Ramucirumab

osimertinib

Phase 1 Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer. We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR TKI osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant NSCLC. ### Experimental Design This open-label, single-arm phase 1 study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose de-escalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. ### results Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common Grade 3 or higher treatment-related adverse events (TRAEs) were hypertension (8%) and platelet count decreased (16%); Grade 5 TRAE (subdural hemorrhage) occurred in one patient. Patients with (N=10) and without CNS metastasis (N=15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months (90% CI: 9.6-21.2). Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations post progression included C797S, MET amplification, and EGFR amplification. ### conclusions Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC .


etoposide

cytarabine

mitoxantrone

[Refractory acute myeloid leukemia developed malignancy-associated hemophagocytic lymphohistiocytosis during treatment of invasive fungal infection]. We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3'-RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone . Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription-polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients.


cyclosporine

tacrolimus

tacrolimus

cyclosporine

Cyclosporine: advantages versus disadvantages vis-à-vis tacrolimus. Despite a different molecular structure and biochemical properties, cyclosporine and tacrolimus--by inhibiting calcineurin activity--have been shown in the previous two decades of solid organ transplantation to be well tolerated and effective immunosuppressants. Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine. But in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear. In general, short- and medium-term outcome variables (1-year serum creatinine, graft and patient survival) with cyclosporine and tacrolimus are excellent, and (almost) identical, with both substances having the same intrinsic nephrotoxic potential. On the other hand , cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism . However, at present no data are available to discern that these differences in risk profile alter patient or graft survival or long-term cardiovascular morbidity/mortality. Therefore, prospective long-term trials are needed to study the quantitative impact of different immunosuppressive agents and concomitant cardiovascular risk factors on long-term patient and graft survival, before evidence-based (patient, graft, or cardiovascular) risk reduction can be firmly claimed by tailoring calcineurin inhibitors.


Isoniazid

streptomycin

rifampin

ethambutol

Rapid radiometric susceptibility testing of Mycobacterium tuberculosis. A 48-hour radiometric test for determining the drug susceptibility of Mycobacterium tuberculosis has been developed. The test is based on the measurement of 14CO2 produced by the oxidation of formate labeled with carbon-14. The test system uses 5 X 10(7) organisms in 1 ml of Middlebrook 7H9 medium plus albumin-dextrose-catalase enrichment and 1 muCi of [14C]formate. The 14CO2 produced is measured in an ionization chamber at 24-, 48-, and 72-hour intervals, with and without the addition of antituberculous drugs. Isoniazid , streptomycin , rifampin , and ethambutol were each tested at 3 concentrations by the radiometric method and the reference ( agar dilution ) method . Six standard strains and 21 patient isolates were compared by both methods. Production of 14CO2 was quantitatively decreased in the presence of drugs that inhibit the organism. The radiometric method requires 2 days; the agar dilution, 14 to 21 days.


methamphetamine

haloperidol

haloperidol

Enhancement of haloperidol-induced increase in rat striatal or mesolimbic 3,4-dihydroxyphenylacetic acid and homovanillic acid by pretreatment with chronic methamphetamine. After a drug-free period of 1 week following 2 weeks of haloperidol treatment, the increased response of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a challenge dose of haloperidol was significantly reduced. Tolerance to this effect was not, however, seen in the mesolimbic system. Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas . The reduced response of striatal DOPAC or HVA after chronic haloperidol was prevented by pretreatment with MAP. The data suggest that the long-term dopamine receptor stimulation induced by MAP may antagonize the tolerance produced by chronic haloperidol treatment.


cyclophosphamide

daclizumab

denileukin diftitox

Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Regulatory T cells (Tregs) are thought to inhibit antitumor immune responses, and their depletion could therefore have a synergistic effect with therapeutic cancer vaccines. We investigated the impact of three medications on blood Treg frequency in vaccinated cancer patients. ### Experimental Design To date, the most specific marker for human Tregs is demethylation in the DNA that encodes the transcription factor FOXP3. Thus, we used a FOXP3 methylation-specific quantitative PCR assay (MS-qPCR) to measure Treg frequencies in the peripheral blood mononuclear cells (PBMCs) of melanoma patients. The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents : low-dose cyclophosphamide , anti-CD25 monoclonal antibody daclizumab , and the IL-2/diphtheria toxin fusion protein denileukin diftitox . ### results In the nine control patients, blood Treg frequencies varied over time; there was a 46% reduction in one patient. In treated patients, a more than 2-fold decrease in Tregs was observed in one out of 11 patients receiving cyclophosphamide and in four out of 13 receiving daclizumab, but there was no such Treg decrease in any of the six patients who received denileukin diftitox. As a positive control, a more than 2-fold increase in blood Tregs was detected in four out of nine patients who were treated with interleukin-2. ### conclusions We used a MS-qPCR method that detects Tregs but not other activated T lymphocytes; however, none of the Treg-depleting strategies that we tested led, in the majority of patients, to a conservative 50% reduction in blood Tregs.


