgically resected specimens of NSCLC , p53 status was immunohistochemically evaluated , and in vitro chemosensitivity to 5-fluorouracil ( 5-Fu ) , cisplatin ( CDDP ) , mitomycin C ( MMC ) , etoposide ( VP-16 ) , doxorubicin hydrochloride ( ADM ) , and vindesine sulfate ( VDS ) was examined by a collagen gel-droplet embedded culture drug sensitivity test ( CD-DST , Int J Oncol , 1997;11:449 ) .

Immunohistochemical p53 protein status in nonsmall cell lung cancer is a promising indicator in determining in vitro chemosensitivity to some anticancer drugs. The tumor suppressor oncogene p53 abnormalities have been closely associated with resistance or sensitivity of cancer cells to some chemotherapeutic agents. We examined the association between p53 protein status in nonsmall cell lung cancer (NSCLC) and in vitro chemosensitivity to several chemotherapeutic agents. ### methods Using 146 surgically resected specimens of NSCLC , p53 status was immunohistochemically evaluated , and in vitro chemosensitivity to 5-fluorouracil ( 5-Fu ) , cisplatin ( CDDP ) , mitomycin C ( MMC ) , etoposide ( VP-16 ) , doxorubicin hydrochloride ( ADM ) , and vindesine sulfate ( VDS ) was examined by a collagen gel-droplet embedded culture drug sensitivity test ( CD-DST , Int J Oncol , 1997;11:449 ) . ### results Sixty-five of 146 materials (45%) showed immunohistochemically abnormal p53 protein accumulation in >10% of cancer cells within the tumor tissue, being regarded as p53+, whereas 81 (55%) were to p53-, in which no or less than 10% positive immunostaining cancer cells were detected. By CD-DST, the incidence of chemosensitive, borderline, and resistant p53- materials (N=81) to 5-Fu was 37%(N=30), 14%(N=11), and 49%(N=40), whereas that of p53+ materials (N=65) was 20%(N=13), 6%(N=4), and 74%(N=48), respectively, showing that p53- materials were significantly more sensitive to 5-Fu than p53+ materials (P=0.011), especially in the adenocarcinoma type. As similar borderline association between p53 protein status and in vitro chemosensitivity was also shown in ADM (P=0.078), but not in other chemoagents. ### conclusions Immunohistochemically detected p53 protein status in NSCLC patients may be a promising indicator in determining in vitro chemosensitivity to some anticancer drugs, especially 5-Fu and ADM.

https://pubmed.ncbi.nlm.nih.gov/9610658/

58d7a5eb30426ed2c40cf19b0ca6846b

The objective was to compare the pharmacodynamic ( PD ) and pharmacokinetic ( PK ) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity , as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known .

A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease. The objective was to compare the pharmacodynamic ( PD ) and pharmacokinetic ( PK ) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity , as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known . This was a randomised, open-label, crossover PD/PK study of 40 Hispanic subjects with stable coronary artery disease (CAD). Subjects were allocated to either ticagrelor 180 mg loading dose (LD)/90 mg twice-daily maintenance dose (MD) followed by clopidogrel 600 mg LD/75 mg once-daily MD with an intervening washout period, or vice versa. The primary endpoint was on-treatment reactivity (OTR) at 2 h post-LD according to the VerifyNow P2Y12 test. OTR was significantly lower at 2 h post-LD with ticagrelor compared with clopidogrel (34 PRU vs. 201 PRU, least square means difference = -167 PRU [95 % CI, -197, -137], P < 0.001). OTR was also lower with ticagrelor at 30 min and 8 h post-LD (P < 0.001). The greater magnitude of antiplatelet effect with ticagrelor persisted after 7 days of MD (52 PRU [95 % CI, 30, 73] vs. 182 PRU [95 % CI, 160, 205], P < 0.001). Mean plasma concentration of ticagrelor and its active metabolite were greatest at 2 h post-LD, with similar levels at 2 h post-MD after 7 days of MD. Among Hispanic subjects with stable CAD, ticagrelor provides a more rapid onset of platelet inhibition and a significantly greater antiplatelet effect compared with clopidogrel during both the loading and maintenance phases of treatment.

https://pubmed.ncbi.nlm.nih.gov/25305090/

bf2ed1a581b3786c1931ffde4782c39f

For example , the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids , such as probenecid , salicylates and penicillin , which compete for tubular secretion , resulting in delayed clearance of methotrexate .

Pharmacokinetic drug interactions of commonly used anticancer drugs. With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example , the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids , such as probenecid , salicylates and penicillin , which compete for tubular secretion , resulting in delayed clearance of methotrexate . The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.

https://pubmed.ncbi.nlm.nih.gov/2426030/

9920556fa0edb1a7ba30504dc54c88d2

To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin ( NPL-DOX ) combined to Cyclophosphamide ( CTX ) and followed by weekly Paclitaxel , in older patients ( ≥65 years ) with diagnosis of high risk breast cancer .

Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients. To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin ( NPL-DOX ) combined to Cyclophosphamide ( CTX ) and followed by weekly Paclitaxel , in older patients ( ≥65 years ) with diagnosis of high risk breast cancer . The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). ### methods The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. ### results Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. ### conclusions This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.

https://pubmed.ncbi.nlm.nih.gov/27886643/

ec9541a245e674b905a510f820f1c0b6

The high incidence of imported malaria ( 0.70 % ) and the low costs of providing chemoprophylaxis resulted in a cost-benefit ratio of 0.19 for chloroquine and proguanil and 0.57 for a regimen containing mefloquine .

Is travel prophylaxis worth while? Economic appraisal of prophylactic measures against malaria, hepatitis A, and typhoid in travellers. To estimate the costs and benefits of prophylaxis against travel acquired malaria, typhoid fever, and hepatitis A in United Kingdom residents during 1991. ### design Retrospective analysis of national epidemiological and economic data. ### Main Outcome Measures Incidence of travel associated infections in susceptible United Kingdom residents per visit; costs of prophylaxis provision from historical data; benefits to the health sector, community, and individuals in terms of avoided morbidity and mortality based on hospital and community costs of disease. ### results The high incidence of imported malaria ( 0.70 % ) and the low costs of providing chemoprophylaxis resulted in a cost-benefit ratio of 0.19 for chloroquine and proguanil and 0.57 for a regimen containing mefloquine . Hepatitis A infection occurred in 0.05% of visits and the cost of prophylaxis invariably exceeded the benefits for immunoglobulin (cost-benefit ratio 5.8) and inactivated hepatitis A vaccine (cost-benefit ratio 15.8). Similarly, low incidence of typhoid (0.02%) and its high cost gave whole cell killed, polysaccharide Vi, and oral Ty 21a typhoid vaccines cost-benefit ratios of 18.1, 18.0, and 22.0 respectively. ### conclusions Fewer than one third of travellers receive vaccines but the total cost of providing typhoid and hepatitis A prophylaxis of 25.8m pounds is significantly higher than the treatment costs to the NHS (1.03m pounds) of cases avoided by prophylaxis. Neither hepatitis A prophylaxis nor typhoid prophylaxis is cost effective, but costs of treating malaria greatly exceed costs of chemoprophylaxis, which is therefore highly cost effective.

https://pubmed.ncbi.nlm.nih.gov/7726905/

4014e3f6e9dace4cbb1fb59841c57db0

Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin .

Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer. The antibody cetuximab, targeting epidermal growth factor receptor (EGFR), is used to treat metastatic colorectal cancer (mCRC). Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin . The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin. ### methods Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions. Reactive oxygen species (ROS) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production. Chromatin immunoprecipitation (ChIP) measured signal transducer and activator of transcription 1 (STAT-1) binding to dual oxidase 2 (DUOX2) promoter. SW48, DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab, oxaliplatin, or oxaliplatin + cetuximab (control [saline]; n = 3 mice per treatment group) were used. Statistical tests were two-sided. ### results cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis (caspase 3/7 activity reduced by 1.4-fold, 95% confidence interval [CI] = 0.78 to 2.11, P = .003) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38). Although both oxaliplatin and SN-38 produced ROS, only oxaliplatin-mediated apoptosis was ROS dependent. Production of ROS by oxaliplatin was secondary to STAT1-mediated transcriptional upregulation of DUOX2 (3.1-fold, 95% CI = 1.75 to 2.41, P < .001). Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity. ### conclusions Inhibition of STAT1 and DUOX2-mediated ROS generation by cetuximab impairs p38-dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings. Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR inhibitors with chemotherapeutic agents in future therapeutic use.

https://pubmed.ncbi.nlm.nih.gov/26719345/

38545112e53419e113dc91fa390d8757

L-carnitine was administered 1 h before doxorubicin injection and daily thereafter for 15 days .

L-carnitine ameliorates doxorubicin-induced nephrotic syndrome in rats. Effects of l-carnitine on nephrotoxicity and oxidative stress induced by doxorubicin (DOX) in rats were investigated. ### methods The rats were divided into four groups: group 1, control (0.9% NaCl); group 2, DOX injection (7.5 mg/kg, i.v.); group 3, DOX plus low dose (40 mg/kg) l-carnitine; and group 4, DOX plus high dose (200 mg/kg) l-carnitine. L-carnitine was administered 1 h before doxorubicin injection and daily thereafter for 15 days . ### results Rats in group 2 were associated with hypoalbuminaemia, hyperlipidaemia, high urinary excretion of protein and elevated plasma creatinine and urea nitrogen. The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) decreased with increased renal vascular resistance (RVR). Kidney catalase (CAT) activity was decreased. In group 3 and 4, plasma triglyceride and cholesterol declined. l-carnitine improved renal functions by elevated GFR and ERPF and decreased plasma creatinine and urea nitrogen. The kidney CAT activity were increased significantly compared with group 2. From histopathological results, group 2 rats were found to have glomerular capillary dilation and tubular dilation. The lesions were less in group 3 and 4 rats. ### conclusion l-carnitine can protect renal impairment functionally, biochemically and histopathologically with a corresponding reduction of oxidative stress.

https://pubmed.ncbi.nlm.nih.gov/16889571/

a1772c44e757e1514b82a6df2b030604

New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil .

Current and emerging treatments for pancreatic cancer. The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil . Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.

https://pubmed.ncbi.nlm.nih.gov/9342558/

8e80b2ee5e4c1611cf8e52e7988d7b76

Comparative effectiveness of rituximab , abatacept , and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors : prospective cohort study .

