granisetron

palonosetron

Biochronomer™ technology and the development of APF530, a sustained release formulation of granisetron. granisetron and other 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are first-line agents for preventing chemotherapy-induced nausea and vomiting (CINV). Current treatment guidelines prefer the longer-acting agent, palonosetron, for CINV prevention in some chemotherapy regimens. A new granisetron formulation, APF530, has been developed as an alternative long-acting agent. APF530 utilizes Biochronomer(™) technology to formulate a viscous tri(ethylene glycol) poly(orthoester)-based formulation that delivers - by single subcutaneous (SC) injection - therapeutic granisetron concentrations over 5 days. The poly(orthoester) polymer family contain an orthoester linkage; these bioerodible polymer systems are specifically designed for controlled, sustained drug delivery. Pharmacokinetics and pharmacodynamics of APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively) administered 30-60 minutes before chemotherapy were evaluated in two Phase II trials in cancer patients receiving moderately (MEC) or highly (HEC) emetogenic chemotherapy. Pharmacokinetics were dose proportional, with slow granisetron absorption and elimination. Both trials demonstrated similar results for median half-life, time to maximum concentration, and exposure for APF530 250 and 500 mg, with no differences between patients receiving MEC or HEC. A randomized Phase III trial demonstrated noninferiority of APF530 500 mg SC ( granisetron 10 mg ) to intravenous palonosetron 0.25 mg in preventing CINV in patients receiving MEC or HEC in acute ( 0 - 24 hours ) and delayed ( 24 - 120 hours ) settings , with activity over 120 hours . Mean maximum granisetron plasma concentrations were 10.8 and 17.8 ng/mL, and mean half-lives were 30.8 and 35.9 hours after SC administration of APF530 250 and 500 mg, respectively. Therapeutic granisetron concentrations were maintained for greater than 120 hours (5 days) in both APF530 dose groups. These data suggest that APF530 - an SC-administered formulation of granisetron delivered via Biochronomer technology - represents an effective treatment option for the prevention of both acute and delayed CINV in patients receiving either MEC or HEC.


naproxen

celecoxib

rofecoxib

Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen , celecoxib and rofecoxib in AD clinical trials . Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.


vincristine

methotrexate

Survival of adults treated for medulloblastoma using paediatric protocols. We retrospectively studied 26 consecutive adults treated for medulloblastoma using paediatric protocols. Between 1987 and 2003 , patients 18 years old were given adjuvant chemotherapy consisting of one of two ' paediatric ' regimens ( depending on the time of presentation ) and craniospinal local-boost radiotherapy : regimen A ( n = 12 ) , vincristine ( VCR ) , intrathecal and/or intravenous methotrexate and conventional radiotherapy ; or regimen B ( n = 11 ) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy ( HART ) . A VCR-lomustine-based maintenance followed both regimens. Three additional patients received a tailored treatment due to their impaired neurological status after surgery. The median age at diagnosis was 26 years (range 18-41 years). With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65+/-11% and 73+/-10%, respectively, for the series as a whole. All patients who received regimen B (5 of whom had metastatic Chang M2-M3 disease) are alive with no evidence of disease at 39 months. Although the number of patients is limited, our data suggest that the sandwich sequential, moderately intensive chemotherapy in combination with HART is an effective treatment for medulloblastoma in adults, and this approach seems to overcome previously-recognised risk factors.


omeprazole

clopidogrel

Proton pump inhibitor and clopidogrel interaction: fact or fiction? Current consensus recommendations state that patients prescribed clopidogrel plus aspirin should receive a proton pump inhibitor (PPI) to reduce gastrointestinal bleeding. clopidogrel is converted to its active metabolite by cytochrome P450 (CYP) enzymes. clopidogrel users with decreased CYP2C19 function have less inhibition of platelet aggregation and increased cardiovascular (CV) events. As PPI metabolism also involves CYP2C19, it was hypothesized that competition by PPIs might interfere with clopidogrel's action. omeprazole, but not other PPIs, worsens surrogate markers of clopidogrel efficacy. Some (but not all) observational studies show that clopidogrel users prescribed PPIs have increased risks of CV events (hazard/odds ratios=1.25-1.5). When effect sizes are small to moderate (relative risks<1.5-2.0), however, it is only possible to conclude whether statistical associations are valid in randomized trials. A randomized trial of omeprazole vs. placebo in clopidogrel users showed no difference in CV events (hazard ratio=1.02,0.70-1.51). Thus, current evidence does not justify a conclusion that PPIs are associated with CV events among clopidogrel users, let alone a judgment of causality. Nonetheless, positive results from some observational studies and biological plausibility have led some health-care providers to accept that PPIs reduce clopidogrel's efficacy. The US Food and Drug Administration ( FDA ) recommends that " concomitant use of drugs that inhibit CYP2C19 ( e.g. , omeprazole ) should be discouraged . " As the presence of PPIs and clopidogrel in plasma is short lived , separation by 12 - 20 h should in theory prevent competitive inhibition of CYP metabolism and minimize any potential , though unproven , clinical interaction . PPI may be given before breakfast and clopidogrel at bedtime, or PPI may be taken before dinner and clopidogrel at lunchtime.


cyclophosphamide

rituximab

pentostatin

Long-term overall- and progression-free survival after pentostatin , cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma . In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL.


isoniazid

rifapentine

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine.  Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection . This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. ### methods This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. ### results The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. ### conclusions The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. ### Clinical Trials Registration NCT02771249.