vancomycin

ampicillin

Related Enteric Viruses Have Different Requirements for Host Microbiota in Mice. Accumulating evidence suggests that intestinal bacteria promote enteric virus infection in mice. For example, previous work demonstrated that antibiotic treatment of mice prior to oral infection with poliovirus reduced viral replication and pathogenesis. Here, we examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a picornavirus closely related to poliovirus. We treated mice with a mixture of five antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis following oral inoculation. We found that, as seen with poliovirus, CVB3 shedding and pathogenesis were reduced in antibiotic-treated mice. While treatment with just two antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and pathogenesis, this treatment had no effect on poliovirus. The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin . To determine whether more-subtle changes in bacterial populations impact viral replication, we examined viral infection in mice treated with milder antibiotic regimens. Mice treated with one-tenth the standard concentration of the normal antibiotic cocktail supported replication of poliovirus but not CVB3. Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 shedding and pathogenesis while having no effect on poliovirus shedding and pathogenesis. Overall, replication and pathogenesis of CVB3 are more sensitive to antibiotic treatment than poliovirus, indicating that closely related viruses may differ with respect to their reliance on microbiota.


Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy .

etoposide

prednisone

vincristine

cyclophosphamide

doxorubicin


Tremelimumab

gemcitabine

A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. ### Patients And Methods gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. ### results From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). ### conclusion Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer . ### Clinicaltrialsgov Id NCT00556023.


etoposide

doxorubicin

Response of short-term cultures derived from human malignant glioma to aziridinylbenzoquinone, etoposide and doxorubicin: an in vitro phase II trial. The relative resistance of malignant glioma to chemotherapy makes the identification of new cytotoxic drugs critically important. The use of short-term cultures derived from these tumors to screen drugs at doses that can be attained within human intracranial tumors provides a model system that should be capable of identifying effective drugs suitable for clinical evaluation. The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone ( AZQ ) , etoposide and doxorubicin ( DOX ) using a [ (35)S ] methione uptake assay . The ID(50) of each culture was compared to the levels of drug which could be achieved in the tumor using standard doses. There was marked heterogeneity between cultures in response to each drug. Whilst there was no evidence that cultures derived from grade III astrocytoma were more sensitive to any of the drugs than cultures derived from grade IV astrocytoma, cultures derived from oligodendroglioma tended to be more sensitive to the alkylating agent AZQ, but not to either of the other drugs. The sensitivity of these short-term cultures at concentrations that can be achieved in situ corresponded well with the clinical efficacy of AZQ and etoposide. Although DOX appeared to be toxic to human gliomas cells in vitro, its limited penetration into the intact brain would seem to preclude its use i.v., but it is likely to be effective if local drug delivery techniques could be employed. The study suggests that short-term cultures derived from malignant glioma should be used to screen investigational agents for potential clinical efficacy.


capecitabine

lapatinib

Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. ### Experimental Design Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. ### results Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups . PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. ### conclusions Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR.


Apalutamide

Abiraterone

Prednisone

Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study . apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). ### Patients And Methods Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. ### results Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. ### conclusions Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.


nintedanib

letrozole

Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition. The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. ### Patients And Methods Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). ### results A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. ### conclusion Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials . However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. ### Trial Registration This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.


trastuzumab

vinorelbine

A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation . Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients.


carboplatin

ifosfamide

Dex

GM-CSF

Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide. Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide . No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.


methylprednisolone

prednisolone

tacrolimus

The association between dermatomyositis and papillary thyroid cancer: a case report. We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy . However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions.


vinorelbine

pemetrexed

imexon

Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. This study evaluated the cytotoxic effects of imexon (NSC-714597) in tumor cells when combined with a broad panel of chemotherapeutic drugs. ### methods The sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays were used to analyze the degree of growth inhibition for the combination studies in the A375 human malignant melanoma and RPMI 8226 human multiple myeloma cell lines, respectively. Cells were continuously exposed to both drugs at a constant molar ratio for 4-5 days. Combination effects were analyzed using the Median Effect method. Statistical significance was inferred if the 95% confidence interval for the combination interaction (C.I.) values for a particular two-drug combination did not include 1.0 (additivity). Synergy was inferred for C.I. values<1.0 and antagonism for CI values>1.0. ### results Imexon was synergistic when combined with DNA-binding agents (cisplatin, dacarbazine, melphalan) and pyrimidine-based antimetabolites (cytarabine, fluorouracil, gemcitabine) in both cell lines. Antagonistic combinations with imexon included methotrexate and the topoisomerase I (TOPO I) and II (TOPO II) inhibitors irinotecan, doxorubicin, mitoxantrone and etoposide. docetaxel was synergistic with imexon in both cell lines whereas paclitaxel and fludarabine showed a mixed result. dexamethasone and the proteasome inhibitor bortezomib showed synergy in myeloma cells and additivity in the melanoma cells. The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines . ### discussion The consistent synergy seen for imexon and alkylating agents may relate to the sulfhydryl-lowering effect of imexon, which would render cells more sensitive to electrophilic species from the alkylators. The marked synergy noted with pyrimidine-based antimetabolites was unexpected and may relate to the induction of cell cycle arrest in S-phase. The strong antagonism noted for imexon with topoisomerase I and II inhibitors may be due to the effect of imexon at increasing oxidant levels which are known to antagonize the cytotoxic effects of topoisomerase poisons. In contrast, the synergy seen with bortezomib in myeloma cells may be related to an increase in reactive oxygen species (ROS) from both drugs. These results suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in therapeutic studies in vivo.


enalapril

atenolol

enalapril

atenolol

enalapril

atenolol

enalapril

atenolol

Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker.


fluorouracil

folinic acid

oxaliplatin

Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer.  To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer . ### Patients And Methods Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. ### results All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. ### conclusion Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.