Comparative effectiveness of rituximab , abatacept , and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors : prospective cohort study . To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis. ### design Population based prospective study. ### setting 53 university and 54 non-university clinical centres in France. ### participants 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months. ### intervention Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis. ### Main Outcome Measure The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED ### results Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED ### conclusion Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.

https://pubmed.ncbi.nlm.nih.gov/30679233/

40c387814e8b0757ef731fa545f66bcc

Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine ( 100 microM , given under halothane anaesthesia ) , pretreatment with reserpine ( 4 mg/kg , i.p . , 24 h beforehand ) , unilateral pretreatment of the medial forebrain bundle with 6-OHDA ( 8 microg/4 microl ) , and by the systemic ( 1 mg/kg , i.p . ) or bilateral intrastriatal ( 7 microg/0.5 microl under halothane anaesthesia ) administration of the dopamine D2 receptor antagonist haloperidol , but not raclopride ( 2 mg/kg , i.p . ) .

Extracellular levels of glutamate and aspartate in the entopeduncular nucleus of the rat determined by microdialysis: regulation by striatal dopamine D2 receptors via the indirect striatal output pathway? This study used intracerebral microdialysis to monitor the outputs of excitatory amino acids in the entopeduncular nucleus (EPN) of conscious or halothane-anaesthetized rats, in an attempt to obtain direct biochemical evidence for the theory that neuronal inputs to the EPN by the indirect striatal output pathway are glutamatergic and regulated primarily by dopamine D2 receptors in the striatum. In dopamine-intact animals, both glutamate and asparate were readily detectable in EPN dialysates. Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine ( 100 microM , given under halothane anaesthesia ) , pretreatment with reserpine ( 4 mg/kg , i.p . , 24 h beforehand ) , unilateral pretreatment of the medial forebrain bundle with 6-OHDA ( 8 microg/4 microl ) , and by the systemic ( 1 mg/kg , i.p . ) or bilateral intrastriatal ( 7 microg/0.5 microl under halothane anaesthesia ) administration of the dopamine D2 receptor antagonist haloperidol , but not raclopride ( 2 mg/kg , i.p . ) . The dopamine D1 receptor antagonist SCH 23390 was ineffective both systemically (0.25 mg/kg, i.p.) and intrastriatally (0.125 microg/0.5 microl/side), as also were control intrastriatal injections of saline (0.5 microl/side). By contrast, the dopamine D2/3 receptor agonist quinpirole (4 mg/kg, i.p.) lowered the outputs of glutamate and aspartate in the EPN of reserpine-treated and normal individuals, whilst the dopamine D1 receptor agonist SKF 38393 (30 mg/kg, i.p.) was inactive; however, both drugs caused behavioural arousal. The dopamine D2/3 receptor agonist RU 24213 reversed reserpine-induced akinesia, yet paradoxically increased glutamate (not aspartate) output in the EPN still further. The combination of benserazide (30 mg/kg, i.p.) and L-DOPA (50 mg/kg, i.p.) evoked intense contraversive circling in unilaterally 6-OHDA-lesioned rats, together with a drop in EPN glutamate (but not aspartate) output in the intact but not lesioned hemisphere. These results offer biochemical support for the hypothesis that excitatory neurones innervating the EPN via the indirect striatal output pathway, may utilise glutamate and/or aspartate as their neurotransmitter. They further endorse the view that the EPN receives information from striatal D2 and not D1 receptors via excitatory synapses, which become hyperactive following dopamine depletion or inactivation, and which are subject to control by the contralateral as well as by the ipsilateral hemisphere. The results obtained with RU 24213 and L-DOPA, however, indicate that dopaminergic behaviours can also occur independently of glutamate or aspartate release in the EPN.

https://pubmed.ncbi.nlm.nih.gov/9125444/

58c98ab45fc1f4589ee167ae35e2162b

Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure .

Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure . The article presents a patient with severe paraquat poisoning from dermal exposure, who had chemical bums to more than 10% of his body surface area, serum paraquat level 0.13 microg/mL 60 hr after exposure, and severe hypoxemia (PaO2 41.6 mmHg). The patient was successfully treated with combined initial megadoses of cyclophosphamide (15 mg/kg/day, total 2 days) with repeated methylprednisolone pulse therapy (15 mg/kg/day, total 6 days) and continuous dexamethasone administration (5 mg every 8 hr), and recovered completely without sequelae 3 months later. This treatment deserves further investigation in future clinical trials.

https://pubmed.ncbi.nlm.nih.gov/14677801/

5b6afe03121f818dd0a426d51cd826d3

These adverse effects were all more frequent than with docetaxel or pemetrexed .

