epirubicin

cyclophosphamide

paclitaxel

filgrastim

Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer . Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. ### Experimental Design Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. ### results Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. ### conclusions Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.


omeprazole

clarithromycin

amoxicillin

tetracycline

metronidazole

Pharmacist-managed Helicobacter pylori clinic. A pharmacist-managed Helicobacter pylori assessment clinic for ambulatory patients is described. The pharmacy service at a 400-bed Veterans Affairs Medical Center established a pharmacist-managed clinic to assess patients who were receiving long-term acid-suppressive medications (histamine H2-receptor antagonists, sucralfate, or omeprazole). Patients with active ulcer disease and those receiving ulcer prophylaxis are screened for the presence of H. pylori. Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole . The pharmacist also may adjust or discontinue acid-suppressive drug regimens. The pharmacist is responsible for ordering all appropriate laboratory tests, monitoring patients for adverse effects, collecting data on patient outcomes, and providing patient education. The clinic provides opportunities for pharmacists to study the clinical effectiveness and pharmacoeconomics of various regimens for treating H. pylori-associated disease and for pharmacy students and residents to interact with patients. As of fall 1994, 20 patients had been evaluated at the clinic: 12 tested positive for H. pylori and were treated with antimicrobials and all were pain-free without medication at the end of treatment. An H. pylori assessment clinic enabled pharmacists to assume a primary care role, document improvement in patient outcomes, and study the effectiveness of various antimicrobial regimens.


abiraterone

enzalutamide

Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). ### Methods And Analysis Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC . Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. ### Ethics And Dissemination Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. ### Trial Registration Number NCT02730338.


tramadol

hydrocodone

Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied . It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.


Atracurium

vecuronium

Prediction of oculocardiac reflex in strabismus surgery using neural networks. Successfully predicting an oculocardiac reflex (OCR) is difficult to achieve despite various proposed maneuvers. The aim of this study was to test the models built up by neural networks to predict the occurrence of OCR during strabismus surgery in children. Premedication was not given. atropine 0.01 mg/kg was medicated just before induction. Induction was performed with fentanyl or ketorolac, followed by propofol. Atracurium or vecuronium was given for intubation . Anesthesia was maintained with O2-N2O with continuous propofol infusion. Chi-square test was performed for induction agents, gender, weight, muscle blockade, repaired muscle, number of repaired muscles, duration of operation to detect any association between the occurrence of OCR and to develop the model of neural networks. The multi-layer perceptron, radial basis function and Bayesian backpropagation network were tested. The occurrence of OCR was significantly associated with gender and repaired muscle (p < 0.05). Gender, repaired muscle and age were considered as input for the multi-layer perceptron, radial basis function and Bayesian backpropagation network. Three neural networks had predicted the same correction rate in the occurrence of OCR as being 87.5% overall among 16 patients' records tested. These models are conceptually different in predicting compared to conventional maneuvers, and have the advantage of testing individually and foretelling the propensity. By comparison neural networks use grouped experiential data and predict OCR by the learning rule. Neural networks require a relatively abundant number of experienced and homogenous patients' records to establish an accurate model. The multi-layer perceptron, radial basis function and Bayesian backpropagation modeling network may be an alternative way, and preferable to vagal tone maneuvers if the associated relationships to the occurrence of OCR are more clearly defined.


temozolomide

nimustine

Rad51 and BRCA2--New molecular targets for sensitizing glioma cells to alkylating anticancer drugs. First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) . It did not sensitize to ionizing radiation (IR). The expression of O(6)-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O(6)-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O(6)-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide.


vincristine

actinomycin

cyclophosphamide

adriamycin

vincristine

actinomycin

ifosfamide

adriamycin

Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. ### Materials And Methods From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol . Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. ### results The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. ### conclusions The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.


fosinopril

pravastatin

Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) . This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease.


nicotine

epinephrine

Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine. Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress . nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the "stress test" to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system.


prednisone

prednisone

Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 . Orteronel (tak-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. ### Patients And Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. ### results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). ### conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.


temozolomide

dacarbazine

Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients. O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results . We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. ### Patients And Methods Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). ### results One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001). ### conclusion In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting.