Bevacizumab

interferon alfa

The bevacizumab experience in advanced renal cell carcinoma.  Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma ( RCC ) in both the US and Europe . Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative.


rituximab

A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. This phase II study evaluated ym155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received ym155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients .


droperidol

dolasetron

[Dolasetron, droperidol and a combination of both in prevention of postoperative nausea and vomiting after extracapsular cataract extraction under general anesthesia].  Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) . It was the aim of this prospective double blind placebo controlled study to determine the efficacy of low-dose droperidol, dolasetron, and a combination of both drugs in the prevention of PONV after extracapsular cataract extraction. ### methods 148 inpatients undergoing cataract surgery were stratified according to gender and then randomised to receive one of four antiemetic regimens: placebo, droperiodol (10 micrograms x kg-1), dolasetron (12.5 mg), or the combination of both drugs (10 micrograms x kg-1 + 12.5 mg). The drugs were administered intravenously 5-10 minutes before the end of anaesthesia. General anaesthesia and the perioperative management of the patients were standardised: benzodiazepine premedication, induction with etomidate, alfentanil and mivacurium. Maintenance using desflurane in N2O/O2, and a continuous infusion of mivacurium was used. Postoperative analgesia (diclofenac or paracetamol) and antiemetic rescue medication (dimenhydrinate and metoclopramide) was standardised. Nausea, episodes of vomiting, retching and the need for additional antiemetics were recorded for 24-hours. The severity of PONV was categorised using a standardised scoring algorithm. The main aim of the study was the number of patients who stayed completely free from PONV. ### results There were no differences between the two groups with regard to biometric data, type of surgery, and distribution of risk factors for developing PONV. In all three treatment groups significantly less patients suffered from PONV (placebo: 66%; droperidol: 89%, dolasetron: 92%, combination: 89%; p = 0.011). Furthermore, the severity of PONV was reduced (p = 0.012). ### conclusion Low-dose droperidol and dolasetron are equally effective to reduce the incidence of PONV after cataract surgery under general anaesthesia. The combination of both drugs revealed no additional effect.


doxycycline

azithromycin

Antibiotic prophylaxis for intrauterine contraceptive device insertion. Concern about the risk of upper genital tract infection (pelvic inflammatory disease) often limits use of the IUD, a highly effective contraceptive. Prophylactic antibiotic administration around the time of induced abortion significantly reduces the risk of postoperative endometritis.(Sawaya, 1996) Since the risk of IUD-related infection is limited to the first few weeks to months after insertion,(Lee, 1983; Farley, 1992) contamination of the endometrial cavity at the time of insertion(Mishell, 1966) appears to be the mechanism, rather than the IUD or string itself. Thus, antibiotic administration before IUD insertion might reduce the risk of upper genital tract infection from passive introduction of bacteria at insertion. ### objectives To assess the effectiveness of prophylactic antibiotic administration before IUD insertion in reducing IUD-related complications and discontinuations within three months of insertion. The primary outcome was pelvic inflammatory disease (four reports) or early removals of the device (two reports). ### Search Strategy We searched both MEDLINE and EMBASE, handsearches of journals through CENTRAL, and lists of references. We also wrote to international experts in the field to identify unpublished studies. ### Selection Criteria We included randomized controlled trials using any antibiotic compared with a placebo. We found four such trials; two had pilot study data available. ### Data Extraction We used searches of MEDLINE, EMBASE, and handsearches of journals available through CENTRAL. We also reviewed lists of references in original research and in review articles. We wrote to experts to identify unpublished trials and made telephone calls to authors to supply missing information. Two independent reviewers abstracted data. We assessed the validity of each study using methods suggested in the Cochrane Handbook. ### Data Synthesis We generated 2x2 tables for the principal outcome measures. We used the Peto modified Mantel-Haenszel technique to calculate odds ratios and assessed statistical heterogeneity between studies. ### Main Results The odds ratios for pelvic inflammatory disease associated with use of prophylactic doxycycline or azithromycin compared with placebo or no treatment was 0.89 (95%CI 0.53-1.51). Use of prophylaxis was associated with a small reduction in unscheduled vists to the provider (OR 0.82; 95% CI 0.70-0.98). Use of doxycycline or azithromycin had little effect on the likelihood of removal of the IUD within 90 days of insertion ( OR 1.05 ; 95 % CI 0.68 - 1.63 ) . Significant heterogeneity did not exist between studies. ### Reviewer S Conclusions Use of either doxycycline 200 mg or azithromycin 500 mg by mouth before IUD insertion confers little benefit. While the reduction in unscheduled visits to the provider was marginally significant, the cost-effectiveness of routine prophylaxis remains questionable. A uniform finding in these trials was the low risk of IUD-associated infection, with or without use of antibiotic prophylaxis.