docetaxel

vinblastine

doxorubicin

cisplatin

paclitaxel

docetaxel

vinblastine

The Upregulation of PI3K/Akt and MAP Kinase Pathways is Associated with Resistance of Microtubule-Targeting Drugs in Prostate Cancer. Resistance is a significant limitation to the effectiveness of cancer therapies. The PI3K/Akt and MAP kinase pathways play important roles in a variety of normal cellular processes and tumorigenesis. This study is designed to explore the relationship of these signaling pathways with multidrug resistance in prostate cancer (PCa). The PI3K/Akt and MAP kinase pathways were investigated utilizing paclitaxel resistant DU145-TxR PCa cells and their parental non-resistant DU145 cells to determine their relationship with resistance to paclitaxel and other anticancer drugs. Our results demonstrate that the PI3K/Akt and MAP kinase pathways are upregulated in DU145-TxR cells compared to the DU145 cells. Inactivating these pathways using the PI3K/Akt pathway inhibitor LY294002 or the MAP kinase pathway inhibitor PD98059 renders the DU145-TxR cells more sensitive to paclitaxel. We investigated the effects of these inhibitors on other anticancer drugs including docetaxel , vinblastine , doxorubicin , 10-Hydroxycamptothecin ( 10-HCPT ) and cisplatin and find that both inhibitors induces DU145-TxR cells to be more sensitive only to the microtubule-targeting drugs ( paclitaxel , docetaxel and vinblastine ) . Furthermore, the treatment with these inhibitors induces cleaved-PARP production in DU145-TxR cells, suggesting that apoptosis induction might be one of the mechanisms for the reversal of drug resistance. In conclusion, the PI3K/Akt and MAP kinase pathways are associated with resistance to multiple chemotherapeutic drugs. Inactivating these pathways renders these PCa cells more sensitive to microtubule-targeting drugs such as paclitaxel, docetaxel and vinblastine. Combination therapies with novel inhibitors of these two signaling pathways potentially represents a more effective treatment for drug resistant PCa.


doxorubicin

cyclophosphamide

Comparison of two consecutive trials for treatment of childhood non-Hodgkin's lymphoma. Two consecutive trials for the treatment of childhood non-Hodgkin's lymphoma were evaluated, carried out by the same cooperative groups. Group A: From June, 1973 to December, 1975, 50 evaluable patients under 16 years of age participated in a study that included vincristine and prednisone plus surgery and/or radiotherapy as induction. This was followed by 2400 rad of cranial radiotherapy plus 5 doses of intrathecal methotrexate-dexamethasone and anti-leukemia (6-mercaptopurine, methotrexate, cyclophosphamide) or anti-lymphoma (cyclophosphamide, vincristine, procarbazine, and prednisone) maintenance treatment. Group B : From January , 1976 to December , 1980 , 55 evaluable patients participated in a consecutive study that added Adriamycin ( doxorubicin ) and cyclophosphamide to the former induction regimen . Central nervous system (CNS) prevention was performed with 5 doses of intrathecal methotrexate-dexamethasone. Maintenance treatment was the same. Prognostic factors as stage and primary site were comparable in both groups. A total of 33 (66%) of 50 children of Group A and 48 (87%) of 55 children of Group B achieved complete remission (P less than 0.005). Disease-free survival at 60 months was 27% in Group A and 49% in Group B; for Stage I-II, 30% in Group A and 85% in Group B (P less than 0.025); for Stage III-IV 28% in Group A and 36% in Group B (not significant). In Group A, 9.1% and in Group B, 8.3% had primary CNS relapse. Both maintenance schedules had the same relapse rate. It was concluded that: (1) the addition of Adriamycin and cyclophosphamide to vincristine-prednisone in Group B produces a higher rate of complete remission in Stage III-IV, a higher rate of disease-free survival in Stage I-II, and a higher survival rate in all stages; (2) CNS prevention with intrathecal methotrexate-dexamethasone is equally effective as cranial radiation plus intrathecal methotrexate-dexamethasone; and (3) anti-leukemia and anti-lymphoma maintenance are equally effective in the context of this study.


amitriptyline

nortriptyline

Pharmacokinetics of amitriptyline influenced by oral charcoal and urine pH. The effects of orally given activated charcoal, sodium bicarbonate and ammonium chloride on the pharmacokinetics of amitriptyline were studied in 6 volunteers in a randomized, cross-over study. The serum and urine concentrations of amitriptyline and nortriptyline were determined by HPLC for up to 72 h. activated charcoal (50 g), given within 5 min of the amitriptyline hydrochloride dose (75 mg), reduced its absorption by 99%. When given in repeated doses from 6 h on , 50 g followed by 12.5 g at 6-h intervals , charcoal shortened the serum half-life of amitriptyline by 20 % and that of nortriptyline by 35 % ( p less than 0.05 ) . The renal excretions of amitriptyline and nortriptyline increased 1000-fold by the acidification of urine pH to 4. However, the cumulative excretion of amitriptyline and nortriptyline even into acidic urine only accounted for up to 5% of the dose during 72 h. Since urinary pH has a great influence on the ratio of urinary versus serum amitriptyline and nortriptyline concentrations, pH should be taken into consideration, when the clinical significance of their concentrations in urine is evaluated. activated charcoal in adequate doses very effectively prevents the absorption of that fraction of amitriptyline which is in the stomach at the time of charcoal administration. Furthermore, given in repeated oral doses, charcoal increases, to some extent, the rate of elimination of amitriptyline and nortriptyline, probably by interrupting their enterohepatic or enteroenteric circulation.


docetaxel

paclitaxel

A phase II randomized study of two taxanes and cisplatin for metastatic breast cancer after anthracycline: a final analysis. The purpose of the study is to compare two taxanes/cisplatin combinations for metastatic breast cancer in terms of time to disease progression, response rates and toxicity. ### methods Between April 2000 and December 2002, 101 patients with advanced breast carcinoma, previously treated with an anthracycline but not with a taxane, were enrolled. Fifty patients were treated with docetaxel 60 mg/m2 and cisplatin 50 mg/m2, and 51 patients were treated with paclitaxel 175 mg/m2 and cisplatin 50 mg/m2. Each cycle repeated every 3 weeks. ### results The overall response rate was 62.5 and 42.6% in the docetaxel and palcitaxel groups respectively (P = 0.06). Median time to disease progression was 9.8 and 6.5 months in docetaxel and paclitaxel groups respectively (P = 0.15). The median overall survival time was 22.7 months in the docetaxel arm and 22.4 months in the paclitaxel arm . Grade 3/4 arthralgia/myalgia, sensory neuropathy and anemia occurred more frequently in the paclitaxel arm, while more mucositis, fatigue and neutropenia occurred in the docetaxel arm. ### conclusion Taxane/cisplatin combinations were active for advanced breast cancer, while there appeared to be evidence in favor of a docetaxel/cisplatin combination. The toxicity in favor of docetaxel/cisplatin warrants future first-line clinical trials.


alisertib

abiraterone

A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone. Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. ### background We hypothesized that Aurora A kinase ( AK ) contributes to castrate resistance in prostate cancer ( PCa ) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor ( AR ) inhibitor abiraterone . ### methods This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design. ### results Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. ### conclusion A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.