Heparin

warfarin

Therapy for postoperative thromboembolic disease:  indications and treatment. Postarthroplasty patients develop venous thromboembolic disease because of venous stasis, hypercoaguability, and vessel wall injury.  However, most venous thrombi are nonocclusive or small and elicit few symptoms; pulmonary emboli also tend to be asymptomatic.  Noninvasive techniques to detect deep vein thrombosis do not appear to be reliable in this population, so venography may be required.  Postoperative perfusion lung scans, with comparison to preoperative perfusion scans, are the best screen for asymptomatic pulmonary emboli. Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli .


Fluoxetine

paroxetine

tamoxifen

Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug . Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.


Epirubicin

doxorubicin

A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma. Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern . As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n=59), had a Karnofsky performance status of 80 or more (n=62) and presented with an epithelial histologic subtype (n=43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease.


omeprazole

clarithromycin

amoxicillin

omeprazole

levofloxacin

amoxicillin

omeprazole

amoxicillin

omeprazole

clarithromycin

metronidazole

levofloxacin

clarithromycin

Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels. ### aim To compare clarithromycin and levofloxacin in triple and sequential first-line regimens. ### methods A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin . Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. ### results Per protocol cure rates were: OCA (66%; 95% CI: 57-74%), OLA (82.6%; 75-89%), OACM (80.8%; 73-88%) and OALM (85.2%; 78-91%). Intention-to-treat cure rates were: OCA (64%; 55-73%), OLA (80.8%; 73-88%), OACM (76.5%; 69-85%) and OALM (82.5%; 75-89%). Eradication rates were lower with OCA than with all the other regimens (P < 0.05). No differences in compliance or adverse effects were demonstrated among treatments. ### conclusions levofloxacin-based and sequential therapy are superior to standard triple scheme as first-line regimens in a setting with high clarithromycin resistance. However, all of these therapies still have a 20% failure rate.


Captopril

HYZ

captopril

Testosterone increases blood pressure and cardiovascular and renal pathology in spontaneously hypertensive rats. The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment .


sirolimus+

crizotinib

abraxane+

celecoxib

Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy. ### Patients And Methods Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis. ### results In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib . In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy. ### conclusions Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.


ifosfamide

etoposide

postoperative chemotherapy

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. ### methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m ### findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. ### interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival . The results define standard of care for this population. New strategies are required to improve outcomes in this setting. ### funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.


trastuzumab

lapatinib

Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib . Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21.


ceftriaxone

norfloxacin

Parenteral antibiotic prophylaxis of bacterial infections does not improve cost-efficacy of oral norfloxacin in cirrhotic patients with gastrointestinal bleeding. Selective intestinal decontamination with norfloxacin is useful in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding. However, bleeding cirrhotic patients with ascites, encephalopathy, or shock are at high risk to develop bacterial infections in spite of prophylactic norfloxacin. The aim of this study was to assess whether the addition of intravenous ceftriaxone could improve the efficacy of prophylaxis with norfloxacin in these patients. ### methods Fifty-six cirrhotic patients with gastrointestinal hemorrhage and ascites, encephalopathy, or shock were randomized into two groups: Group 1 (n = 28) received oral norfloxacin 400 mg/12 h for 7 days, and group 2 (n = 28) received norfloxacin plus intravenous ceftriaxone 2 g daily during the first 3 days of admission. ### results Ten patients were excluded because of community-acquired infection, surgery, or death within the first 24 h. The incidence of bacterial infections during hospitalization was 18.1% in group 1 and 12.5% in group 2 (p = NS). The incidence of severe infections (spontaneous bacterial peritonitis, bacteremia, or pneumonia) was also similar in both groups: 9% in group 1 versus 8.3% in group 2 (p = NS). There were no statistical differences between the two groups with respect to duration of hospitalization or mortality. The cost of antibiotic therapy (including prophylaxis and treatment of infections) was significantly higher in group 2. ### conclusion These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection .


clindamycin

lincomycin

Microbial kinetics of drug action against gram-positive and gram-negative organisms. III: Effect of lincomycin and clindamycin combinations on Staphylococcus aureus and Escherichia coli. The functional dependencies of apparent first-order generation rate constants kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli . The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show "equivalence" or "indifference" of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism.