carboplatin

gemcitabine

carboplatin

Management of platinum-sensitive recurrent ovarian cancer. The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial . The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens.


betamethasone

tazarotene

Tazarotene cream (0.1%) in combination with betamethasone valerate foam (0.12%) for plaque-type psoriasis. A combination of multiple agents is often required to achieve treatment success for plaque-type psoriasis. We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared . Erythema, scale, and thickness along with an aggregate severity score were determined at weeks 4, 8, and 12. One patient was lost to follow-up. Eight of the other 9 patients experienced improvement in their disease by week 12. Two patients were clear of their psoriasis at week 4 and 4 were clear at week 8. No adverse events, including irritation were reported; the use of the corticosteroid foam may protect against potential local irritation reported with tazarotene. The combination of tazarotene cream and betamethasone valerate foam is an effective combination approach to treating localized plaque-type psoriasis.


Valsartan

sulfasalazine

The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration . Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis.


Mitoxantrone

Glatiramer

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone , occurring in the two patients who had previously been treated with Glatiramer Acetate . In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of mitoxantrone, no enhancing lesions were identified on MRI brain scans. glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.


oxaliplatin

irinotecan

Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.


aspirin

naproxen

sulindac

celecoxib

licofelone

Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives. Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological , clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs ( NSAIDs ) ( aspirin , naproxen , sulindac , celecoxib , and licofelone ) , statins and other natural agents-both individually , and in combinations . Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.


Lenalidomide

bortezomib

Lenalidomide for mantle cell lymphoma. Mantle cell lymphoma accounts for 6% of all non-Hodgkin lymphomas. It is a biologically and clinically heterogeneous disease and treatment may be difficult, since most patients present at an older age, being unable to undergo intensive chemotherapy. Lenalidomide is an approved medication for relapsed mantle cell lymphoma in patients who received at least two lines of therapy , including bortezomib . New insights into the mechanisms of action of lenalidomide provided ground for novel combinations that may be more tolerable, while still efficient, for this patient population. In this review, we evaluate the current paradigm for lenalidomide in mantle cell lymphoma.


mefloquine

praziquantel

praziquantel

mefloquine

Therapeutic effect of mefloquine on Schistosoma mansoni in experimental infection in mice. Schistosomiasis is one of the most prevalent parasitic infections worldwide. praziquantel is the drug of choice for treatment of schistosomiasis for its high efficacy. The present work was carried out on 160 mice to evaluate the therapeutic effect of mefloquine on experimental schistosomiasis mansoni. Mice were classified into 3 groups; group I (20 infected non-treated mice), group II included 60 infected mice which were further divided into group IIm (20 mice treated with 400 mg/kg mefloquine), group IIp (20 mice treated with 1,000 mg/kg/2 days praziquantel) and group IIpm (20 mice treated with 200 mg/kg mefloquine and 500 mg/kg praziquantel), group III included 80 non-infected mice subdivided into group IIIn (20 non-treated mice), group IIIm (20 mice treated with 400 mg/kg mefloquine), group IIIp (20 mice treated with 1,000 mg/kg/2 days praziquantel), group IIIpm (20 mice treated with 200 mg mefloquine and 500 mg praziquantel). mefloquine significantly reduced worm burden, tissue egg load, number of liver granulomas and increased the percent of dead ova within granulomas. Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone .


trastuzumab

epirubicin

Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients. Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites . ### Patients And Methods Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). ### results No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. ### conclusion Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.


doxorubicin

cyclophosphamide

paclitaxel

trastuzumab

Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial . To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. ### Patients And Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. ### results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. ### conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.


Bupropion

nicotine

Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice . The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1-2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1-20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Experiment 1b). Mice were administered vehicle or bupropion (1-20 mg/kg) 15 (Experiment 2b) or 30 (Experiment 2c) minutes (min) prior to vehicle or nicotine during CPP training. The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP. bupropion dose-dependently blocked nicotine CTA. For the 15-min pretreatment interval, bupropion dose-dependently increased locomotor activity and produced CPPs when administered alone; whereas for the 30-min pretreatment interval, only the highest bupropion dose increased locomotor activity and produced a CPP. However, bupropion failed to alter nicotine CPP and the co-administration of bupropion and nicotine did not increase locomotor activity more so than when bupropion was administered alone regardless as to the pretreatment interval. Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice.