Tanespimycin

trastuzumab

trastuzumab

Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. ### Patients And Methods Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. ### results Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. ### conclusion Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2 + breast cancer whose tumors have progressed during treatment with trastuzumab . These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.


mefloquine

chloroquine

chloroquine

proguanil

Tolerability and Effectiveness of Malaria Chemoprophylaxis with Mefloquine or Chloroquine with or without Co-medication. Background: To determine the relevance of drug interactions with co-medication for effectiveness and tolerability of antimalarial chemoprophylaxis. Method: A database (MALPRO2) on travelers on their flight home from Africa to Europe between July 1988 and December 1991 was reanalyzed. It contains data on prophylaxis with mefloquine ( n = 48,264 ) , with chloroquine ( 6,752 ) , with chloroquine plus proguanil ( 19,727 ) , and with no prophylaxis ( 3,871 ) . The comparison of rates of malaria incidence and adverse events (AEs) between users and nonusers of co-medication was expressed by relative risk (RR). Results: Fifty-three percent of travelers (63% of females, 43% of males) used co-medication in all prophylaxis groups, with an average of 1.35 additional drugs per person and about two AEs reported per person. With the exception of antidiarrheals plus mefloquine, malaria incidence with co-medication was lower (RR = 0.8) than without co-medication. In all regimens, the proportion of travelers reporting AEs was about 1.5-fold with co-medication (p<.01); that reporting severe AEs was twice as high as compared to with no co-medication. mefloquine AE rates for various classes of co-medication were similar to that of chloroquine, with highest AE and severity rates with neuropsychiatric drugs (excluding antiepileptics, RR = 1.9 and 2.9), and lowest rates with cardiovasculars (RR = 1.1 and 1.0). Various co-medications were used with different frequencies in males and females, and the latter reported more AEs. Conclusion: These data suggest that co-medications commonly used by travelers have no significant clinical impact on safety and effectiveness of prophylaxis with mefloquine or chloroquine. Increased frequency and severity of AEs when using co-medication rather is explained by underlying illness.


phenytoin

methylprednisolone

Thiopental combination treatments for cerebral resuscitation after prolonged cardiac arrest in dogs. Exploratory outcome study. We postulate that mitigating the multifactorial pathogenesis of postischemic encephalopathy requires multifaceted treatments. In preparation for expensive definitive studies, we are reporting here the results of small exploratory series, compared with historic controls with the same model. We hypothesized that the brain damage mitigating effect of mild hypothermia after cardiac arrest can be enhanced with thiopental loading , and even more so with the further addition of phenytoin and methylprednisolone . Twenty-four dogs (four groups of six dogs each) received VF 12.5 min no-flow, reversed with brief cardiopulmonary bypass (CPB), controlled ventilation to 20 h, and intensive care to 96 h. Group 1 with normothermia throughout and randomized group 2 with mild hypothermia (from reperfusion to 2 h) were controls. Then, group 3 received in addition, thiopental 90 mg/kg i.v. over the first 6 h. Then, group 4 received, in addition to group 2 treatment, thiopental 30 mg/kg i.v. over the first 90 min (because the larger dose had produced cardiopulmonary complications), plus phenytoin 15 mg/kg i.v. at 15 min after reperfusion, and methylprednisolone 130 mg/kg i.v. over 20 h. All dogs survived. Best overall performance categories (OPC) achieved (OPC 1 = normal, OPC 5 = brain death) were better in group 2 than group 1 (< 0.05) and numerically better in groups 3 or 4 than in groups 1 or 2. Good cerebral outcome (OPC 1 or 2) was achieved by all six dogs only in group 4 (P < 0.05 group 4 vs. 2). Best NDS were 44 +/- 3% in group 1; 20 +/- 14% in group 2 (P = 0.002); 21 +/- 15% in group 3 (NS vs. group 2); and 7 +/- 8% in group 4 (P = 0.08 vs. group 2). Total brain histologic damage scores (HDS) at 96 h were 156 +/- 38 in group 1; 81 +/- 12 in group 2 (P < 0.001 vs. group 1); 53 +/- 25 in group 3 (P = 0.02 vs. group 2); and 48 +/- 5 in group 4 (P = 0.02 vs. group 2). We conclude that after prolonged cardiac arrest, the already established brain damage mitigating effect of mild immediate postarrest hypothermia might be enhanced by thiopental, and perhaps then further enhanced by adding phenytoin and methylprednisolone.


Artesunate

Dihydroartemisinin

Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma. Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms , mainly based on increased oxidative stress , result from 2-methoxyestradiol , Artesunate , ascorbic acid , Dihydroartemisinin , Evodiamine , b-AP15 , VLX1570 , Erw-ASNase , and TAK-242 . Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.


bortezomib

gemcitabine

gemcitabine

Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer. Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor κB (NF-κB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor. ### methods The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo. ### results vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model , more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone . The down-regulation of pAkt and suppression of NF-κB activity was induced by the triple combination. ### conclusions The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-κB seems to be involved in this process.


afatinib

bevacizumab

Combination therapy with afatinib and bevacizumab in an EGFR-mutated non-small cell lung cancer patient with acquired ERBB2 amplification: A case report. Acquired resistance to reversible EGFR tyrosine kinase inhibitors remains a significant obstacle, and acquired ERBB2 amplification is the most common "bypass" mechanism. For patients with sensitizing EGFR mutation who experience resistance via ERBB2 amplification, no targeted drug has been demonstrated to be effective. ### Patient Concerns A 56-year-old female nonsmoker suffered from left leg paralysis and low back pain. Imaging examination revealed a mass in the anterior segment of the right upper lobe lung and possible multiple metastases in the right hilar, mediastinal lymph nodes, bone metastases, and soft tissue invasion. ### diagnosis Transbronchial lung biopsy revealed a moderately differentiated adenocarcinoma (cT4N2M1c, stage IV). An EGFR exon 19 deletion was identified using amplification refractory mutation system. ### interventions After the patient was treated with gefitinib initiation (250 mg/d) for 15 months, the tumor progressed with ERBB2 amplification revealed by next-generation sequencing test. Then, the patient was started on afatinib (40 mg/d) plus bevacizumab (7.5 mg/kg every 3 weeks). ### outcomes The combination therapy of afatinib and bevacizumab in this patient was effective with some slight side effects. Computed tomography scans showed the tumor shrinkage and the pleural effusion disappeared in the right lung. The overall survival was 23.5 months. ### conclusion To date, there is no targeted therapy approved and demonstrated to be effective for non-small cell lung cancer patients with EGFR sensitizing mutations, and ERBB2 amplification. The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients .


enzalutamide

docetaxel

abiraterone

Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone . The optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone. ### methods We performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups. ### results Compared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups. ### conclusions Treatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.


cyclophosphamide

prednisone

cyclophosphamide

prednisone

Therapy for vasculitic neuropathies. The term vasculitis refers to a pathologic condition defined by inflammatory cell infiltration and destruction of blood vessels. Systemic vasculitis is classified as primary (eg, polyarteritis nodosa, Churg-Strauss syndrome) or secondary, the latter associated with connective tissue disorders, infections, medications, and rarely, as a paraneoplastic phenomenon. Neuropathy is a common complication of systemic vasculitis and is related to ischemic nerve fiber damage with axon loss. Peripheral neuropathy may be the sole manifestation of vasculitis, a condition termed nonsystemic vasculitic neuropathy (NSVN). Treatment of vasculitic neuropathy requires long-term immunosuppressive therapies with potential side effects. The diagnosis of vasculitis should be established by tissue (preferably nerve) biopsy. High-dose prednisone is the standard platform therapy for patients with systemic and NSVN; for those with systemic vasculitis, at least 3 to 12 months of treatment with cyclophosphamide (monthly intravenous pulse or daily oral therapy) is also necessary to sustain remission and allow successful prednisone tapering. The use of cyclophosphamide in patients with NSVN is controversial , but recent retrospective data suggest that those treated with prednisone and cyclophosphamide from the outset fare better than those initially treated only with prednisone . If prednisone is administered as monotherapy, cyclophosphamide should be added after several months if there is no improvement or relapse occurs with tapering of prednisone. Intravenous pulse and daily oral cyclophosphamide probably offer similar efficacy, although the risk of complications is greater with oral therapy. azathioprine can be safely substituted for cyclophosphamide after 3 months without an increased relapse rate. azathioprine, methotrexate, intravenous immune globulin, mycophenolate mofetil, plasma exchange, and rituximab can be offered to patients who are intolerant or have a contraindication to cyclophosphamide. However, efficacy is unproven for any of these therapies. Interferon-alpha, sometimes combined with plasma exchange, is used to treat vasculitis associated with hepatitis B infection. Some patients also may improve with corticosteroids. The classification of diabetic lumbosacral radiculoplexus neuropathy as a vasculitic disorder remains controversial. However, there is compelling pathological evidence that this condition represents a T-cell-mediated microvasculitis. Some patients treated with intravenous corticosteroids may have greater recovery and improved pain control.


cediranib

gefitinib

cediranib

Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. ### Methods And Findings This was a multi-center randomized , two-armed , double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy . The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. ### conclusions cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. ### Trial Registration ClinicalTrials.gov NCT01310855.


Chloroquine

Hydroxychloroquine

Remdesivir

Biological, molecular and pharmacological characteristics of chloroquine, hydroxychloroquine, convalescent plasma, and remdesivir for COVID-19 pandemic: A comparative analysis. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, also known as COVID-19 pandemic has caused an alarming situation worldwide. Since the first detection, in December 2019, there have been no effective drug therapy options for treating the SARS-CoV-2 pandemic. However, healthcare professionals are using chloroquine, hydroxychloroquine, remdesivir, convalescent plasma and some other options of treatments. This study aims to compare the biological , molecular , pharmacological , and clinical characteristics of these three treatment modalities for SARS-COV-2 infections , Chloroquine and Hydroxychloroquine , Convalescent Plasma , and Remdesivir . ### methods A search was conducted in the "Institute of Science Information (ISI)-Web of Science, PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library databases, Scopus, and Google Scholar" for peer reviewed, published studies and clinical trials through July 30, 2020. The search was based on keywords "COVID-19" SARS-COV-2, chloroquine, hydroxychloroquine, convalescent plasma, remdesivir and treatment modalities. ### results As of July 30, 2020, a total of 36,640 relevant documents were published. From them 672 peer reviewed, published articles, and clinical trials were screened. We selected 17 relevant published original articles and clinical trials: 05 for chloroquine and/or hydroxychloroquine with total sample size (n = 220), 05 for remdesivir (n = 1,781), and 07 for Convalescent Plasma therapy (n = 398), with a combined total sample size (n = 2,399). Based on the available data, convalescent plasma therapy showed clinical advantages in SARS-COV-2 patients. ### conclusions All three treatment modalities have both favorable and unfavorable characteristics, but none showed clear evidence of benefit for early outpatient disease or prophylaxis. Based on the current available data, convalescent plasma therapy appears to show clinical advantages for inpatient use. In the future, ongoing large sample size randomized controlled clinical trials may further clarify the comparative efficacy and safety of these three treatment classes, to conclusively determine whom to treat with which drug and when to treat them.


bevacizumab

ranibizumab

Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel (DERBI study). To evaluate the outcome of second-line intravitreal ranibizumab treatment in eyes with diabetic macular edema having persistent edema following initial therapy with intravitreal bevacizumab. ### Methods Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel was a retrospective, multi-center study. Consecutive eyes with persistent diabetic macular edema following at least three previous intravitreal bevacizumab injections prior to intravitreal ranibizumab, at least three-monthly intravitreal ranibizumab injections and at least 12 months of follow-up were included. Data collected included demographics, ocular findings, diabetes control, details of intravitreal bevacizumab and ranibizumab injections, and visual and anatomical measurements before and after intravitreal ranibizumab treatment. ### Results In total, 202 eyes of 162 patients treated at 11 medical centers across Israel were included. Patients received a mean ( ±standard deviation ) of 8.8 ± 4.9 intravitreal bevacizumab injections prior to the switch to intravitreal ranibizumab . A mean of 7.0 ± 2.7 intravitreal ranibizumab injections were given during the 12 months following the switch to intravitreal ranibizumab. The median central subfield retinal thickness (±interquartile range) by spectral-domain optical coherence tomography decreased from 436 ± 162 µm at baseline to 319 ± 113 µm at month 12 (p < 0.001). Median logMAR visual acuity (±interquartile range) improved from 0.40 ± 0.48 at baseline to 0.38 ± 0.40 at month 12 (p = 0.001). Linear regression suggested that higher number of intravitreal ranibizumab injections and higher pre-switch central subfield retinal thickness were associated with favorable visual outcome. Higher number of intravitreal bevacizumab injections and the presence of intraretinal fluid before the switch lessened the odds of favorable outcome. ### Conclusion Switching from bevacizumab to ranibizumab in persistent diabetic macular edema was associated with anatomical improvement in the majority of eyes and ⩾2 lines of vision improvement in 22% of eyes.


