metronidazole

vancomycin

A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity. The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy ( RR=0.88 , 95 % CI=0.64 - 1.21 , p=0.43 ) . Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection.


etoposide

cytarabine

Stability and compatibility of a mixture of the anti-cancer drugs etoposide, cytarabine and daunorubicine for infusion. We evaluated (i) the stability of a mixture of the three anti-cancer agents used for the treatment of leukemia, namely etoposide, cytarabine and daunorubicine, in 5% glucose, and (ii) its compatibility towards various materials during an infusion protocol as performed for therapeutic purposes in hospital practice. etoposide and cytarabine were assayed by high-performance liquid chromatography with a C18 type column and UV detection. daunorubicine was assayed by visible spectrophotometry. The stability study showed all three anti-cancer drugs to be stable in 5% glucose solution, both alone and mixed. Best conservation was obtained by keeping bottles containing the mixture in the dark at room temperature. During the infusion protocol used in clinical practice , etoposide , cytarabine and daunorubicine were stable and compatible with the various materials present in the infusion sets and extension tubing ( polyvinyl chloride , polyethylene ) and catheters ( silicone ) . Observed variations in concentration did not exceed 10% of initial concentrations of each drug, though we would advocate changing infusion sets and extension tubing daily.


doxorubicin

etoposide

Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma. Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance. ### methods We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo. ### results First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control . Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo. ### conclusion Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.


amiodarone

carvedilol

[Correction of baroreflex sensitivity impairment and efficacy of prevention of sudden arrhythmic death in patients with postinfarction left ventricular dysfunction]. Baroreflex sensitivity was assessed in 287 patients with history of myocardial infarction and left ventricular ejection fraction < or =40% by phenylephrine test and was found to be depressed (4.44+/-0.38 ms/mm Hg). Repeat study in 3, 6 and 12 months revealed substantial improvement of baroreflex sensitivity in patients treated with perindopril especially when it was combined with amiodarone, metoprolol, bisoprolol and carvedilol but not with atenolol. Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality . Superiority of combination of amiodarone with lipophilic beta-adrenoblocker over monotherapy had been anticipate but was not confirmed in any of large prospective studies.


paclitaxel

carboplatin

bevacizumab

Efficacy of paclitaxel , carboplatin , and bevacizumab for cervical cancer : A protocol for systematic review and meta-analysis . Cervical cancer (CC) is a very common and malignant tumor in female population. Although a variety of single medications are reported to treat this condition, they all have limited efficacy. Previous studies have reported the combination of paclitaxel, carboplatin, and bevacizumab (PCB) can be used for the treatment of patients with CC effectively. However, no systematic review has explored its efficacy and safety. This study will address its efficacy and safety systematically and comprehensively. ### methods The following electronic databases will be retrieved from their inceptions to the January 1, 2020 to identify all potential associated studies: MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Google scholar, and Chinese Biomedical Literature Database. We will include randomized controlled trials (RCTs) of adult women (≥18 years) with CC globally. Eligible interventions will target any forms of PCB. The study methodological quality of all included studies will be appraised using Cochrane risk of bias tool. Statistical analysis will be undertaken using RevMan 5.3 software. In addition, we will perform a narrative synthesis to describe quality and content of the evidence. ### results This study will summarize recent evidence and provide quality evidence for the efficacy and safety of PCB on CC. ### conclusion The findings of this study will seek to identify the efficacy and safety of PCB and suggest future directions for research efforts targeting CC among this population. ### Systematic Review Registration INPLASY202040195.