amoxicillin

clarithromycin

metronidazole

tetracycline

levofloxacin

Helicobacter pylori antibiotic susceptibility patterns in Bangladesh: Emerging levofloxacin resistance. The most recent study to report Helicobacter pylori antibiotic resistance rates in Bangladesh was published 15 years ago and did not include levofloxacin. We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin , clarithromycin , metronidazole , tetracycline and levofloxacin in Bangladesh . ### methodology This study included 133 consecutive patients who underwent endoscopy examination at Dhaka Medical College in November 2014. The serial two-fold agar dilution method was used to determine the minimum inhibitory concentrations of the five antibiotics. ### results Among 56 cultured strains, H. pylori showed high rates of resistance to clarithromycin and metronidazole (39.3% and 94.6%, respectively). Moreover, levofloxacin showed an emerging antimicrobial resistance pattern (66.1%), which was higher in patients with gastritis than that in those with peptic ulcers (p = 0.02). The resistance rate of levofloxacin was significantly higher in patients living in Dhaka city compared to those living in the village (p = 0.049). However, amoxicillin and tetracycline resistance rates were very low. Resistance to both metronidazole and levofloxacin was most commonly observed. ### conclusions The rates of resistance to clarithromycin, metronidazole, and levofloxacin were high in Bangladesh, which suggests that triple therapy based on these drugs may not be useful as first-line therapies in Bangladesh. Alternative strategies such as furazolidone-based triple therapy, bismuth-based quadruple therapies, or sequential therapy may be more effective for patients in in Bangladesh.


tetracycline

streptomycin

Antibiotic susceptibilities of Yersinia enterocolitica and Y. intermedia isolates from aquatic environments. Of 37 Yersinia isolates from various aquatic environments, seven were Y. enterocolitica and 30 Y. intermedia. These isolates were biotyped, serotyped and tested for their susceptibility to 20 antibiotics. All Y. enterocolitica isolates were of biovar 1; those of Y. intermedia were distributed amongst four biovars (1, 2, 4 and 6). On the basis of combined biotyping and serotyping results, Y. enterocolitica isolates were distributed in five and Y. intermedia in 17 groups. With the exception of one Y. enterocolitica isolate which was resistant to tetracycline and streptomycin , the isolates were sensitive to the non-beta-lactam antibiotics . In contrast, various patterns of beta-lactam insensitivity were detected, including ampicillin and ticarcillin (35 isolates), cephalothin (33 isolates), carbenicillin (32 isolates), amoxycillin/clavulanate (23 isolates) and cefoxitin (22 isolates). No correlation between biotype or serotype and the susceptibility pattern of the isolates was apparent. Both inducible cephalosporinase activity against third-generation cephalosporins and inhibition of resistance to penicillins were detected in all Y. enterocolitica and Y. intermedia isolates by double-disk tests.


Meropenem

vancomycin

[Colonization of cental venous catheter in the Intensive Care Units at the Institute of Cardiovascular Disease "Dedinje"--one year study]. The application of Central Venous Catheters (CVC) is associated with increased risk of microbial colonization and infection. The aim of present study was to assess the frequency of pathogens colonizing CVC and to determine their susceptibility pattern to various antimicrobial agents. ### Materials And Methods A total of 253 samples of CVC from intensive care units (ICU) patients were received for culture during 2003. All microorganisms were identified by standard microbiological methods and the susceptibility to antimicrobial agents was determined according to NCCLS recommendations. ### results A total of 184 (72.7%) cultures were positive and 223 pathogens were isolated. Coagulase negative staphylococci (CNS) were the dominant isolates (24.7%), followed by Enterobacter spp. (12.1%), Pseudomonas spp. (11.7%), Enterococcus spp. (9.9%), Klebsiella spp. (8.6%), Candida spp. (7.6%), Acinetobacter spp. (7.6%), other Gram negative nonfermentative bacilli (5.8%), Serratia spp. (4.5%), Staphylococcus aureus (2.6%), Proteus mirabilis (2.2%), E. coli (1.8%) and Citrobacter spp. (0.9%). Meropenem ( 84.5 % ) and vancomycin ( 100 % ) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria , respectively . ### conclusion Gram negative bacilli and CNS are the commonest microorganisms colonizing CVC from ICU patients. The increasing resistance of the bacteria to antimicrobial agents is the major problem in spite of restricted policy of using antimicrobial agents in ICU.


glycopyrrolate

atropine

glycopyrrolate

Anticholinergic premedication for fibreoptic bronchoscopy. atropine is routinely used as part of the premedication regimen for fibreoptic bronchoscopy. This study was performed, firstly, to evaluate the effect of anticholinergic agents on the ease of bronchoscopy, haemodynamic parameters and patient comfort during the procedure; and secondly, to compare atropine with glycopyrrolate, a newer acetylcholine antagonist which is claimed to cause less tachycardia and sedation, whilst suppressing salivation more effectively. One hundred and ninety consecutive patients were randomly allocated to three treatment groups: diazepam 5 mg; diazepam 5 mg + atropine 600 micrograms; and diazepam 5 mg + glycopyrrolate 300 micrograms. Diazepam was given orally one hour before bronchoscopy, and glycopyrrolate/atropine intramuscularly 30 min before bronchoscopy. All patients received thalamonal intravenously, lignocaine gel into one nostril, and lignocaine by transtracheal injection just prior to the procedure. The incidence of bronchoscopy related haemodynamic problems was similar in all three groups. Troublesome coughing , as observed by the operator , was less frequent with glycopyrrolate ( control 51 % , atropine 42 % , glycopyrrolate 30 % ) , as was patient movement ( 40 % , 32 % , 19 % , respectively ) . Uncomfortable dryness of the mouth was most common with glycopyrrolate (37%, 32%, 66%, respectively), but overall assessment of discomfort, and the number of patients who would agree to a repeat bronchoscopy (73%, 76%, 70%, respectively) were very similar in all three groups. In conclusion, the differences between the three groups were slight. glycopyrrolate made the bronchoscopy slightly easier for the operator because of significantly improved cough and movement suppression, though atropine was marginally preferable in terms of patient comfort.


doxorubicin/cyclophosphamide

paclitaxel

trastuzumab

vinorelbine

trastuzumab

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. ### methods The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab . All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. ### results Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. ### conclusions Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.


Peginterferon alfa-2a

ribavirin

Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients . We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.


pyrimethamine

mefloquine

Simultaneous determination of pyrimethamine and mefloquine in human plasma by high-performance liquid chromatography with ultraviolet detection . A rapid, sensitive and selective method was developed for the simultaneous determination of pyrimethamine and mefloquine, two of the active ingredients of Fansimef, in human plasma. The procedure involved extraction of the compounds and the internal standard nitrazepam from basified plasma with dichloromethane and chromatography on a C18 column (microBondapak, 300 X 3.9 mm I.D.) with acetonitrile-phosphate buffer as the mobile phase and UV detection at 222 nm. The limit of quantification was 10 ng/ml for both substances, using a 1-ml plasma specimen. The mean inter-assay precision was 2.8% for pyrimethamine and 4.7% for mefloquine up to 800 ng/ml. The practicability of the method was demonstrated by the analysis of more than 1200 plasma samples from several pharmacokinetic studies involving single-dose administration of Fansimef to both patients and volunteers.


erlotinib

celecoxib

Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study. Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions . Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.


docetaxel

cetuximab

methotrexate

carboplatin

everolimus

A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option. Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel , cetuximab , methotrexate , carboplatin , 5-fluorouracil and everolimus . Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers.


verapamil

trifluoperazine

reserpine

Comparison of effects of surfactants with other MDR reversing agents on intracellular uptake of epirubicin in Caco-2 cell line. P-glycoprotein (P-gp) actively pumps out a number of anticancer drugs, such as epirubicin, from tumor cells. P-gp is also expressed in the small intestine under normal physiological conditions. Inhibition of intestinal P-gp function using MDR reversing agents may enhance the oral bioavailability of some chemotherapeutic agents. Human colon adenocarcinoma (Caco-2) cell line expresses many characteristics of differentiated cells of the normal small intestine. Using Caco-2 as an in vitro intestinal model, the overall goal of the present study was to evaluate the MDR-reversing effects of some commonly used nonabsorptive pharmaceutical surfactants, such as Tween 20, Tween 80 and acacia on the intracellular accumulation of epirubicin by flow cytometry. Tween 20, Tween 80 or acacia all significantly increased intracellular accumulation of epirubicin with the highest enhancing effect for acacia and the lowest for Tween 20. Apart from progesterone , the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil , trifluoperazine and reserpine . In conclusion, our results demonstrate that progesterone, acacia, Tween 20 and Tween 80 are potent MDR modifiers of epirubicin in Caco-2 at concentrations that could be achieved in vivo. Use of surfactants in excipients may increase the intestinal absorption of some drugs through P-gp inhibition and thus improve drug bioavailability for P-gp substrate.


vincristine

etoposide

cisplatin

cytarabine

paclitaxel

[Development and characterization of a gemcitabine-resistant variant of human lung adenocarcinoma cell line A549]. gemcitabine (2',2-difluorodeo- xycytide) has antitumor activity in both experimental and clinical treatment of solid tumors. Although resistance to gemcitabine in ovarian cancer cell line and erythroleukemic cell line was described, there was no report on the lung cancer resistant variant. In order to elucidate the mechanism by which gemcitabine induce resistance in lung cancer, we have established the resistance to gemcitabine in human lung adenocarcinoma cell line A549 and described the characteristics of its resistant variant. ### methods Resistance to gemcitabine was established by exposing A549 cells to increasing concentration of gemcitabine, which was designated as A549-Gem. The IC(50) and resistance index(RI) were tested by MTT assay and colony formation test. The growth curve and cell cycle of A549 and A549-Gem were compared. The cross-resistance profile of A549-Gem was also tested. ### results The IC(50) increased from 6.56+/-1.19 micromol/L in A549 to 921.09+/-225.27 micromol/L in A549-Gem as tested by MTT assay at 72h exposure, the RI was 140.52 (P=0.019 5). The RI of colony formation test was 132.95. Double time of A549 and A549-Gem were 29.7 h and 36.4 h, respectively, as evaluated by the growth curve. A549-Gem was cross-resistant to vincristine and etoposide(54.38-fold and 6.18-fold)(P< 0.01), but not to adriamycin, cisplatin, cytarabine, and paclitaxel. ### conclusion A549-Gem, the gemcitabine resistant phenotype, is stable and suitable for the study of gemcitabine resistance in lung cancer. A549-Gem is cross-resistant to vincristine and etoposide , but not resistant to adriamycin , cisplatin , cytarabine and paclitaxel .