aprinocarsen

gemcitabine

carboplatin

Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) . Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.


ceftazidime

amoxy-clavulanic

co-trimoxazole

doxycycline

Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India. Melioidosis, an infection due to gram negative Burkholderia pseudomallei, is an important cause of sepsis in east Asia especially Thailand and northern Australia. It usually causes abscesses in lung, liver, spleen, skeletal muscle and parotids especially in patients with diabetes, chronic renal failure and thalassemia. Musculoskeletal melioidosis is not common in India even though sporadic cases have been reported mostly involving soft tissues. During a two-year-period, we had five patients with musculoskeletal melioidosis. All patients presented with multifocal osteomyelitis, recurrent osteomyelitis or septic arthritis. One patient died early because of septicemia and multi-organ failure. All patients were diagnosed on the basis of positive pus culture. All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia . All other patients recovered completely with no recurrences. With increasing awareness and better diagnostic facilities, probably musculoskeletal melioidosis will be increasingly diagnosed in future.


lansoprazole

clarithromycin

Dual therapy with lansoprazole and clarithromycin for eradication of Helicobacter pylori.  To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin . ### Patients And Methods In an open therapeutic trial, 30 H. pylori-positive patients with active ulcer disease took 30 mg lansoprazole twice a day and 400 mg clarithromycin twice a day for the first 2 weeks, followed by 30 mg lansoprazole once a day for 4-6 weeks. Endoscopy was performed both before and at the end of therapy, and 4 weeks after the end of the therapy. H. pylori was detected by using a combination of smear, culture and tissue sections. ### results Complete pain relief occurred within 3 days in all patients and all ulcers were healed by the end of the therapy. The H. pylori clearance rate was 83.3% and the eradication rate was 73.3%. A minor side effect (metallic taste) was reported by only one patient (3.3%). ### conclusions Therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin is efficacious in the eradication of H. pylori and has the advantage of a low incidence of side effects and quick pain relief for patients with active ulcers.


vincristine

doxorubicin

cyclophosphamide

actinomycin-D

ifosfamide

etoposide

Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome. The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. ### methods Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. ### results The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks . In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ### conclusions Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.


sorafenib

sunitinib

Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). ### methods We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 . ### results Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Heng's risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. ### conclusion The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small.


pemetrexed

cetuximab

Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer.  We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer . ### Patients And Methods Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. ### results Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. ### conclusion The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.


darunavir

ritonavir

cobicistat

darunavir

etravirine

Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. ### methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. ### results etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. ### conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice .


paclitaxel

vinorelbine

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).  Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis . This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. ### methods Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m ### results The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. ### conclusion Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).


leucovorin

gemcitabine

cisplatin

Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 ) Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. ### methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m ### discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. ### Trial Registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.


terbutaline

budesonide

Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid, budesonide, with that of an inhaled beta 2-agonist, terbutaline, in the long-term treatment of newly detected asthma. ### methods We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day, and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. ### results After six weeks of treatment, the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step, P less than 0.001), and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value, 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group . The adverse reactions to both treatments were few and mild. ### conclusions Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected, mild asthma, and it is superior to the use of terbutaline in such patients.


propyphenazone

ethylmorphine

caffeine

dipyrone

diphenhydramine

adiphenine

aminobenzoate

[Electric stimulation of the dental pulp in the evaluation of the central effect of analgesics].  We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp . Constant voltage stimuli were delivered through silver chloride electrodes placed in contact with the vestibular surface of the upper medial incisor. At the beginning of the session, the pain input was graded by asking the subject to identify the weakest stimulus perceived (threshold level) and the strongest stimulus endurable (tolerance level). The range between threshold and tolerance level was divided in nine steps plus a subliminal step. The ten steps were delivered randomly, and each series of steps was repeated eight times. The subjects were instructed to rate the pain sensation in an arbitrary scale of 5 degrees. The procedure was repeated at 60 min and 180 min after drug administration. Each subject received two tablets of drug A or drug B in two different sessions at weekly intervals. Statistical analysis of the procedures showed that neither drug A nor drug B significantly affected the pain threshold. Drug A significantly reduced the total pain score (P less than 0.01) and its action peaked 60 min after administration.(ABSTRACT TRUNCATED AT 250 WORDS)


cetuximab

panitumumab

Hypomagnesemia is a reliable predictor for efficacy of anti-EGFR monoclonal antibody used in combination with first-line chemotherapy for metastatic colorectal cancer. Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. ### methods Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study . All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. ### results The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. ### conclusion Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients.


idarubicin

vepesid

cytarabine

Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes--first experience with their reversal. P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission . Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients.