streptomycin

amikacin

streptomycin

kanamycin

penicillin

penicillin

Species-specific resistance to antimocrobial synergism in Streptococcus faecium and Streptococcus faecalis. Combinations of penicillin with various aminoglycosidic aminocyclitols were tested against a collection of clinical isolates of Streptococcus faecium in vitro and were used to treat endocarditis caused by S. faecium in the rabbit model. S. faecium proved more resistant to penicillin than Streptococcus faecalis. Even more striking, however, was the resistance to in vitro synergism by combinations of penicillin and various aminoglycosides. At clinically achievable concentrations, penicillin-gentamicin was the only combination that was synergistic against all strains that were tested. Combinations of penicillin and streptomycin and penicillin and amikacin were synergistic only against those strains that were not highly resistant to streptomycin and kanamycin , respectively . Combinations of penicillin with kanamycin, tobramycin, sisomicin, or netilmicin failed to produce synergism against any of these strains. The possible clinical significance of these findings was verified by use of the rabbit model of endocarditis. Combinations of penicillin with gentamicin or streptomycin were synergistic in the therapy of endocarditis that was produced by a strain of S. faecium that did not have a high level of resistance to aminoglycosides. However, the combination of penicillin and netilmicin was no more effective than penicillin alone.


cyclophosphamide

vincristine

dacarbazine

Combination chemotherapy for malignant paraganglioma.  Treatment with a combination chemotherapeutic regimen consisting of cyclophosphamide , vincristine , and dacarbazine for malignant paraganglioma with hepatic metastasis is reported . A 51-year-old male presented with tumors in the retroperitoneal space and liver. The patient was diagnosed as having paraganglioma based on elevated levels of serum neuron-specific enolase, urinary catecholamine and vanillylmandelic acid, and on histological findings of the liver specimen. The patient was treated with this combination chemotherapy in repeated 21-day cycles. Temporary improvement in laboratory findings and a 20% reduction in the size of the hepatic masses were observed without severe adverse effects.


ciprofloxacin

ceftazidime

ampicillin

In vitro evaluation of antibiotic prophylaxis in the prevention of biliary stent blockage. Bacterial adherence and biofilm formation are important factors in the blockage of biliary stents. Clinical studies with oral antibiotic prophylaxis to prevent stent blockage have produced conflicting results. The aim of this study was to evaluate the in vitro effect of single antibiotic ( ciprofloxacin , ceftazidime , or ampicillin ) treatment on adherence of Escherichia coli and Enterococcus to plastic stents . ### methods Selected clinical isolates of E coli and Enterococcus were perfused through a modified Robbins device containing segments of polyethylene stents. The stents were removed daily and the number of bacteria attached was measured. The effect of antibiotic treatment on bacterial adherence was tested by the perfusion of individual antibiotics into separate modified Robbins devices using a side-arm adaptor and the results were compared with saline controls. ### results Compared with the saline controls, ciprofloxacin and ceftazidime caused a 10- to 100-fold reduction in the number of E coli attached to the stents, whereas ampicillin had no effect on adherence of E coli. ampicillin caused a 5- to 10-fold reduction in Enterococcus adherence but there was no change with ceftazidime. Sustained reduction in E coli adherence was observed with prolonged ciprofloxacin perfusion. ### conclusion Timely treatment with appropriate antibiotics reduced bacterial adherence in vitro and may be potentially beneficial in the prevention of stent blockage.


Paclitaxel

docetaxel

Current and future perspectives in advanced bladder cancer: is there a new standard? The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7 % to 56 % , depending on whether the patients have received prior chemotherapy for metastatic disease . The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk-benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated.


vinblastine

bleomycin

[Preoperative chemotherapy of testicular cancer and Wilm's tumor]. Of the various urogenital malignancies, preoperative chemotherapy is most effective for testicular cancer and Wilms' tumor. The most effective treatment regimens for advanced nonseminomatous testicular tumors employ vinblastine , CDDP and bleomycin and adjunctive surgery . Another effective chemotherapy regimen is combination of vinblastine, actinomycin D, bleomycin, cyclophosphamide and CDDP presented by MSKCC. Available pretreatment with 4 courses of platinum, vinblastine and bleomycin before any surgical treatment in those with massive bulk metastatic disease seems to provide the most effective cytoreduction and best survival. Donohue has shown that in a primary chemotherapy group, there is only 20% active carcinoma after primary chemotherapy, whereas in a salvage chemotherapy group there is approximately 50% active carcinoma at surgery. It must therefore be emphasized that complete remission should be obtained by primary chemotherapy and adjunctive surgery. In Wilms' tumor preoperative chemotherapy with vincristine and actinomycin D should be given.


vincristine

cyclophosphamide

[Chemotherapeutic combinations of mutually potentializing drugs. 1-Application to the treatment of breast cancers].  27 patients suffering from disseminated carcinoma of the breast with at least two visceral metastases , and two had become resistant to conventional chemotherpy and hormones , received a combination of , in the present trial , vincristine followed by cyclophosphamide with 5-fluoro-uracil . Chemotherapy was administered intermittently: each cycle of treatment lasted 6 days and was followed by a period without treatment of 25 days. Haematological tolerance was satisfactory. No serious incidents occurred during two years use of the combination. 20 out of 27 patients showed objective tumour regression of more than 50 p.cent lasting for more than 6 months, whilst 9 showed apparent complete regression of the malignant lesions. There was one complete failure. Chemotherapy was continued in all cases after regression of the neoplastic process was obtained.


estramustine

etoposide

A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer.  We previously demonstrated that the combination of oral estramustine ( 15 mg/kg/day ) and oral etoposide ( 50 mg/m2/day ) is effective first-line therapy for the treatment of hormone refractory prostate cancer . We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. ### methods estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. ### results Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. ### conclusions We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.


bendamustine

ofatumumab

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine ( 70 mg/m(2 ) ) for 2 consecutive days every 28 days , and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle , and 1000 mg on day 1 subsequently . Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.