lamivudine

adefovir

[ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] . To evaluate the efficacy of combination therapy of lamivudine (LAM) and adefovir dipivoxyl (ADV) for patients with hepatitis B-induced decompensated cirrhosis. ### methods A total of 81 patients were randomly divided into a combination group and an ADV group over 48 week treatment course. The combination group were treated with LAM (100 mg/d) plus ADV (10 mg/d), and the ADV group with ADV (10 mg/d ) for 48 weeks. All patients received hepatic function support and symptomatic treatment. The levels of HBV DNA, liver function, Child-Pugh scores and HBV DNA indicators were observed before and after the treatment. ### results At week 4, the mean reduction of HBV DNA was 1.83 lgIU/mL, 17.9% of the patients achieved undetectable HBV DNA and 28.2% showed normal ALT in the combination group. The counterpart in the ADV group was 0.96 lgIU/mL, 5.3% and 10.5%. At week 4, 12, 24 and 48, the differences in the mean reduction of HBV DNA, undetectable HBV DNA and ALT normalization were statistically significant between the 2 groups. The difference in HBeAg negative conversion rates and HBeAg seroconversion at week 24 and 48 was not significant. ### conclusion The combination therapy results in HBV suppression and improved liver function and Child-Pugh score. The combination treatment has an advantage over ADV due to low drug resistance rate and good tolerance.


aspirin

aspirin

metoclopramide

Aspirin in the treatment of acute migraine attacks. Acetylsalicylic acid (aspirin or ASA) has been used for many years as an analgesic, antipyretic and anti-inflammatory drug. In recent years, evidence for its effectiveness in migraine headache has been demonstrated in several clinical trials. The effervescent highly buffered preparation of aspirin was shown to be effective, safe and well tolerated compared with placebo or other treatment options. The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects . This review summarizes and analyzes clinical data of aspirin in the treatment of acute migraine attacks with respect to the different galenic formulations.


neratinib

emtansine

trastuzumab deruxtecan

Neratinib: an option for HER2-positive metastatic breast cancer. Metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is currently incurable. The primary goals of treatment are to prolong survival while optimizing quality of life. Several agents are now available in this setting , including neratinib , tucatinib , ado-trastuzumab emtansine , and trastuzumab deruxtecan . neratinib in combination with capecitabine was recently approved for the treatment of adult patients with advanced or metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. neratinib is an oral pan-HER inhibitor that binds covalently to the kinase site, providing irreversible binding. Phase 3 data showed that the combination of neratinib plus capecitabine improved progression-free survival vs lapatinib plus capecitabine. The duration of response was longer among patients in the neratinib arm. neratinib plus capecitabine was also active against brain metastases associated with refractory, HER2-positive breast cancer, and this combination is listed in guidelines from the National Comprehensive Cancer Network for this indication. When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status. Ongoing trials are evaluating the ability of neratinib to treat brain metastases, as well as the efficacy and safety of the triplet combination of neratinib, fulvestrant, and trastuzumab in this setting.


adalimumab

methotrexate

adalimumab

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. ### methods This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis . The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. ### discussion OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. ### Trial Registration NTR4499 . Registered on 7 April 2014.


lapatinib

irinotecan

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas .


atorvastatin

sulfamethoxazole

carbamazepine

levofloxacin

sertraline

trimethoprim

Microcosm evaluation of the effects of an eight pharmaceutical mixture to the aquatic macrophytes Lemna gibba and Myriophyllum sibiricum. Pharmaceuticals have been detected in surface waters of the US and Europe, originating largely from two sources, sewage effluent and agricultural runoff. These compounds often occur as mixtures leading to potential combined effects. In order to investigate the effects of a realistic pharmaceutical mixture on an ecosystem , a study utilizing 15 of 12,000 L aquatic microcosms treated with eight common pharmaceuticals ( atorvastatin , acetaminophen , caffeine , sulfamethoxazole , carbamazepine , levofloxacin , sertraline , and trimethoprim ) at total ( summed ) molar concentrations of 0 , 0.044 , 0.608 , 2.664 , and 24.538 micromol/L ( n = 3 ) was conducted . Phytotoxicity was assessed on a variety of somatic and pigment endpoints in rooted (Myriophyllum sibiricum) and floating (Lemna gibba) macrophytes over a 35-day period. EC10, EC25 and EC50 values were calculated for each endpoint exhibiting a concentration-dependent response. Generally, M. sibiricum and L. gibba displayed similar sensitivity to the pharmaceutical mixture, with phytotoxic injury evident in both species, which was concentration dependent. Through single compound 7-day daily static renewal toxicity tests with L. gibba, the sulfonamide antibiotic sulfamethoxazole, the fluoroquinolone antibiotic levofloxacin and the blood lipid regulator atorvastatin were found to be the only compounds to elicit phytotoxic effects in the concentration range utilized (0-1000 microg/L). atorvastatin concentration was highly correlated to decreased pigment content in L. gibba, likely inhibiting the known target enzyme HMGR, the rate-limiting enzyme in isoprenoid biosynthesis. Hazard quotients were calculated for both microcosm and laboratory studies; the highest HQ values were 0.235 (L. gibba) and 0.051 (L. gibba), which are below the threshold value of 1 for chronic risks. The microcosm data suggest that at an ecological effect size of >20%, biologically significant risks are low for L. gibba and M. sibiricum exposed to similar mixtures of pharmaceutical compounds. For M. sibiricum and L. gibba, respective minimum differences of 5 and 1%, were detectable, however, these effect sizes are not considered ecologically significant.