azithromycin

doxycycline

Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. One hundred and twenty male patients with signs and symptoms compatible with non-gonococcal urethritis were enrolled in a prospective-randomized study to compare the efficacy and safety of a single oral-dose of 1 g azithromycin and a seven-day course of 100 mg doxycycline twice-daily. Clinical examination and culture samples for Chlamydia trachomatis were performed before and approximately 8, 15 and 35 days after starting treatment. Both treatment groups were comprised of 30 chlamydia-positive patients evaluable for efficacy. The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96 % with one persistent case , and 100 % in the doxycycline group . After about two weeks, there were two re-occurrences in the azithromycin group, resulting in a cumulative eradication rate of 90% with three culture-positive cases. The corresponding figure in the doxycycline group was still 100%, but there were leucocytes present in the urethral smear of two patients who later proved to be true culture-positive re-occurrences. After about five weeks, there was an additional re-occurrence in the azithromycin group leading to a cumulative eradication rate of 87%, while two re-occurrences in the doxycycline group gave a cumulative eradication rate of 93%. There was no statistically significant difference in efficacy between the single-dose azithromycin and seven-day course of doxycycline in the treatment of patients with chlamydial urethritis.(ABSTRACT TRUNCATED AT 250 WORDS)


sunitinib

pemetrexed

docetaxel

Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example , the overall objective response rate of 9.5 % with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients , but toxicity , notably fatigue , lead to discontinuation in 38 % of patients . Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.


erlotinib

erlotinib

sorafenib

sorafenib

Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. ### Patients And Methods Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone . Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. ### results Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. ### conclusions These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.


aflibercept

irinotecan

Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. ### Areas Covered A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. ### Expert Opinion In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment . Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.


paclitaxel

carboplatin

etoposide

Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active in previously untreated patients with small cell lung cancer (SCLC). We evaluated the toxicity and efficacy of a 1-hour infusion of paclitaxel added to a combination regimen of carboplatin and etoposide in a phase II trial for the treatment of patients with SCLC. Thirty-eight patients with previously untreated SCLC were treated with paclitaxel 135 mg/m2 (1-hour intravenous infusion), day 1; carboplatin at area under the concentration-time curve of 5, day 1; and oral etoposide 100 and 50 mg (alternating days), days 1 to 10. Treatment cycles were repeated every 21 days for a total of four courses. Patients with limited-stage disease received radiation therapy (4,500 cGy in 25 fractions) concurrently with the last two courses of chemotherapy. This outpatient combination was easily tolerated. Grade 3 or 4 leukopenia was experienced in only 8% of courses; grades 3 and 4 thrombocytopenia and anemia were also infrequent. Nonhematologic toxicity was uncommon, with the exception of transient esophagitis, which occurred in six of 15 patients (grade 3 in five patients, grade 4 in one) receiving concurrent chemoradiotherapy. Of 35 evaluable patients, 29 (83%) achieved a response to treatment. The complete response rate was 29% (40% in patients with limited-stage disease). Median survival was 7 months for patients with extensive-stage disease and 17 months in limited-stage patients. Prophylactic whole brain irradiation was not used, and seven patients developed brain metastases as their initial site of relapse. The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial . This treatment was highly active and the results are comparable to other standard regimens. Increased doses of both paclitaxel and carboplatin could probably be tolerated and are currently being evaluated. Precise definition of the role of paclitaxel in the treatment of SCLC will require randomized studies.


pemetrexed

gemcitabine

Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment. Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) . Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.


artesunate

mefloquine

An 11-year-old boy with Plasmodium falciparum malaria and dengue co-infection. Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites of Plasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved . However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications.


vinblastine

ifosfamide

cisplatin

Update on malignant ovarian germ cell tumors. The evolution of therapy for malignant ovarian germ cell tumors has been one of the true success stories in oncology. This article reviews the major advances in this field, with emphasis on more recent developments. During the past two decades, the nomenclature and histologic criteria for the major histologic subtypes have been standardized. Although the role of secondary debulking is uncertain, it probably has merit in selected patients. The use of second-look laparotomy should be limited as much as possible. Chemotherapeutic regimens have evolved to the current "gold standard"--the combination of bleomycin, etoposide, and cisplatin, with overall disease-free survival rates of greater than 95%. For patients with metastatic dysgerminoma, chemotherapy has replaced radiation therapy as the treatment of choice. For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors . For those with platinum-resistant tumors, dose intensification with autologous bone marrow rescue or Phase II drugs are being investigated. Studies on the late effects of treatment reveal that reproductive potential can be preserved in most young patients. In summary, although the progress in this field has been phenomenal, small incremental advances will continue to occur during the 1990s.