Crizotinib. Patients with advanced-stage or metastatic non-small cell lung cancer have a grim prognosis when first-line chemotherapy fails. Some cytotoxic drugs such as docetaxel and pemetrexed prolong overall survival by a few months, but at a cost of severe toxicity. crizotinib (Xalkori*, Pfizer), a drug that inhibits ALK (among other tyrosine kinases) has been authorised for use in patients whose tumours overexpress this tyrosine kinase. Preliminary results of a comparative, randomised but unblinded trial in 347 patients suggest that crizotinib delays cancer progression and death more effectively than pemetrexed or docetaxel (median 7.7 months versus 3 months). However, it remains to be seen whether or not this translates into longer overall survival. Two uncontrolled trials including 136 and 119 patients also suggest that crizotinib delays tumour progression and death by about 8 months. crizotinib is highly toxic, causing gastrointestinal, visual and hepatic disorders, cardiac arrhythmias (including QT prolongation) and pneumonia. These adverse effects were all more frequent than with docetaxel or pemetrexed . Some of these effects are more difficult to predict and manage than haematological disorders, which are the main adverse effects of docetaxel and pemetrexed. crizotinib is extensively metabolised by cytochrome P450 isoenzymes and also inhibits P-glycoprotein, creating a risk of numerous pharmacokinetic interactions. Other interactions, with drugs that prolong the QT interval, may increase the risk of serious adverse effects. In practice, in patients with non-small cell lung cancer overexpressing ALK tyrosine kinase in whom first-line chemotherapy has failed, crizotinib appears to delay cancer progression and death, but at a cost of serious adverse effects. Further evaluation of crizotinib in well-designed comparative trials is needed before deciding whether or not to include it in the therapeutic arsenal.

https://pubmed.ncbi.nlm.nih.gov/24427836/

e5700462572f4de98ab4591b1d026ef0

Hyper-CVAD , given in odd-number courses ( Courses 1 , 3 , 5 , and 7 ) , was alternated with methotrexate and cytarabine ( MTX/Ara-C ) , given in even-number courses ( Courses 2 , 4 , 6 , and 8) .

Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Hyperglycemia, which is not uncommon during the treatment of acute lymphocytic leukemia (ALL), has been shown to be an independent predictor of adverse outcomes among hospitalized patients with undiagnosed diabetes; it also may have the potential to affect leukemic cell proliferation through altered metabolism. The purpose of the current study was to determine the prevalence of hyperglycemia during induction chemotherapy for ALL using a regimen comprised of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and to determine its effect on survival, duration of disease remission, and treatment-related complications. ### methods Two hundred seventy-eight adult patients with previously untreated ALL who achieved a complete remission with the hyper-CVAD regimen were evaluated. Hyperglycemia was defined as > or = 2 glucose determinations of > or = 200 mg/dL during the first 30 days of induction chemotherapy. Induction chemotherapy was comprised of fractionated cyclophosphamide at a dose of 300 mg/m2 twice daily on Days 1-3, doxorubicin at a dose of 50 mg/m2 on Day 4, vincristine at a dose of 2 mg on Days 4 and 11, and dexamethasone at a dose of 40 mg on Days 1-4 and Days 11-14 (hyper-CVAD). Hyper-CVAD , given in odd-number courses ( Courses 1 , 3 , 5 , and 7 ) , was alternated with methotrexate and cytarabine ( MTX/Ara-C ) , given in even-number courses ( Courses 2 , 4 , 6 , and 8) . MTX/Ara-C was comprised of MTX at a dose of 200 mg/m2 over 2 hours followed by 800 mg/m2 over 22 hours on Day 1, Ara-C at a dose of 3 g/m2 every 12 hours for 4 doses over 2 days (Days 2 and 3), and intravenous methylprednisolone given at a dose of 50 mg twice daily on Days 1-3. The complete remission duration (CRD), survival, and treatment-related complications were determined for patients with and without hyperglycemia; differences between the two groups were assessed using standard statistical methods. ### results Hyperglycemia was found to occur in 103 patients (37%). Patients with hyperglycemia had a shorter median CRD (24 months vs. 52 months; P = 0.001) and a shorter median survival (29 months vs. 88 months; P < 0.001); they also were more likely to develop sepsis (16.5% vs. 8.0%; P = 0.03) or any complicated infection (sepsis, pneumonia, or fungal) (38.8% vs. 25.1%; P = 0.016) compared with patients without hyperglycemia. ### conclusions Patients with hyperglycemia during induction chemotherapy for ALL with the hyper-CVAD regimen were found to have a shorter CRD, experience a significant increase in overall mortality, and be at an increased risk for developing complicated infections.

https://pubmed.ncbi.nlm.nih.gov/15022284/

d68d2fb14b6930de59e1746f6be132ff

Despite systemic chemotherapy combining pemetrexed , bevacizumab and Cisplatinum , the disease relapsed eight months later with multiple metastatic lung nodules leading to a treatment shift .

The necessity of a more aggressive initial surgical treatment in patients with mesothelioma of the testicular tunica vaginalis. Mesothelioma of the tunica vaginalis of the testis (MTVM) is a rare tumor encountering for less than 1% of mesothelioma. Patients suffering from these tumors have poor survival due to local and distant metastasis despite treatment. Actually, no specific treatment recommendations exist for this tumor, yet radical orchidectomy is the gold standard in limited disease. We herein report the case of a 71 patient with MTVM who underwent radical orchidectomy without inguinal lymph node dissection and recurred 2 years later with metastasis in pelvic and mediastinal lymph nodes. Despite systemic chemotherapy combining pemetrexed , bevacizumab and Cisplatinum , the disease relapsed eight months later with multiple metastatic lung nodules leading to a treatment shift . We believe that systematic inguinal-iliac lymph node resection should be included in the initial treatment of this tumor.

https://pubmed.ncbi.nlm.nih.gov/31692693/

7b50d48684b8c2fee436950bf35cb0d1

Trastuzumab , which is still the first-line therapy in breast cancer , increases the pCR rate more than lapatinib .

Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis of randomized controlled trials. This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR = 0.82, 95% CI: 0.73-0.93; Z = 3.00; P = 0.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR = 1.33, 95% CI: 1.18-1.50; Z = 4.70; P < 0.00001), diarrhea (RR = 14.59, 95% CI: 7.69-27.67; Z = 8.20; P < 0.00001), and dermatologic toxicity (RR = 3.10, 95% CI: 1.61-5.96; Z = 3.39; P = 0.007), but none was found for neutropenia (RR = 1.38, 95% CI: 0.82-2.31; Z = 1.22; P = 0.22) or CHF (RR = 0.14, 95% CI: 0.02-1.17; Z = 1.02; P = 0.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2-positive breast cancer patients with no additional cardiac events. Trastuzumab , which is still the first-line therapy in breast cancer , increases the pCR rate more than lapatinib .

https://pubmed.ncbi.nlm.nih.gov/27882700/

ff41f8ada1aa59e48542817d10e7a13b

Recently , several novel agents are under clinical development for advanced colorectal cancer , including irinotecan , oxaliplatin , oral fluoropyrimidines , raltitrexed , monoclonal antibody 17 - 1A and tumour vaccines .

Novel agents for colorectal cancer. The compound 5-fluorouracil (5-FU) has been investigated for over four decades; research has focussed on examining various schedules and biochemical modulators in an attempt to improve its therapeutic activity in advanced colorectal cancer. Combination chemotherapy regimens have not been developed because of the lack of other active agents. Recently , several novel agents are under clinical development for advanced colorectal cancer , including irinotecan , oxaliplatin , oral fluoropyrimidines , raltitrexed , monoclonal antibody 17 - 1A and tumour vaccines . Both irinotecan and oxaliplatin have uniquely different mechanisms of action compared to 5-FU, and have demonstrated activity in patients whose disease has progressed with 5-FU treatment. Recent randomised trials comparing 5-FU plus leucovorin (5-FU/LV) to combinations of either irinotecan or oxaliplatin plus 5-FU/LV have demonstrated that the addition of these novel agents to 5-FU improve response rates (RRs) and time to progression (TTP). The role and acceptance of these combinations need to be defined, but are rapidly being introduced into the adjuvant therapy of colorectal cancer. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU, and S-1) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. To gain clinical acceptance, oral fluoropyrimidines must provide not only convenience and toxicity reduction, but also maintenance of survival advantages associated with optimal use of iv. 5-FU/LV regimens. These novel agents discussed herein provide treatment options which may allow for more individualised treatment strategies.

https://pubmed.ncbi.nlm.nih.gov/11139816/

bdf4194d4f3640ac2215ef4cbaacba52

Pretreatment with NaHCO3 , NH4Cl , SKF 525A , piperonyl butoxide , progesterone , cysteamine , phenobarbital or metyrapone prior to the administration of [methyl-14C]nicotine was studied .

Inhibition by metyrapone of the accumulation of nicotine-14C in bronchial epithelium of mice. Further studies have been conducted in an attempt to define the mechanism of the intense accumulation of radioactivity in bronchial epithelium following the administration of nicotine-14C to mice. Male and female pigmented (C57B1/6J) and nonpigmented (A/HeJ) mice were studied by whole-body autoradiography following administration of either nicotine-14C (methyl- or 2'-labeled) or nicotine-1'-N-oxide-14C. When each of these compounds was administered at the same specific activity the radioactivity retained in the bronchial epithelium was much greater for the methyl-labeled nicotine-14C than for the ring-labeled. Following administration of the N-oxide very little radioactivity was retained at this site and this was seen only at a few time intervals. Pretreatment with NaHCO3 , NH4Cl , SKF 525A , piperonyl butoxide , progesterone , cysteamine , phenobarbital or metyrapone prior to the administration of [methyl-14C]nicotine was studied . metyrapone totally prevented the accumulation of radioactivity in the bronchial epithelium and progesterone reduced this accumulation; the other substances used for pretreatment had no effect on the uptake of radioactivity. These results are interpreted to indicate that the accumulation of nicotine in bronchial epithelium is not accounted for by transcellular pH gradients but is due to a high affinity of nicotine for a cytochrome P-450 in this tissue which demethylates the nicotine. The relationship and significance of metabolism of nicotine in this tissue to metabolism at other sites in the body are discussed.

https://pubmed.ncbi.nlm.nih.gov/708156/

495b0332d40be56154a40837c4031e51

Capecitabine is an oral pro-drug of fluorouracil .

[New drugs for colorectal cancer]. Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to fluorouracil new anticancer drugs like irinotecan and oxaliplatin have become available. The activity of fluorouracil was optimized by using schedules of prolonged infusion. Capecitabine is an oral pro-drug of fluorouracil . When colorectal metastases are limited to the liver they should be resected if possible. Sometimes they can be reduced in size by primary chemotherapy (downstaging) and resected later. Very new and exciting are reports with the monoclonal antibody bevacizumab in combination with chemotherapy. bevacizumab blocks angiogenesis. So far it is available only in the USA.

https://pubmed.ncbi.nlm.nih.gov/15487860/

278d71de134cee74edc0ce47d5f18854

However , the current artemisinin FDC products , such as β-artemether and lumefantrine , are inherently unstable and require controlled distribution and storage conditions , which are not always available in resource-limited settings .