Bavituximab

Carboplatin

Pemetrexed

Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer . bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC). ### Patients And Methods Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m ### results Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively. ### conclusion The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role.


isoniazid

rifampin

ethambutol

streptomycin

Multicenter laboratory evaluation of the MB/BacT Mycobacterium detection system and the BACTEC MGIT 960 system in comparison with the BACTEC 460TB system for susceptibility testing of Mycobacterium tuberculosis.  In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system . The arbitration of discrepant results was done by the reanalysis of the strain, the determination of the MIC, and the molecular characterization of some resistance determinants. The overall level of agreement with BACTEC 460TB results was 96% with the MB/BacT test and 97.2% with the BACTEC MGIT 960 system. With both methods, the level of agreement with BACTEC 460TB results was 96.3% for isoniazid, 98.8% for rifampin, and 98.8% for ethambutol. The level of agreement for streptomycin was 90.2% with MB/BacT and 97.5% with BACTEC MGIT 960. Overall, there were 11 very major errors and 2 major errors with the MB/BacT method and 5 very major errors and 2 major errors with the BACTEC MGIT 960 system. In general, the MB/BacT and BACTEC MGIT 960 systems showed good performance for susceptibility testing with first-line antituberculosis drugs.


Sunitinib

Sorafenib

Pazopanib

The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort. Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). ### objective To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. ### methods Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). ### results Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) . After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. ### conclusion The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.


imatinib

sunitinib

A gastrointestinal stromal tumour with pulmonary metastases mimicking unilateral gynaecomastia. Gastrointestinal stromal tumours (GISTs) represent 1% of primary gastrointestinal cancers. These neoplasms most frequently metastasise to the liver and peritoneum and rarely to the lungs and bones. Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs . We report the case of a 52-year-old man with GIST who developed a right-sided subareolar breast swelling and subsequently discovered to be an invasive metastatic pulmonary GIST. Given that gynaecomastia is a known adverse effect of imatinib and sunitinib, this case report illustrates the importance of including metastatic disease in the differential diagnosis of patients with GIST and with the new onset of soft tissue masses.


paclitaxel

topotecan

carboplatin

doxorubicin

carboplatin/cisplatin

Role of weekly paclitaxel in the treatment of advanced ovarian cancer. Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin . In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer.


temozolomide

docetaxel

Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma . ### Patients And Methods Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. ### results Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. ### conclusion The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.


verapamil

tamoxifen

Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer . Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study.


pembrolizumab

ipilimumab

Cost-effectiveness analysis of pembrolizumab compared to standard of care as first line treatment for patients with advanced melanoma in Hong Kong. pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-naïve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. ### methods A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer's perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. ### results In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 . ### conclusions pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong.


lapatinib

trastuzumab

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial . Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. ### methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. ### results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m ### conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. ### Trial Registration Number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.


ivermectin

abamectin

praziquantel

fenbendazole

A field study on the anthelmintic resistance of Parascaris spp. in Arab foals in the Riyadh region, Saudi Arabia. In the last decade, Parascaris spp. resistance to anthelmintics has been recorded in many countries. In Saudi Arabia, there are limited data available on Parascaris spp. resistance to anthelmintics. ### objective To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia . ### methods Three hundred and forty-one foals from eleven different farms were examined by faecal egg count (FEC). The foals were all Arab horses aged 17.2 ± 4.5 (SD) months. ivermectin (n = 46 foals), abamectin and praziquantel combined (n = 46), and fenbendazole (n = 46) were administered on day 0 and faeces were collected on day 14. The study comprised 41 untreated foals as controls. Animals that have FEC of ≥100 eggs per gram (EPG) were used to measure anthelmintic efficacy. Parascaris spp. populations were considered susceptible when faecal egg count reduction (FECR) was ≥95% associated with a lower 95% confidence limit (LCL) >90%, suspected resistant when FECR ≤90% or LCL <90% and resistant when FECR <90% and LCL <90%. ### results Prevalence of Parascaris spp. infection was 53% (179/341 horses). Anthelmintic resistance to Parascaris spp. were highest following fenbendazole (55% of farms and 65% of foals) and to a lower extent following ivermectin or the combination of abamectin and praziquantel which comprised 27% of farms (and 46% of foals) and 18% of farms (and 10% of foals), respectively. ### conclusion These data indicate that anthelmintics-resistant Parascaris spp. populations are present on horse farms in Saudi Arabia.