piperacillin

gentamicin

clarithromycin

erythromycin

minocycline

[Legionella pneumonia successfully treated despite late diagnosis]. Status asthmaticus developed in a 72-year-old man who was being treated with oral prednisolone for severe persistent asthma. The dosage of prednisolone was increased, and amikacin was injected to treat pneumonia that had developed in the right lung. Progressive pulmonary infiltrates, respiratory compromise, and hypoxemia developed, and the patient eventually required mechanical ventilation. Antibiotic treatment was changed to imipenem/cilastatin , piperacillin , gentamicin , clarithromycin , erythromycin , and minocycline . Liver injury developed. More than one month after the patient was admitted, Legionella pneumonia was diagnosed. levofloxacin (400 mg/day) was then given orally, in combination with injected imipenem/cilastatin. Liver function did not deteriorate, and the pneumonia resolved. Most diagnoses of Legionnaires' disease are made retrospectively by examination of serum. In this case, antibiotics active against Legionella pneumophila had been used before the diagnosis was established, which probably contributed to the patient's recovery. When aminoglycosides or beta-lactam antibiotics are ineffective, administration of agents effective against Legionnaires' disease should be considered.


vandetanib

paclitaxel

carboplatin

Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection. Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. ### methods Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) . ### results A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. ### conclusions vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.


tamoxifen

toremifene

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer . To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. ### Materials And Methods Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). ### results The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. ### conclusion The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.


etoposide

prednisone

vincristine

cyclophosphamide

doxorubicin

and cyclophospha

e , doxorub

n , vincris

and predni

HIV-associated plasmablastic lymphoma in the era of HAART: a single-center experience of 21 patients. Patients with HIV infection have an increased risk of developing plasmablastic lymphoma (PBL). In this study, we reviewed the clinicopathologic features of PBL in HIV+ patients in the era of HAART from a single health center. ### design Retrospective study. ### methods The morphologic, immunophenotypic, and clinical features were reviewed in these HIV+ patients with PBL and univariate analysis was employed to determine the survival prognosis. ### results During the interval of 1 January 2008 to 30 December 2018, we identified 95 HIV+ patients with aggressive non-Hodgkin B-cell lymphomas. Among these patients, there were 21 (22%) patients with PBL (19 men and two women; median age: 45 years). Seven patients had PBL at their initial HIV diagnosis and 14 developed PBL after a median interval of 7.7 months of HIV diagnosis. Lymph nodes (n = 10), oral cavity/sinonasal mass (n = 6), and rectal masses (n = 5) were the common involved sites, and five of 15 (33%) had bone marrow involvement. Lymphoma cells were immunoreactive for MUM-1/IRF4 (100%), CD138 (90%), CD45 (63%), CD79a (47%), and CD30 (25%). Proliferation rate assessed by Ki67 was at least 90% in 18 of 20 cases. Eighteen patients received chemotherapy including etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( n = 13 ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( n = 2 ) . With a median follow-up time of 19 months, nine out of 17 patients died. Bone marrow involvement was associated with a poorer overall survival (median: 4.7 months, P = 0.015). ### conclusion PBL is the second most common type of aggressive lymphoma and often presents in lymph nodes of patients with poorly controlled HIV infection. Bone marrow involvement is associated with a poorer outcome.