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products. artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However , the current artemisinin FDC products , such as β-artemether and lumefantrine , are inherently unstable and require controlled distribution and storage conditions , which are not always available in resource-limited settings . Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products. ### methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1 mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®. ### results Both β-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to β-artemether active pharmaceutical ingredient (API) itself. ### conclusions A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of β-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus® indicated that the overall toxicity risk for β-artemether-related impurities is comparable to that of β-artemether API.

https://pubmed.ncbi.nlm.nih.gov/23631682/

06aa63233bdab39481aa15cf612fb2a3

Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum , she received palliative chemotherapy using vincristine , doxorubicin , cyclophosphamide , ifosfamide , and etoposide .

A case of desmoplastic small round cell tumor diagnosed in a young female patient. Desmoplastic small round cell tumor is a very rare malignancy. We report the case of a 26-year-old woman who suffered from dyspepsia and abdominal pain for 2 months. We performed an endoscopic biopsy of the duodenal mass and diagnosed her disease as desmoplastic small round cell tumor using immunohistochemical staining, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction. Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum , she received palliative chemotherapy using vincristine , doxorubicin , cyclophosphamide , ifosfamide , and etoposide . The maximal response to chemotherapy was stable disease. The patient expired 9 months after diagnosis.

https://pubmed.ncbi.nlm.nih.gov/20057970/

33615bfabfbbd2bf4dec81f0c8c3cae4

In HCV genotype 1 infection and F3 or F4 liver fibrosis , treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended .

[Treatment of chronic hepatitis C in human immunodeficiency virus infected patients]. Treatment of HCV infection offers the possibility of viral eradication, thus every person with a detectable HCV viral load is a candidate for treatment. Treatment is recommended to all HCV/HIV co-infected patients with: 1) repeatedly elevated aminotransferase levels; 2) F2 stage of liver fibrosis or higher, regardless of alanine aminotransferase values; and 3) more than 200 CD4+ lymphocytes per microL of blood. Treatment with a combination of pegylated interferon and weight-based ribavirin (1000 mg/day if < 75 kg and 1200 mg/day if > 75 kg) is recommended. Pegylated interferon is used as 180 microg for the alfa-2a form and 1.5 mg/kg for the alfa-2b form once weekly subcutaneously. HCV RNA should be measured after 4 weeks of treatment, and later as needed, in weeks 12, 24, 48 or 72. For evaluation of a sustained virologic response, HCV RNA should be measured 24 weeks after the end of treatment. Treatment duration for patients who have a rapid viral response (undetectable levels of HCV RNA after 4 weeks of treatment) is 24 weeks (genotypes 2 and 3) or 48 weeks (genotypes 1 and 4). For patients without a rapid virologic response, but with an adequate response after 12 and 24 weeks, we generally recommend treatment for 48 weeks. Treatment discontinuation is recommended for patients with < 2 log viral load decline after 12 weeks or with a detectable viral load after 24 weeks of treatment. In HCV genotype 1 infection and F3 or F4 liver fibrosis , treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended . In case of persistent HCV replication during therapy stopping rules should be applied.

https://pubmed.ncbi.nlm.nih.gov/24984336/

d7ad522d1f7eaa6dd4f5b41387f73a8a

Membrane-modifying agents such as reserpine , calcium antagonists ( nicardipine , verapamil ) and calmodulin inhibitor ( trifluoperazine ) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 ( C 6/ACNU ) glioma .

[Possibility of overcoming of ACNU resistance in an ACNU-resistant subline of C6 rat glioma]. Membrane-modifying agents such as reserpine , calcium antagonists ( nicardipine , verapamil ) and calmodulin inhibitor ( trifluoperazine ) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 ( C 6/ACNU ) glioma . In in vitro experiments, uptake and retention studies with [14C] ACNU revealed that intracellular uptake and retention of ACNU in C 6 cells were larger than those in C 6/ACNU cells, and that these membrane-modifying agents increased the cellular uptake and retention of ACNU in C 6, especially in C 6/ACNU cells. The amount of ACNU in C 6/ACNU cells reached the same level as that detected in C 6/ACNU cells. When these drugs were added along with ACNU at the concentration of 10 to 20 microM to the culture in vitro, ACNU resistance was completely overcome. In in vivo experiment, reserpine, nicardipine, verapamil and trifluoperazine in doses 250 to 500 micrograms/kg intrathecally administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly enhanced the chemotherapeutic effect of ACNU in C 6/ACNU bearing (C 6/ACNU-MG) rats. It might be concluded that the mechanism of enhancement of ACNU cytotoxicity presented in in vitro and in vivo is explained by the enhanced accumulation of ACNU by these membrane-modifying agents in C 6, especially in ACNU-resistant (C 6/ACNU) cells, and, furthermore, that combination chemotherapy with ACNU and such membrane interacting drugs as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) could lead to the capability of overcoming resistance to ACNU in glioma.

https://pubmed.ncbi.nlm.nih.gov/3468959/

e814c77d08e9c7d24b065d8ba760cf4a

To investigate the efficacy of temozolomide in relation to response rate , toxicity , time to progression . and median survival time , a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea , procarbazine and vincristine .

Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study. To investigate the efficacy of temozolomide in relation to response rate , toxicity , time to progression . and median survival time , a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea , procarbazine and vincristine . ### Patients And Methods Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. ### results Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%-35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. ### conclusions On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.

https://pubmed.ncbi.nlm.nih.gov/11300334/

77d0a181f8d82c9a814b0cc95af49608

Ketoconazole inhibited the entire pathway , while exposure to genistein resulted in increased hormone levels upstream of 3-β-hydroxysteroid dehydrogenase ( 3β-HSD ) and decreases downstream .

H295R cells as a model for steroidogenic disruption: a broader perspective using simultaneous chemical analysis of 7 key steroid hormones. The effects of three model endocrine disruptors, prochloraz, ketoconazole and genistein on steroidogenesis were tested in the adrenocortical H295R cell line to demonstrate that a broader mechanistic understanding can be achieved in one assay by applying chemical analysis to the H295R assay. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and 17β-estradiol) were analyzed using a novel and thoroughly validated GC-MS/MS method. In addition to the simultaneous quantification of 7 steroid hormones, the present method also negates the potential problems of cross-reactivity that can be encountered in some immunoassays. Although all 3 test compounds decrease the concentrations of the main sex steroids, the chemicals exerted different effects upstream in the pathway. Exposure to prochloraz resulted in increased hormone levels upstream of steroid 17 alpha-hydroxylase/17,20 lyase (P450c17) and decreases downstream. Ketoconazole inhibited the entire pathway , while exposure to genistein resulted in increased hormone levels upstream of 3-β-hydroxysteroid dehydrogenase ( 3β-HSD ) and decreases downstream . The results demonstrate that chemical analysis combined with the H295R cell assay is an useful tool for studying the mechanisms by which endocrine disruptors interfere with the steroidogenic pathway.

https://pubmed.ncbi.nlm.nih.gov/22198065/

a67a955015d89bd9210042765e9bfba1

Melphalan , cisplatin , carboplatin , doxorubicin , and etoposide cytotoxicities were determined by DIMSCAN assay .

Drug resistance in human neuroblastoma cell lines correlates with clinical therapy. To determine if neuroblastoma acquires a sustained drug-resistant phenotype from patient exposure to therapy, we studied neuroblastoma cell lines established at different points of therapy: at diagnosis prior to therapy, at progressive disease after induction therapy and at relapse after intensive chemoradiotherapy and bone marrow transplantation (post-BMT). Melphalan , cisplatin , carboplatin , doxorubicin , and etoposide cytotoxicities were determined by DIMSCAN assay . Drug resistance progressively increased with therapy and 3/5 post-BMT lines showed high resistance to most drugs. IC 90s 37, 78, 719 and 256 times higher than clinically achievable drug levels were obtained in post-BMT cell lines for melphalan, cisplatin, doxorubicin and etoposide, respectively. Resistance correlated with the therapies patients received: considerable etoposide and doxorubicin resistance (> 1000-fold resistance) was seen in cell lines obtained from patients treated with these drugs. These cell lines indicate that neuroblastoma acquires resistance to cytotoxic drugs that is probably due to stable genetic alterations occurring during therapy.

https://pubmed.ncbi.nlm.nih.gov/9516842/

8eaa87363fa72a9071d0b5d4982767c3

As a treatment at the time of progression after pemetrexed-based chemotherapy , erlotinib conferred a survival benefit when compared to docetaxel ( p=0.024 ; hazard ratio , 0.377 ) .

Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR. pemetrexed is a multi-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated a potential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with a survival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As a treatment at the time of progression after pemetrexed-based chemotherapy , erlotinib conferred a survival benefit when compared to docetaxel ( p=0.024 ; hazard ratio , 0.377 ) . The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers a survival benefit in NSCLC patients with wild-type EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.

https://pubmed.ncbi.nlm.nih.gov/26458306/

27a22f42ae6e4491d8b1c48b5b59e484

The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer .

Ifosfamide plus oral etoposide salvage chemotherapy for platinum-resistant paclitaxel-pretreated ovarian cancer. The prognosis of platinum resistant ovarian cancer is very poor and the treatment of choice has not been clearly defined. ### Patients And Methods We conducted a phase II study with the combination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) and etoposide per os at 100 mg daily (days 1-10) every four weeks. To be eligible for the study patients had to be resistant to platinum and paclitaxel pretreated. ### results Forty-one patients entered the study. The median interval from the previous chemotherapy was 3.9 months. The median number of previous chemotherapeutic regimens was 2. Severe toxicities included neutropenia (41% of patients), leukopenia (29%) and thrombocytopenia (13%). Thirty-five patients are assessable for response. Nine patients responded (22% of the eligible, 26% of the assessable), four of them demonstrated complete response to chemotherapy (10% and 12%, respectively), while three patients demonstrated stabilization of their progressive disease. After a median follow-up of 18 months, time to progression is 3 months (range 0.9-14.4), duration of response is 9 months (2.5-11) and median survival is 13 months (2.5-37.4+). ### conclusions The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer .

https://pubmed.ncbi.nlm.nih.gov/10907957/

315a17c64404a20e865c08463645946d

After switching from ranibizumab treatment to aflibercept , ORTs remained present in 75 % of eyes , and significant reductions in CMT , PED , and SRF , and presence of intraretinal cysts were observed .