carboplatin

gemcitabine

Results of a Phase II study of carboplatin plus gemcitabine in patients with untreated extensive small cell lung cancer.  To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) . ### Patients And Methods Treatment consisted of carboplatin (AUC = 5) on day 1 and gemcitabine (1100 mg/m(2)) on days 1 and 8 of each 21-day cycle for 4 planned cycles (additional cycles allowed as per treating physician). ECOG performance status 0/1/2 was 29, 58, and 13%. Median age was 66.5 years (range: 41.3-83.1), 94% were white, and 50.7% were female. ### results Between August 2000 and February 2002, 69 patients with ESCLC were enrolled. All 69 patients were included in the safety analysis, and 66 patients were evaluable for response. There were 2 CR (3.0%), 26 PR (39.5%), 23 SD (34.8%), and 15 PD (22.7%) resulting in a RR of 42.5%. The median survival was 9.2 months (range: <1-22.6), and the estimated 1-year survival was 33%. The median TTP was 3.9 months (range: <1-12.8), and the estimated 6-month progression free survival was 24%. The median duration of response was 3.8 months (range: 1.0-9.9). Out of 69 patients, 29, 3, and 16 received 4, 5, and 6 cycles of therapy, respectively. The major Grade 3, 4 toxicities included neutropenia (39.1%), thrombocytopenia (31.9%), anemia (13.0%), and fatigue (4.3%). ### conclusion This regimen resulted in survival data that was similar to other regimens for ESCLC and treatment appeared to be well tolerated. gemcitabine in combination with carboplatin or other active drugs in ESCLC may be worth further investigation.


chloroquine

citalopram

Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo. citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents . citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.


Isoniazid

Pyrazinamide

Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide . Tuberculosis (TB) is one of the major health challenge in the world. The current treatment of TB needs daily administration of combined drug therapy for six or more months. Sometime non-adherence and less bioavailability from current therapy develops multidrug resistance, as a result, high dose requirement and subsequent intolerable toxicity are seen. Therefore, nanotechnology gained special attention as it has potential to improve patient compliance, bioavailability and reduction in dosing frequency. ### objective The aim of this study is to fabricate alginate-chitosan nanoparticles (AL-CS NPs) under appropriate conditions using ionic gelation method. The use of natural polymers in nanoparticle fabrication has a vast application due to their biodegradability, biocompatibility and nontoxic nature. Ionic gelation method involves the interaction between macromolecules with opposite charged ionizable groups forming polyelectrolyte complex. Hence, it is rational to formulate natural polymerbased sustained release nano-particulate matrix to improve patient adherence, reducing dose frequency and drug toxicity. ### method The formulations were based on 32 factorial designs. Nanoparticles of combined drug (isoniazid- INH and pyrazinamide-PYZ) were fabricated using natural polymer. Formulation process involved the use of pregelated sodium alginate followed by ionic gelation with chitosan. Pregelation of sodium alginate included calcium chloride. The effects of sodium alginate concentration and chitosan concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. ### results Optimized Batch-3s showed particle size 539.7 ± 2.33 nm, zeta potential -26.4 ± 0.55 mV, and entrapment efficiency is 70.21 ± 0.24% and 73.45 ± 0.21% of INH and PYZ, respectively. Dissolution release study of Batch-3s in 7.4 pH phosphate buffer exhibited the initial burst of 5.04 ±0.45% and 19.68 ± 0.87% at 0.25 hrs followed by slow, sustained release of drug 74.53 ± 2.53 and 57.87 ± 2.04% at 10 hrs of INH and PYZ, respectively. ### conclusion It concluded that chitosan (CS) and sodium alginate (AL) concentration are rate-limiting factors in formulation development. Natural polymer based combined drug nano-particulate system could be an innovative and optimistic approach in the treatment of TB.