verapamil

doxorubicin

doxorubicin

Inhibitory effects of a calcium antagonist on ornithine decarboxylase induction in pancreatic cancer cell lines.  The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin . Because of our interest in polyamine biosynthesis and metabolism and the known involvement of calcium in the induction of ornithine decarboxylase (ODC) by serum refeeding of cultured cells, the effects of verapamil on the serum-stimulated ODC activity in two hamster pancreatic adenocarcinoma cell lines were examined. In plateau phase well-differentiated (WD) PaCa and poorly differentiated (PD) PaCa cells, a dose-dependent inhibition of the 4-h serum induction of ODC was seen at concentrations of 1, 5, and 10 microM verapamil. At the higher concentrations of verapamil, the inhibition of ODC induction was comparable to that achieved with 5 mM alpha-difluoromethylornithine (DFMO, a specific enzyme inhibitor of ODC) and greater than that seen with 2 mM EGTA plus calcium-depleted serum. Log phase PD PaCa cells, included for comparison, showed less ODC induction with serum and lesser degrees of inhibition of the response to serum refeeding with verapamil, DFMO, and calcium depletion. No direct inhibition of the ODC enzyme was found when verapamil was added at the time the activity was measured. Based on our present data, a possible influence of intracellular calcium pools in the verapamil effect on ODC activity is unclear. Nevertheless, the present findings suggest that verapamil's effects on cytotoxicity may be mediated (at least in part) by inhibition of the serum-mediated induction of ODC.


cetuximab

irinotecan

Current status of second-line therapy for metastatic colorectal cancer. Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients . The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC.


digoxin

flecainide

Direct fetal administration of adenosine for the termination of incessant supraventricular tachycardia. Adenosine terminates supraventricular reentry tachycardia safely and effectively in the pediatric age group. ### case The recurrence of pretreated incessant tachycardia led to severe hydrops in a 28-week-old fetus. The tachycardia was terminated instantly with direct fetal administration of adenosine via the umbilical vein. Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide . ### conclusion Direct fetal adenosine administration might be helpful in the treatment of fetal reentry tachycardias if the sinus rhythm achieved quickly can be preserved by long-acting antiarrhythmic drugs. Such a combined therapeutic approach might be especially advantageous in hydropic fetuses.


irinotecan

capecitabine

A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer . The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. ### Patients And Methods One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. ### results The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. ### conclusions irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.


vancomycin

TZP

vancomycin

cefepime

Incidence of Nephrotoxicity Among Pediatric Patients Receiving Vancomycin With Either Piperacillin-Tazobactam or Cefepime: A Cohort Study. Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime . ### methods We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group. ### results Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results. ### conclusion Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime.


etoposide

doxorubicin

cisplatin

mitotane

gemcitabine

capecitabine

streptozotocin

Adrenocortical carcinoma: current treatment options. In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). ### Recent Findings Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option . temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. ### summary ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.


ropivacaine

epinephrine

Effects of regional anesthesia with ropivacaine on arterial pressure and heart rate in healthy subjects. The anesthetic, ropivacaine, has been used extensively in clinical practice, but few studies have evaluated this long-acting local anesthetic in dentistry. In this study we evaluated the effects of ropivacaine alone and ropivacaine + vasoconstrictor on the cardiovascular system when used as a dental anesthetic in volunteers. Thirty-two healthy subjects received two consecutive infiltrations of 1.8 ml of either 0.75% ropivacaine or ropivacaine + epinephrine into the pterygomandibular region. Pain sensation, numbness of the lip, arterial pressure, heart rate, and electrocardiogram changes were monitored for 2 h. The onset of anesthesia was 10 min after the injection and lasted for more than 2 h, and numbness of the lip lasted for approximately 8 h. ropivacaine alone did not cause significant changes in the cardiovascular parameters, but ropivacaine + epinephrine caused a transient increase in arterial pressure and heart rate 2 min postinjection. We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect . This finding may be relevant to dentists endeavoring to find an anesthetic of minimal cardiovascular risk to produce regional anesthesia for long-lasting procedures without the need of a vasoconstrictor.