gemcitabine

oxaliplatin

Experience of gemcitabine plus oxaliplatin chemotherapy in patients with advanced biliary tract carcinoma. The combination gemcitabine-oxaliplatin (GEMOX) is frequently used in patients with advanced biliary tract carcinoma (BTC). However, this is only based on phase II studies performed in selected patients.We assessed the efficacy and safety of the GEMOX regimen in non-selected patients with advanced BTC. ### methods All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study : gemcitabine 1,000 mg/m(2 ) on day 1 , and oxaliplatin 100 mg/m(2 ) on day 2 , treatment repeated every 2 weeks until progression or unacceptable toxicity . ### results Forty-four patients were enrolled. ### efficacy 1 complete and 6 partial responses (objective response rate = 16.3%), 18 tumour stabilizations (41.9%, disease control rate = 58.1%), median progression-free survival was 5.0 months and median overall survival was 11.0 months. ### toxicity grade 3 neuropathy in 4 patients, grade 3 asthenia in 5 patients. ### conclusion The GEMOX combination was well tolerated, with a modest activity in non-selected patients with advanced BTC. This regimen should be compared to the new standard gemcitabine-cisplatin combination.


rituximab

intravenous immunoglobulin

bortezomib

Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial. Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials ( RCT ) have failed to demonstrate the efficacy of widely used therapies , such as rituximab plus intravenous immunoglobulin or proteasome inhibition ( bortezomib ) , reinforcing a great need for new therapeutic concepts . One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. ### methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4-12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. ### discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. ### Trial Registration ClinicalTrials.gov, NCT03444103 . Registered on 23 February 2018 (retrospective registration).


methylprednisolone

cyclosporine

azathioprine

An experimental model of chronic renal allograft rejection in the rat using triple drug immunosuppression. Chronic rejection is a major problem in renal transplantation. Various experimental models have been developed to study vasculopathy of chronic rejection. However, animal models resembling the clinical situation of renal transplantation with combination therapy of basic immunosuppression are not available. The aim of this study was to find an experimental model of a donor-recipient rat strain combination that , under triple drug immunosuppressive treatment ( methylprednisolone , cyclosporine , and azathioprine ) , would develop chronic rejection within a few weeks . ### methods Renal transplantations were performed in strain combinations of DA-->AO, PVG-->BN, and DA-->BN. In each group, 5-8 animals received triple drug treatment of methylprednisolone (2 mg/kg), azathioprine (2 mg/kg), and cyclosporine (5 mg/kg) daily, 5-10 animals were left without treatment, and 6 syngenic transplantations were performed. The grafts were monitored with ultrasound-guided fine needle aspiration biopsies to quantify the inflammation in the graft. Graft histology was performed in parallel and quantified by using the chronic allograft damage index (CADI). ### results In nonimmunosuppressed animals, irreversible acute rejection with a high peak of inflammation appeared in every strain combination within 5-8 days. In triple drug-treated rats, the DA-->AO combination demonstrated a prolonged acute rejection but no characteristic chronic changes, and the PVG-->BN combination showed practically no inflammation and did not develop any signs of chronic rejection within 60 days (CADI: 2.7+/-2.1), but the DA-->BN combination showed an early, mild inflammatory response 5-7 days after transplantation and developed chronic rejection within 40-60 days after transplantation (CADI: 7.9+/-3.1). Syngenic animals showed no inflammation or histological alterations (CADI: 1.7+/-2.0). ### conclusions In conclusion, in the DA-->BN combination with triple drug treatment, early mild inflammation was followed by the development of chronic rejection and can be used as an experimental model that resembles the clinical situation in renal transplantation.


R-CHOP

cyclophosphamide

vincristine

prednisone

fludarabine

mitoxantrone

Rituximab and new regimens for indolent lymphoma: a brief update from 2012 ASCO Annual Meeting. Indolent lymphoma (IL), the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard frontline regimen for diffuse Large B -cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab) has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial , R-CHOP was compared with R-CVP ( cyclophosphamide , vincristine , prednisone ) and R-FM ( fludarabine , mitoxantrone ) . The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab) has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.


gemcitabine

paclitaxel

capecitabine

Direct percutaneous transhepatic portomesenteric venous stenting in management of locally advanced pancreatic cancer. Pancreatectomy with portal and/or superior mesenteric vein resection remains a controversial procedure because of high complexity and morbidity. Neoadjuvant chemotherapy has been shown to increase resectability of these locally advanced lesions. We aimed to assess the utility and efficacy of direct percutaneous transhepatic portomesenteric venous stenting (THVS) with neoadjuvant chemotherapy in increasing surgical resectability of locally advanced pancreatic carcinoma. ### methods Forty pancreatic carcinoma patients with tumor thrombus involving the portal vein and superior mesenteric vein were identified. Patients underwent THVS followed by neoadjuvant chemotherapy. Whipple procedure was offered to responders. ### results THVS was attempted in all. The tumor thrombus could not be crossed in 2 patients (95% technical success rate). All patients underwent 3 cycles of neoadjuvant gemcitabine , paclitaxel , and capecitabine . Disease progression was noted in 16 patients and surgery was not offered. Twenty-two patients were explored with intent-to-perform a Whipple procedure. In 7 of these (32%), extensive disease precluding surgical resection was identified and the procedure was abandoned. Whipple procedure without vascular resection was performed successfully in 15 patients (68%). There were no perioperative deaths. Negative vascular margins were noted in 3 patients and negative peripancreatic lymph nodes in 5 patients. Median survival was 17 months (range, 5 to 70 mo). In the stented nonoperative group, median survival was 9 months (range, 3 to 19 mo). The stented and resected group achieved a statistically significant (P=0.0422) survival advantage. ### conclusions THVS in combination with neoadjuvant chemotherapy can increase tumor resectability and survival in a select group of locally advanced pancreatic cancer patients.


voriconazole

amphotericin

B.

Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model.  The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. ### methods Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. ### results voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. ### conclusions voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.