topiramate

methamphetamine

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals. Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) . The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.


penicillin

clindamycin

metronidazole

gentamicin

Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups . Clinical isolates of the Bacteroides melaninogenicus and Bacteroides fragilis groups were tested for in vitro and in vivo susceptibility to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in vitro tests consisted of determinations of minimal inhibitory concentrations (MICs) carried out with or without constant amounts of gentamicin. When used alone, gentamicin had negligible effects on the bacteria but significantly reduced the MICs of penicillin, clindamycin, and metronidazole against 11, 10, and 3, of the 15 strains of the B. melaninogenicus group, respectively. The 15 strains of the B. fragilis group were all beta-lactamase producers and were highly resistant to penicillin or the combination of penicillin and gentamicin. However, gentamicin reduced the MICs of clindamycin and metronidazole against 1 and 7 strains of this group, respectively. The in vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the sizes and bacterial content of abscesses induced by subcutaneous injection of bacterial suspensions. The results of the in vivo tests were generally consistent with those obtained in vitro with strains of the B. melaninogenicus group. Synergism between gentamicin and penicillin, clindamycin, or metronidazole was shown in 13, 10, and 3 strains of this group, respectively. In vivo synergism was not clearly demonstrated with the strains of the B. fragilis group, possibly because clindamycin and metronidazole used alone were highly efficacious. We suggest that the synergistic effect of gentamicin is due to its increased transport into the bacterial cell in the presence of penicillin and, possibly, other antimicrobial agents. The newly recognized in vitro and in vivo synergism between penicillin and other antimicrobial agents and an aminoglycoside in B. melaninogenicus may have clinical implications that deserve to be investigated.


aspirin

heparin

heparin

Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model. To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. ### methods Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) . ### results Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. ### conclusions At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis.


evofosfamide

paclitaxel

Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth . Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.


Paclitaxel

vinorelbine

Phase I/II study of paclitaxel and vinorelbine in metastatic breast cancer.  Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer . Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in all three patients treated at the 6th dose level. Other toxicities were mild. paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing.


leptin

erythropoietin

Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Differentiated articular chondrocytes express a functional bisoform of the leptin receptor (LRb); however, leptin-LRb signaling in these cells is poorly understood. We hypothesized that leptin-LRb signaling in articular chondrocytes functions to modulate canonical Wnt signaling events by altering the expression of Frizzled (FZD) receptors. ### methods Human chondrocyte cell lines and primary articular chondrocytes were grown in serum containing growth media for 24h, followed by a media change to Dulbecco's modified Eagle's medium (DMEM) containing 1% Nutridoma-SP to obtain a serum-deficient environment for 24h before treatment. Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) . Cells were harvested 30min-48h after treatment and whole cell lysates were analyzed using immunoblots or luciferase assays. ### results Treatment of cells with leptin resulted in activation of Janus kinase 2 (JAK2) and subsequent phosphorylation of specific tyrosine residues on LRb, followed by dose- and time-dependent increases in the expression of Frizzled-1 (FZD1) and Frizzled-7 (FZD7). leptin-mediated increases in the expression of FZD1 were blocked by pre-treatment with the protein synthesis inhibitor cycloheximide or the JAK2 inhibitor AG490. Experiments using a series of hybrid Epo extracellular domain-leptin intracellular domain receptors (ELR) harboring mutations of specific tyrosine residues in the cytoplasmic tail showed that increases in the expression of FZD1 were dependent on LRb-mediated phosphorylation of STAT3, but not ERK1/2 or STAT5. leptin pre-treatment of chondrocytes prior to Wnt3a stimulation resulted in an increased magnitude of canonical Wnt signaling. ### conclusion These experiments show that leptin-LRb signaling in articular chondrocytes modulates expression of canonical Wnt signaling receptors and suggests that direct cross-talk between these pathways is important in determining chondrocyte homeostasis.