ethionamide

rifampin

capreomycin

kanamycin

streptomycin

ethambutol

ansamycin

Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs? The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and d-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to d-cycloserine. The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol . Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria.


gefitinib

capecitabine

Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer . The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). ### Methods And Patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. ### results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. ### conclusions capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.


ibrutinib

venetoclax

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.  Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma . Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. ### methods We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. ### results The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%). ### conclusions In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).


lomustine

temozolomide

dacarbazine

procarbazine

New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance.  The chloroethylating nitrosoureas ( lomustine , fotemustine , cystemustine ( BCNU ) and methylating agents temozolomide ( TMZ ) , dacarbazine ( DTIC ) , procarbazine ) have documented activity in metastatic malignant melanoma with single agent response rates of 15 - 25 % . Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.


chlortetracycline

sulfamethazine

sulfathiazole

Risk assessment of chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin in aquatic environment: are the current environmental concentrations safe? To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). In general, D. magna exhibited greater sensitivity than M. macrocopa, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline , sulfamethazine , or sulfathiazole in water fleas , but reduction in population size was not expected . In O. latipes, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by Daphnia and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation.


ifosfamide

paclitaxel

carboplatin

Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients. The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 . The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.


Ticlopidine

clopidogrel

The antiplatelet effects of ticlopidine and clopidogrel.  Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor . ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. clopidogrel was recently approved by the U.S. Food and Drug Administration for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease (incidence, 5.32% per year compared with 5.83% per year for aspirin; P = 0.043) with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the utility of clopidogrel in other patient populations and in stenting, requires further study. ticlopidine and clopidogrel seem to have beneficial effects compared with aspirin (the current standard) in a broad range of patients. These observations highlight the importance of antiplatelet therapy in cardiovascular disease.


Irinotecan

gemcitabine

Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer . This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. ### Patients And Methods Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. ### results Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). ### conclusion irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.


cyclophosphamide

doxorubicin

vincristine

prednisone

Lymphomatoid granulomatosis. Successful treatment with CHOP combination chemotherapy. A patient with lymphomatoid granulomatosis is reported. The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis . She obtained a complete remission and remains free of disease 3 1/2 years from the time of diagnosis. The favorable outcome in this patient may be related to her initial limited disease or to the use of initial intensive chemotherapy; nonetheless, the generally unfavorable prognosis of this disease appears to mandate early trials of intensive therapy in most patients.


linezolid

methadone

Serotonin syndrome due to co-administration of linezolid and methadone. Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature .


ipilimumab

vemurafenib

Vemurafenib  for the treatment of melanoma. Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene . ### Areas Covered The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma. ### Expert Opinion vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.


epinephrine

phentolamine

Epinephrine induces rapid deterioration in pulmonary oxygen exchange in intact, anesthetized rats: a flow and pulmonary capillary pressure-dependent phenomenon. Previous studies indicate epinephrine adversely affects arterial oxygenation when administered in a rat model of local anesthetic overdose. The authors tested whether epinephrine alone exerts similar effects in the intact animal. ### methods Anesthetized rats received a single intravenous injection of epinephrine ( 25 , 50 , or 100 mcg/kg ) ; matched cohorts were pretreated with phentolamine ( 100 mcg/kg ) ; n = 5 for each of the six treatment groups . Arterial pressure and blood gases were measured at baseline, 1 and 10 min after epinephrine administration. Pulmonary capillary pressures during epinephrine infusion with normal and increased flows were measured in an isolated lung preparation. ### results epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg. Rate pressure product was decreased by 10 min after 100 mcg/kg epinephrine. Pretreatment with phentolamine attenuated these effects except at 100 mcg/kg epinephrine. In the isolated lung preparation, epinephrine in combination with increased pulmonary flow increased pulmonary capillary pressure and lung water. ### conclusions Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. Effects were blunted by α-adrenergic receptor blockade. Edema occurred in the isolated lung above a threshold pulmonary capillary pressure when epinephrine treatment was coupled with an increase in pulmonary flow. These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.