Aspirin

Cilostazol

Dual Therapy with Aspirin and Cilostazol May Improve Platelet Aggregation in Noncardioembolic Stroke Patients : A Pilot Study . Objective Some previous studies have found clinical benefit of dual antiplatelet therapy with aspirin and cilostazol for prevention of secondary stroke, but the physiological mechanism involved remains unknown. We aimed to clarify the effects of aspirin/cilostazol therapy on the platelet and endothelial functions of patients with acute noncardioembolic ischemic stroke, in comparison to patients who were treated with aspirin alone. Methods The present randomized prospective pilot study enrolled 24 patients within a week after the onset of noncardioembolic ischemic stroke. The patients were randomly allocated to receive aspirin (100 mg/day) (A group; 11 patients) or cilostazol (200 mg/day) plus aspirin (100 mg/day) (CA group; 13 patients). We measured platelet aggregation, platelet activation, and the thrombomodulin (TM), highly sensitive C-reactive protein (hs-CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand (vWF) antigen levels and vWF activity over a 4-week period after enrollment. Results There was no significant difference in the platelet functions of the A and CA groups. However, the platelet aggregation induced by adenosine diphosphate (ADP) was decreased at 2 and 4 weeks (p<0.05) after treatment in comparison to the pre-treatment values in the CA group, but not in the A group. Platelet activation, and the hs-CRP, TM, ICAM-1, VCAM-1 and vWF values did not significantly decrease after treatment in either group. Conclusion Although there were no significant differences in platelet aggregation, platelet activation or the endothelial biomarker levels of the A and CA groups, dual therapy with aspirin and cilostazol inhibited platelet aggregation in comparison to the pre-treatment values, similarly to patients who received aspirin alone. This may suggest the clinical usefulness of dual therapy with aspirin and cilostazol in the treatment of patients with noncardioembolic ischemic stroke.


Gemcitabine

vinorelbine

Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting . The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. ### methods From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. ### results A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. ### conclusions The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.


tenofovir disoproxil fumarate

emtricitabine

Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: a European multicenter study.  The combination of tenofovir disoproxil fumarate ( TDF ) plus emtricitabine ( FTC ) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus ( HBV ) infection . The aim of this study was to assess the efficacy and tolerance of TDF + FTC in patients with chronic hepatitis B (CHB). ### methods Seventy eight consecutive CHB patients from five European centers were included. All started a TDF + FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF + FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. ### results TDF + FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4 log10 IU/mL, and median alanine-transaminase (ALT) was 1.10 × ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (≥ F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76 weeks (interquartile range 60-116). Kaplan-Meier analysis showed that, 48 weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1 log10 IU/mL, median ALT 0.79 × ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76 weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. ### conclusions After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF + FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term.


tamoxifen

exemestane

anastrozole

Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04). Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the tamoxifen exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole . HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.


rosiglitazone

glimepiride

Willingness to pay for diabetes drug therapy in type 2 diabetes patients: based on LEAD clinical programme results. The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials. ### methods Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments. ### results People with type 2 diabetes were prepared to pay an extra €2.64/day for liraglutide compared with rosiglitazone, an extra €1.94/day compared with glimepiride, an extra €3.36/day compared with insulin glargine, and an extra €0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators. ### conclusions WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone , glimepiride , and insulin glargine , and administration frequency compared with exenatide .


doxorubicin

cyclophosphamide

paclitaxel

Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer : results of the phase II CAPRICE study . Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 4 weeks for four cycles, followed by 80 mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65 years, 64 % suffered from hypertension, and 10 % had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32 % (95 % CI 19.5-46.7 %) and pCR in breast and axilla was 24 % (95 % CI 12.1-35.8 %). At diagnosis only, 26 % of patients were candidates for breast conservative surgery, which increased to 58.7 % after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.


cisplatin

cyclophosphamide

paclitaxel

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. ### methods We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin ( 75 mg per square meter of body-surface area ) with either cyclophosphamide ( 750 mg per square meter ) or paclitaxel ( 135 mg per square meter over 24 hours ) . ### results Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). ### conclusions Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.


ezetimibe

simvastatin

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men . This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). simvastatin did not significantly affect cholesterol absorption. ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.


pseudoephedrine

methamphetamine

methamphetamine

Impacts of federal precursor chemical regulations on methamphetamine arrests.  The US government regulated precursor chemicals , ephedrine and pseudoephedrine , multiple times to limit methamphetamine production/availability and thus methamphetamine problems . Research has found that the regulations reduced methamphetamine hospital admissions, but authors have argued that other problems were unaffected. This study examines whether the regulations impacted methamphetamine arrests. ### design ARIMA-intervention time-series analysis with control series. ### setting California (1982-2001). ### measurements Dependent variable series: monthly methamphetamine arrests. Control series: monthly marijuana arrests and cocaine/heroin arrests. ### interventions Bulk powder ephedrine and pseudoephedrine: regulated November 1989. Products containing ephedrine as the single active medicinal ingredient: regulated August 1995. pseudoephedrine products: regulated October 1997. Large-scale producers used ephedrine and pseudoephedrine in these forms. Ephedrine combined with other active medicinal ingredients (e.g. various cold medicines)-used mainly by small-scale producers: regulated October 1996. ### findings The regulation targeting small-scale producers (1996) had no significant impact. In contrast, methamphetamine arrests stopped rising and dropped 31% to 45% each of the three times precursor chemicals used by large-scale producers were regulated. Within 3 years of the bulk powder regulation (1989) and again within 2 years of the ephedrine single ingredient regulation (1995), arrests fully rebounded. During the 4 years following the last regulation (pseudoephedrine products, 1997) arrests only partially rebounded. These effects parallel those reported on hospital admissions. The control series were generally unaffected. ### conclusions Precursor regulations targeting large-scale producers impacted methamphetamine arrests, a criminal justice problem, much as they impacted the public health problem of methamphetamine hospital admissions. Ongoing research is needed to determine whether these problems eventually fully rebound from the last regulation.


procarbazine

lomustine

vincristine

radiotherapy

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine , lomustine , and vincristine ( PCV ) chemotherapy to radiotherapy ( RT ) . ### Patients And Methods Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. ### results A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. ### conclusion The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.