meglumine

iopamidol

iohexol

Hepatic dynamic sequential CT: section enhancement profiles with a bolus of ionic and nonionic contrast agents.  The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography ( CT ) with iodinated contrast material ( DSBCT ) were prospectively evaluated in 75 patients by using iothalamate meglumine , iopamidol , and iohexol ( 25 patients received each agent ) . After baseline noncontrast CT was performed, DSBCT was performed with a 180-mL intravenous bolus administered at 2 mL/sec. Scanning was started 25 seconds after the bolus was initiated, by using a 3-second scan time and rapid cephalocaudal table incrementation, yielding contiguous 8-mm-thick sections at a rate of nine sections per minute. On postcontrast images, peak enhancement was 115% for iopamidol and 117% for iohexol, both of which were superior to iothalamate meglumine at 95% (P less than .05). After peaking, enhancement then decreased for all three contrast agents, although the decline was more precipitous for iothalamate meglumine. Enhancement on the more caudal sections with both iopamidol and iohexol was superior to that with iothalamate meglumine (P less than .05). The data suggest that the enhancement characteristics for the two nonionic agents may be more optimal for detection of focal hepatic lesions than the ionic agent.


cisplatin

vincristine

bleomycin

Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. ### Patients And Methods Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. ### results Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. ### conclusion NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.


bupropion

nicotine

Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo.  The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment . ### methods This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. ### results The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). ### conclusion Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo.


azithromycin

doxycycline

Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline. ### methods From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks. ### results Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred. ### conclusions Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline . Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.


cabazitaxel

mitoxantrone

The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use. On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application , a 2.4-month longer median overall survival time and a 30 % lower risk for death were observed for cabazitaxel , compared with mitoxantrone . The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).


vincristine

actinomycin D

cyclophosphamide

etoposide

cisplatin

[Intrascrotal rhabdomyosarcoma in adult: a case report]. The patient was a 34-year-old man presenting with the right intra-scrotal painless mass. With a diagnosis of right intrascrotal tumor, the patient underwent right high orchiectomy. The pathological diagnosis of pleomorphic rhabdomyosarcoma arisen from the right spermatic cord was made. Computed tomography revealed a single metastasis in the para-vena cava lymph node. Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 . But the chemotherapy was ineffective and a retoroperitoneal lymphadenectomy (RPLND) was therefore performed. After 3 months following RPLND, the tumor relapsed in a pelvic lymph node involved in right ureter and ileocaecal valve. Resection of the tumor with ileocaecum was performed and then intraoperative radiotherapy (15 Gy) against the tumor bed was performed to ensure the curative effects. After his recovery, he received a total of 6 courses of systemic chemotherapy consisting of vincristin, ifosphamide, etoposide (IRS-IV Regimen 47). The patient was rigorously followed up for 42 months after the final chemotherapy, with no tumor recurrence.


rituximab

cyclophosphamide

vincristine

doxorubicin

methotrexate/ifosfamide

etoposide

cytarabine

Non-Hodgkin Lymphoma in a Kidney Transplant Patient: A Case Report. Post-transplant lymphoproliferative disorders are a possible complication of kidney transplant due to chronic immunosuppressive therapy, and they can elevate the mortality rate. Furthermore, the type of clinical appearance has a wide range. We describe a case of a 38-year-old male recipient who developed post-transplant lymphoproliferative disorders and received successful treatment. The recipient had received a kidney with 1 HLA-B and 1 HLA-DR match, and the deceased donor allotransplant was performed successfully on December 9, 2012. The cause of kidney failure was membranoproliferative-glomerulonephritis proved by biopsy results. The induction therapy was antithymocyte globulin; the basic immunosuppressive therapy consisted of tacrolimus, steroid, and mycophenolate mofetil. After 2 months the patient had elevated serum creatinine level, and biopsy results revealed cellular rejection (Banff grade I). We applied steroid bolus therapy. After that the graft worked properly for 5 years, and the patient had no symptoms or complaints; then he had right lower abdomen pain. After urgent procedures (laboratory diagnostics, abdominal ultrasonography, computed tomography), we operated on the patient in a short time, and after a few weeks the fluorescence in situ hybridization confirmed the translocation of region C-myc; the diagnosis was diffuse large B-cell lymphoma. With the assistance of hematologists, the patient received adequate therapy. He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission . Our case is worth presenting because immunosuppressive drugs can modify the clinical picture, complicating the diagnosis and delaying treatment.