Ipilimumab

Nivolumab

Ipilimumab

Chemotherapy

Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): ipilimumab, tremelimumab, nivolumab, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy . Four interventions were superior to chemotherapy in CR and PR (all OR > 1): nivolumab, pembrolizumab 10 mg/kg, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. However, the other seven interventions were associated with an increased risk of pruritus compared to chemotherapy (all OR > 1). ipilimumab, tremelimumab, ipilimumab + nivolumab and ipilimumab + Chemotherapy might result in a higher risk of diarrhea compared to chemotherapy (all OR > 1). Immune checkpoint therapy or combined interventions might be more effective than chemotherapy for managing melanoma patients. However, chemotherapy appears to be more tolerable than these combined strategies with respect to adverse events.


doxorubicin

cyclophosphamide

paclitaxel

Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants. To determine the accuracy with which Medicare claims data measure chemotherapy use in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We compared gold-standard clinical trial data for 175 elderly cancer patients treated in two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., 45 from trial 9344 and 130 from trial 9730) with contemporaneous ambulatory and in-patient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel . The lung trial participants studied were those elderly enrolled between 1998 and 2000 and treated with paclitaxel and carboplatin or paclitaxel alone. Comparing CALGB data with Medicare claims, we found the crude sensitivity for chemotherapy administration was 93% (95% confidence interval [CI] = 88% to 96%). Individual chemotherapy agents had similarly high sensitivities, ranging from 81% (95% CI = 70% to 89%) for carboplatin to 91% (95% CI = 79% to 98%) for cyclophosphamide. Agent-specific specificities were 100%. CMS data reliably captured repeat administration of chemotherapy to within one cycle. Administrative Medicare claims data appear to be a valid source of information for chemotherapy administered to elderly Medicare beneficiaries with cancer.


bleomycin

etoposide

doxorubicin

cyclophosphamide

vincristine

procarbazine

prednisone

PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.  The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities . Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. ### methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m ### findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). ### interpretation The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. ### funding Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.


bexarotene

denileukin diftitox

Interventions for mycosis fungoides. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. ### objectives To assess the effects of interventions for mycosis fungoides in all stages of the disease. ### Search Methods We searched the following databases up to January 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also checked reference lists of included studies for further references to relevant RCTs. We searched online trials registries for further references to unpublished trials and undertook a separate search for adverse effects of interventions for mycosis fungoides in non-RCTs in MEDLINE in May 2011. ### Selection Criteria Randomised controlled trials (RCTs) of interventions for mycosis fungoides in people with any stage of the disease. At least 90% of participants in the trials must have been diagnosed with mycosis fungoides (Alibert-Bazin-type). ### Data Collection And Analysis Two authors independently assessed eligibility and methodological quality for each study and carried out data extraction. We resolved any disagreement by discussion. Primary outcomes were the impact on quality of life and the safety of interventions. When available, we reported on our secondary outcomes, which were the improvement or clearance of skin lesions, disease-free intervals, survival rates, relapse rates, and rare adverse effects. When possible, we combined homogeneous studies for meta-analysis. We used The Cochrane Collaboration's 'Risk of bias' tool to assess the internal validity of all included studies in six different domains. ### Main Results The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only (please see Table 1 for definitions of these stages).Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis.Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs.Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. ### Authors Conclusions This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.