vinorelbine

gemcitabine

A phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (stage IIIb/IV) non-small-cell lung cancer patients aged 80 or older. vinorelbine and gemcitabine are two active single agents with mild toxicity profiles that are used in the treatment of non-small-cell lung cancer (NSCLC). Whether or not very old NSCLC patients, such as those aged 80 years or older, should still be considered for chemotherapy is unknown, since their response to the treatment is also unknown. A phase II clinical trial was conducted to evaluate the efficacy and toxicity of vinorelbine plus gemcitabine in very old patients with inoperable ( stage IIIb or IV ) NSCLC . vinorelbine 20 mg/m(2) was given as a 10-min intravenous infusion, followed by a 30-min intravenous infusion of gemcitabine 800 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. From March 1998 to December 2001, 20 patients (16 males, four females) were enrolled in the study. The median age was 83 years, within the range 80-88 years. The median number of treatment cycles per patient was four. With the exception of one, all patients received at least two cycles of treatment. Thirteen patients achieved a partial response, with an overall response rate of 65% (95% confidence interval, 44.1-85.9%). Median survival was 10 months. The significant (WHO grade 3/4) toxicities were myelosuppression, including leukopenia in five (25%) patients, neutropenia in eight (40%), anaemia in six (30%), and thrombocytopenia in three (15%) patients. Febrile neutropenia occurred in two patients and accounted for one treatment-related death. Non-haematological toxicity was generally mild, except one patient who suffered from grade 3 interstitial pneumonitis. Another patient suffered from a cerebral infarction after three cycles of treatment. In conclusion, the combination of vinorelbine and gemcitabine in very old patients with advanced NSCLC is a highly active regimen with an acceptable toxicity profile.


Tobramycin

gentamicin

penicillins

Comparative in vitro activity of nafcillin, oxacillin, and methicillin in combination with gentamicin and tobramycin against enterococci. The in vitro activity of nafcillin, oxacillin, and methicillin alone and in combination with gentamicin and tobramycin against 30 strains of enterococci was investigated. The penicillinase-resistant penicillins were less active than penicillin and ampicillin against the enterococci. nafcillin was more active than oxacillin and methicillin. Sixty-six percent of strains were inhibited by nafcillin at 6.25 mug/ml, but none was inhibited by oxacillin and methicillin at the same concentration. At 12.5 mug/ml, 83, 16, and 0% were inhibited by nafcillin, oxacillin, and methicillin, respectively. By using a variety of criteria and analyses, it was shown that none of the antibiotic combinations studied demonstrated enhanced killing of all strains of enterococci. nafcillin-gentamicin was the best combination, and enhanced killing was demonstrated against most strains. oxacillin was more effective than methicillin when combined with gentamicin. Tobramycin was probably less effective than gentamicin in combination with the penicillinase-resistant penicillins against enterococci .


entecavir

telbivudine

Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides. ### aim To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management. ### methods Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters. ### results NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance <50 mL/min. There are concerns about nephrotoxic potential of the nucleotides, particularly adefovir, while improvements of creatinine clearance have been reported under telbivudine. Most existing data in CHB patients with CKD are for lamivudine and, less frequently, for other NAs, mostly entecavir. Besides CHB, NA should be used in case of immunosuppressive therapy in any HBsAg-positive patient with CKD including renal transplant (RT) recipients and in anti-HBs-positive recipients of kidney grafts from HBsAg-positive donors. ### conclusions Chronic hepatitis B patients with chronic kidney disease receiving nucleoside analogues should be followed carefully for treatment efficacy and renal safety. Despite the absence of strong data , entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease , depending on viraemia and severity of renal dysfunction . More studies are certainly needed in this setting.


ixabepilone

paclitaxel

capecitabine

vinorelbine

pemetrexed

irinotecan

Management of metastatic breast cancer: monotherapy options for patients resistant to anthracyclines and taxanes. Resistance to chemotherapeutic agents is a significant obstacle to the effective treatment of metastatic breast cancer (MBC). Anthracycline- and taxane-based regimens are active as first-line treatment for MBC; however, MBC often progresses because of primary or acquired resistance to anthracyclines and taxanes. There are few options for the treatment of patients with anthracycline- and taxane-resistant or taxane-refractory MBC. This article reviews several single agents that have demonstrated activity as treatment for patients with MBC who progress during, or rapidly following, treatment with anthracyclines and taxanes. Results from clinical trials evaluating agents such as ixabepilone , albumin-bound paclitaxel , capecitabine , vinorelbine , pemetrexed , and irinotecan are presented . Single-agent capecitabine is approved for the treatment of patients after failure of anthracyclines and taxanes. ixabepilone has demonstrated efficacy in patients with MBC resistant to multiple chemotherapeutic agents and is the only agent approved by the Food and Drug Administration as monotherapy for anthracycline-, taxane-, and capecitabine-resistant MBC. Improved treatment strategies and further evaluation of newer agents may reduce the current burden of treatment-resistant or treatment-refractory MBC.


fluticasone

formoterol

fluticasone

formoterol

[A new fixed dose combination of fluticasone and formoterol in a pressurised metered-dose inhaler for the treatment of asthma]. The combination of an inhaled corticosteroid and a long acting beta-2 agonist is indicated for the regular treatment of persistent moderate-to-severe asthmatics whose asthma is not controlled by inhaled corticosteroids and the occasional use of a short acting beta-2 agonist. The aim of this review is to give an overview of the rationale of combining formoterol and fluticasone and to analyze the clinical data concerning a new fixed combination of fluticasone and formoterol in a pressurised metered-dose inhaler with a dose counter (Flutiform(®)) that was approved for the treatment of asthma in France in 2013. The clinical studies provide evidence that combined fluticasone/formoterol is more efficacious than fluticasone or formoterol given alone , and provides similar improvements in lung function to fluticasone ( Flixotide ( ® ) ) and formoterol ( Foradil ( ® ) ) administered concurrently . The combination of fluticasone/formoterol gave a more rapid bronchodilatation than the combination fluticasone/salmeterol. As a whole, the combination of fluticasone/formoterol had similar efficacy and tolerability profiles to the combinations of either budesonide/formoterol or fluticasone/salmeterol.


anastrozole

tamoxifen

Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen : a TransATAC study . PURPOSE To determine whether the Recurrence Score (RS) provided independent information on risk of distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, tamoxifen, Alone or in Combination (ATAC) Trial. PATIENTS AND METHODS RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. RESULTS Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P < .001 for N0 and P = .002 for N+). RS also showed significant prognostic value beyond that provided by Adjuvant! Online (P < .001). Nine-year DR rates in low (RS < 18), intermediate (RS = 18 to 30), and high RS (RS > or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. CONCLUSION This study confirmed the performance of RS in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N+ hormone receptor-positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.