Evaluation of outer retinal tubulations in eyes switched from intravitreal ranibizumab to aflibercept for treatment of exudative age-related macular degeneration. To evaluate the changes of outer retinal tubulations (ORTs) as seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) where treatment was switched from intravitreal ranibizumab to intravitreal aflibercept. ### methods This was a prospective study of eyes diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept, conducted at a single centre (Department of Ophthalmology at Pitié Salpetriere Hospital, Paris VI University) from January to July 2015. Before and after treatment was switched from ranibizumab to aflibercept, SD-OCT was used to evaluate the presence of ORTs. Additional assessments in this patient group included best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA). Changes in pigment epithelium detachments (PED), presence of intraretinal cysts, and presence of subretinal fluid (SRF) were also noted. ### results Twenty-four eyes of 24 consecutive patients (15 female/nine male, mean age 70 years) diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept were included in the analysis. After receiving aflibercept, patients were followed for a mean of 6.1 months. Prior to treatment switch, 97 % of eyes showed ORTs, while after treatment switch to aflibercept, at the end of the study period, 75 % had ORTs (p =  0.219). Changes in BCVA (LogMAR) were not statistically significant (1.16 ± 0.44 to 1.18 ± 1.06, p =  0.12), however, a significant reduction in central macular thickness (CMT) (from 406 μm ± 112 to 263 μm ± 68, p =  0.001), PED (from 70.8 % to 41.7 % , p =  0.016), presence of intraretinal cysts (from 83.3 % to 33.3 %, p =  0.002) and SRF (from 91.7 % to 25 %, p = 0.001 ) were noted. ### conclusion After switching from ranibizumab treatment to aflibercept , ORTs remained present in 75 % of eyes , and significant reductions in CMT , PED , and SRF , and presence of intraretinal cysts were observed .

https://pubmed.ncbi.nlm.nih.gov/27397583/

a8c99f7a4aa7a4ab7501fc6360bafe72

Vinorelbine , gemcitabine , docetaxel , paclitaxel , and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease .

A brief historical review of the development of chemotherapy for the treatment of advanced non-small cell lung cancer: why we should look beyond platinum. We are approaching the end of the fifth decade and the most productive period in the development of chemotherapy for the treatment of advanced non-small cell lung cancer. We began this decade by establishing cisplatin-based combination chemotherapy regimens of the 1980s as effective at improving survival for patients with advanced disease. The observed improvement in survival from these trials appears to be primarily attributed to cisplatin. Furthermore, this decade, unlike the prior, has identified an abundance of novel active agents for the treatment of this disease. Vinorelbine , gemcitabine , docetaxel , paclitaxel , and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease . In contrast to the cisplatin-based chemotherapy trials of the 1980s, these newer chemotherapeutic agents when given in combination with cisplatin add to the survival outcomes for these patients. With these survival advances has come a focus on chemotherapy-induced adverse events, lung cancer symptom management, and overall quality of life. The results of the cisplatin combination trials will be discussed.

https://pubmed.ncbi.nlm.nih.gov/10585002/

11921a640de5c5c816f5ac48cfbc7fbd

This Phase I , randomized , open-label study evaluated the gastric pH-altering effects of omeprazole , a proton pump inhibitor , and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir , an HIV protease inhibitor , on the pharmacokinetics and safety of the hepatitis C virus ( HCV ) non-structural protein 5A ( NS5A ) inhibitor GSK2336805 in healthy male and female subjects .

Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults. This Phase I , randomized , open-label study evaluated the gastric pH-altering effects of omeprazole , a proton pump inhibitor , and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir , an HIV protease inhibitor , on the pharmacokinetics and safety of the hepatitis C virus ( HCV ) non-structural protein 5A ( NS5A ) inhibitor GSK2336805 in healthy male and female subjects . Co-administration of GSK2336805 60 mg with omeprazole decreased GSK2336805 plasma AUC(0-∞) by 10% and Cmax by 18%; no marked effect was observed on t½ . Co-administration of GSK2336805 30 mg with ritonavir increased GSK2336805 plasma AUC(0-∞) by 52%, Cmax by 43%, and t½ by 40%; CL/F was decreased by 34%. All adverse events were minor in intensity. The gastric acid-suppressive effect of omeprazole had minimal impact on the extent and rate of GSK2336805 absorption in vivo; therefore, GSK2336805 may be co-administered with omeprazole without concern about lower GSK2336805 exposures and compromised antiviral efficacy. The modest increases in AUC and Cmax following co-administration of GSK2336805 plus ritonavir suggest that GSK2336805 when given concomitantly with a single CYP3A/Pgp inhibiting drug will not likely require dose adjustment. Final dose recommendation will be based on GSK2336805 efficacy and safety profiles from Phase III trials in HCV-infected patients.

https://pubmed.ncbi.nlm.nih.gov/27129005/