spiramycin

pyrimethamine

azithromycin

[In vitro effect of combined traditional Chinese medicine (Changqing capsule) on the tachyzoites of Toxoplasma gondii]. To detect the in vitro effect of the traditional Chinese medicine on the tachyzoites of Toxoplasma gondii. ### methods Supernatant (1.5 ml) of different doses of the traditional Chinese medicine (Changqing capsule) was collected by normal saline immersion and 2.5 x 10(4) Toxoplasma gondii tachyzoites were added in each paste well for 8 hours. spiramycin, pyrimethamine and azithromycin in different doses were used as controls. Normal saline was used as negative control. Mice were inoculated with drug-treated tachyzoites intraperitoneally or intragastrically. The normal mice were subcultured after 8 days for 3 generations. ### results The incident number of the infected mice was significantly different among groups with different drugs and doses : 2/60 , 16/60 , 10/60 and 10/60 in the groups of Changqing capsule , spiramycin , pyrimethamine and azithromycin respectively ( P < 0.05 ) . No mice were found incident in groups of high and medium dose Changqing capsule while 2 out of 20 found sick in the low dose group (P < 0.05). The subculture observation showed that 2 and 1 mice in the first generation of the low dose Changqing capsule group inoculated intraperitonelly and intragastrically were found infected respectively. 2 mice of the second generation in low dose spiramycin group and 1 mouse of the third generation in low dose pyrimethamine group were also found infected. ### conclusion The in vitro killing effect of the Changqing capsule on the tachyzoites of Toxoplasma gondii is better than the current clinical drugs and shows a positive correlation with the dosages.


Chloroquine

Mefloquine

Mefloquine

artesunate

Proguanil

Pyrimethamine

amodiaquine

Safety and effectiveness of antimalarial therapy in sickle cell disease: a systematic review and network meta-analysis. About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients. ### methods We searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square. ### results Six qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total , seven different interventions ( Chloroquine , Mefloquine , Mefloquine artesunate , Proguanil , Pyrimethamine , Sulfadoxine-pyrimethamine , Sulfadoxine-pyrimethamine amodiaquine ) were evaluated in 912 children with SCD . Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267-1.959; I ### conclusion The data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients. ### Systematic Review Registration PROSPERO (CRD42016052514).


bortezomib

carfilzomib

ixazomib

Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors. While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib , carfilzomib , or ixazomib . Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM.


valsartan

amlodipine

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART. The valsartan amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However , we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group . There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.


chloroquine

mefloquine

quinine

Effects of chloroquine , mefloquine and quinine on natural killer cell activity in vitro . Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF) or interleukin 2 (Il-2); preincubation of mononuclear cells with IF or Il-2 followed by addition of anti-malarial drugs decreased the inhibitory effects of the drugs. The drug-induced inhibition of the NK cell activity was not dependent on the presence of monocytes. Using monocyte depleted Percoll fractionated NK cell enriched populations in a single cell agarose assay, it was shown that the inhibitory effects of mefloquine, but not of chloroquine and quinine were due to an inhibition of the formation of effector/target cell conjugates.


Fulvestrant

anastrozole

Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials. fulvestrant ('Faslodex') is a new type of endocrine treatment--an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. Early efficacy data from phase I/II trials have demonstrated fulvestrant to be effective and well tolerated. Two randomised phase III trials have compared the efficacy of fulvestrant and the aromatase inhibitor, anastrozole, in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy. Fulvestrant ( intramuscular injection 250 mg month(-1 ) ) was found to be at least as effective as anastrozole ( orally 1 mg day(-1 ) ) for time to progression ( 5.5 vs 4.1 months , respectively ( hazard ratio ( HR ): 0.95 ; 95.14 % confidence interval ( CI ) , 0.82 - 1.10 ; P=0.48 ) ) and objective response 19.2 vs 16.5 % , respectively ; treatment difference 2.75 % ; 95.14 % CI , -2.27 to 9.05 % ; P=0.31 ) . More recently, fulvestrant has also been shown to be noninferior to anastrozole in terms of overall survival, with median time to death being 26.4 months in fulvestrant-treated patients and 24.2 months in those treated with anastrozole (HR: 0.97; 95% CI, 0.78-1.21; P=0.82). In a further randomised phase III trial, fulvestrant was compared with tamoxifen as first-line therapy for advanced disease in postmenopausal women. In the overall population, efficacy differences favoured tamoxifen and noninferiority of fulvestrant could not be ruled out. In the prospectively defined subset of patients with ER-positive and/or progesterone receptor-positive disease, there was no statistically significant difference between fulvestrant and tamoxifen. This paper reviews the efficacy and tolerability results from these trials.


doxorubicin

trastuzumab

Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients. Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. ### methods We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. ### results Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. ### conclusions Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.


paclitaxel

carboplatin

Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer. This ongoing phase I study sought to establish the maximum tolerated dose of the combination of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. paclitaxel was administered as a 3-hour intravenous infusion. The carboplatin infusion was administered over 30 minutes immediately afterward. Patients were assigned sequentially to one of eight treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 185 mg/m2 and from 230 to 350 mg/m2, respectively. Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 . The combination has an excellent safety profile, with only a few, short-lasting episodes of neutropenia observed and no evidence of infection. At the doses tested, thrombocytopenia has not occurred.


mitoxantrone

etoposide

cytarabine

Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. Determining in vitro drug resistance may reveal clinically relevant information in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 children with acute myeloid leukemia (AML) and 536 children with acute lymphoblastic leukemia (ALL). The differences between 3 French-American-British (FAB) types (M1/M2, M4, and M5) were also compared. AML was significantly more resistant than ALL to the following drugs, as noted by the median resistance: glucocorticoids (greater than 85-fold), vincristine (4.4-fold), L-asparaginase (6.9-fold), anthracyclines (1.8- to 3.4-fold), mitoxantrone (2.6-fold), etoposide (4.9-fold), platinum analogues (2.4- to 3.4-fold), ifosfamide (3.5-fold), and thiotepa (3.9-fold). For cytarabine and thiopurines, the median LC50 values (the drug concentration that kills 5% of the cells) were equal. Also, busulfan, amsacrine, teniposide, and vindesine showed no significant differences, but the numbers were smaller, and the median LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs demonstrated greater cytotoxicity in AML. FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML , as indicated by the following ratios of median sensitivities : the anthracyclines ( 2.6- to 3.2-fold ) , mitoxantrone ( 12.5-fold ) , etoposide ( 8.7-fold ) , and cytarabine ( 2.9-fold ) . For etoposide and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-asparaginase and vincristine as ALL. Only 15% of the AML samples were "intermediately" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer prognosis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance profiles may be helpful in the rational design of further treatment protocols. (Blood. 2000;96:2879-2886)


Aztreonam

gentamicin

piperacillin

[ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] . Fourty-two febrile episodes of 32 patients with hematologic disease during neutropenia were treated with two randomly assigned antibiotic combinations of either piperacillin plus gentamicin or piperacillin plus aztreonam. Eleven of the 22 febrile episodes treated with piperacillin plus gentamicin and 12 of the 20 febrile episodes treated with piperacillin plus aztreonam responded. Addition of cefamandole to non-responders improved the outcome in 2 of the 16 febrile episodes. Mean nadir leucocyte count, age, sex, and underlying disease were not significantly different in both groups. Side effects were tolerable in both groups, although 1 patient treated with piperacillin plus gentamicin showed severe renal impairment. piperacillin plus aztreonam is as effective as piperacillin plus gentamicin as an empiric antibiotic combination in the treatment of febrile episodes with hematologic disease during neutropenia.


salbutamol

digoxin

Effect of salbutamol on digoxin pharmacokinetics. A single dose of the beta 2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a beta 2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man . Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 micrograms.kg-1.h-1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 micrograms.kg-1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0-6 h was 15% lower during salbutamol infusion than during saline infusion. salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium.(ABSTRACT TRUNCATED AT 250 WORDS)


Mecamylamine

nicotine

Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD). Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance . These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD.


leflunomide

cyclosporin

Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis .