Lenalidomide

bortezomib

Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma .


fluvoxamine

methylphenidate

[ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] . To observe the clinical efficacy of dopamine modulator methylphenidate (MPH) of extended-release formulations (MPH-ER) augmentation of ongoing fluvoxamine treatment in refractory obsessive-compulsive disorder (OCD) and its effects on patient's anxiety and sleep quality.
 Methods: A pilot randomized, placebo-controlled, and double-blind trial was conducted at an outpatient, single-center academic setting. Participants included 44 adults with serotonin reuptake inhibitor treatment-refractory OCD and they received a stable fluvoxamine pharmacotherapy with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores higher than 20. The 44 patients were randomly assigned into a study group and a control group, with 22 patiencs in each group. fluvoxamine and MPH-ER were given to the study group, while fluvoxamine and placebo were given to the control group, with 8 weeks of the treatment course. Y-BOCS, Hamilton Anxiety Scale (HAMA) were used to assess the efficacy, Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality, and Treatment Emergent Symptom Scale (TESS) was used to evaluate the side effects. Data were analyzed in the intention-to-treat sample.
 Results: The improvement in the Y-BOCS total score, Y-BOCS obsession subscale score and HAMA score were more prominent in the study group than those in the control group (P<0.001). There was no significant difference in PSQI score and TESS score between the two groups. MPH-ER was well tolerated.
 Conclusion: fluvoxamine combined with MPH-ER is effective in the treatment of refractory obsessive-compulsive disorder. It can improve anxiety and has no adverse effect on sleep quality.


Pertuzumab

Trastuzumab

Docetaxel

Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer . Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. ### Patients And Methods The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens. ### results The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval. ### conclusion HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen.


floxuridine

gemcitabine

oxaliplatin

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. ### objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. ### Design Setting And Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. ### interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin . ### Main Outcomes And Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. ### results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). ### Conclusions And Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.


celecoxib

rofecoxib

rofecoxib

Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended . Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.


cyclophosphamide

doxorubicin

vincristine

prednisolone

rituximab

Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma.  Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) . However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them. ### methods At our institute, for DLBCL patients aged 65-79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP. ### results Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p < 0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60-80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups. ### Discussion And Conclusions Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.


cyclosporine

tacrolimus

Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine. tacrolimus has been shown to provide superior immunosuppression in various solid organ transplant settings. The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus . ### methods Single lung transplantation from MHC mismatched donors was performed in 10 minipigs. Immunosuppression included 1.5 mg/kg per day methylprednisolone and 1.0 mg/kg per day azathioprine. CsA (n=5) was adjusted to trough levels of 300-500 ng/ml, tacrolimus (n=5) was adjusted to 16-26 ng/ml. All immunosuppressive drugs were discontinued on postoperative day (POD) 28. Allograft survival was monitored by sequential chest radiographs, bronchoscopy and transbronchial biopsy histology. Peripheral blood leukocytes were scanned for donor chimerism and CD3, CD4, CD8 and CD25 expression. ### results The animals survived a 4-week course of immunosuppression without radiological or histological signs of rejection on POD 28. Median allograft survival in CsA-treated animals was 55+/-15 days and all animals rejected their grafts within 42 days after withdrawal of immunosuppression. In tacrolimus-treated animals, median survival was 152+/-65 days with the longest survivor being electively sacrificed on POD 390 (P=0.0064). The degree of donor leukocyte chimerism and the frequency of CD4+CD25+ T-cells were higher in the tacrolimus group, however, these differences were not statistically significant. ### conclusion The results of our study show that primary immunosuppression with tacrolimus is superior to cyclosporine after pulmonary allotransplantation in a large animal model.


Paclitaxel

Bevacizumab

Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review . We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.


bevacizumab

oxaliplatin

irinotecan

A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study). No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. ### methods Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). ### results In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%). ### conclusions The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .


iloperidone

clozapine

haloperidol

Differential effects of iloperidone, clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm. Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available. ### objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol. ### methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0-64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured. ### results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance. ### conclusion In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task . These results might provide important information for the development of NLs with beneficial effects on cognition.


ticagrelor

aspirin

New oral anticoagulants in acute coronary syndrome: is there any advantage over existing treatments? After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated. ### objectives The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., "triple therapy"). ### Materials And Methods The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies. ### results The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of ± 15 % . ### conclusions Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.


indinavir

nelfinavir

ritonavir

saquinavir

Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. To assess the patterns of HIV phenotypic cross-resistance to protease inhibitors (PI) in patients experiencing viral load rebound on combination therapy including a PI. ### methods Phenotypic analysis of sensitivity to indinavir, nelfinavir, saquinavir, ritonavir and amprenavir was carried out using a single-cycle recombinant virus assay. Viral protease was sequenced by automated dideoxynucleotide chain termination. ### results Of the 108 patients studied, 68 had received indinavir, 50 ritonavir, 25 saquinavir and eight nelfinavir. The majority (71%) had received only one PI. The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) . Cross-resistance to amprenavir was less frequent (37-40%). However there was some correlation between levels of sensitivity to amprenavir and indinavir (r2 = 0.34; P < 0.01). Conversely, the correlation between levels of sensitivity to indinavir and saquinavir was poor (r2 = 0.25), particularly for patients who had not received saquinavir. The degree of cross-resistance correlated with the level of resistance and with the total number of mutations in the protease gene (P < 0.05, chi square test) but could not be significantly correlated to any one particular mutation or combination of mutations. Mutation 184V was significantly associated with cross-resistance to amprenavir, with no mutations at codon 50 observed, while mutations associated with cross-resistance to saquinavir differed according to the treatment received. ### conclusions These results suggest that, although the total number of protease mutations correlates with the degree of cross-resistance, the specific mechanisms accounting for primary resistance and for cross-resistance may be different.


Mercaptopurine

Allopurinol

Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis . mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.


capecitabine

irinotecan

Second-Line Chemotherapy of Advanced Colorectal Cancer: Predictive and Prognostic Factors. Colorectal cancer progression presents a significant clinical problem. After its dissemination, the foundation of its treatment comprises of palliative chemotherapy. ### objectives The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression . ### Material And Methods The retrospective analysis of 164 patients with advanced colorectal cancer treated in 2001- -2008 included chosen clinical, pathological and follow-up data. ### results Response to second-line chemotherapy was observed in 34 out of 164 patients: In 18/82 in the irinotecan group (22%) and in 16/82 in the capecitabine group (19.5%). The mean survival time to progression following the second line of treatment amounted to 5.85 and 6.2 months respectively. Statistically, a higher number of patients in good condition of 0 to 1 was documented in the group responding to treatment. Significant correlation was documented between primary stage of the disease and time to progression in patients treated with capecitabine (p = 0.0258). The recurrence of the disease was observed in 44/45 patients following operation with radical intention but with an insufficient number of excised lymph nodes. A significantly longer time to progression was observed in women treated with capecitabine. In logistic regression, lack of treatment response was found to be an independent factor affecting the time to disease progression. Patients who did not respond to the second line of treatment demonstrated a significantly shorter time to disease progression than patients who responded to it and they showed a significantly higher number of patients with leucopenia during treatment. ### conclusions Clinical response to treatment in both treated groups is of significant importance for the probability of local recurrence of the disease, preservation of a good patient's condition and the higher level of leukocytes during treatment.


telmisartan

amlodipine

amlodipine

Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial. Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. ### objective The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. ### methods An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) . ### results Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. ### conclusions In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).


tenofovir

didanosine

Effect of tenofovir on didanosine absorption in patients with HIV. To evaluate the pharmacokinetic interaction between tenofovir and didanosine when used in combination as a highly active antiretroviral therapy regimen. ### Data Sources Literature retrieval was accessed through MEDLINE (1966-January 2003) using the terms tenofovir and didanosine. Abstracts from recent meetings, including the International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were reviewed for relevant abstracts and poster presentations. ### Data Synthesis Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers . tenofovir 300 mg administered concurrently with 400 mg didanosine results in a 48-64% increase in the didanosine maximum plasma concentration and AUC with no significant alterations in the tenofovir pharmacokinetic parameters. tenofovir 300 mg and didanosine 250 mg has been compared with didanosine 400 mg alone. The results demonstrated equivalent didanosine AUCs. ### conclusions When used concurrently, tenofovir significantly increases the maximum plasma concentration and the AUC of didanosine. Additional data in HIV-infected patients are needed to determine the long-term toxicities of this combination therapy. didanosine dose reduction should be considered when these 2 agents are used concurrently.


doxorubicin

epirubicin

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.  This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting . This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.


oxytocin

vasopressin

Oxytocin, vasopressin and trust: Associations with aggressive behavior in healthy young males. oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior . We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior.


Lapatinib

Herceptin

Cetuximab

Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of lapatinib for therapy of ESCC patients, we evaluated the effect of lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated . lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of lapatinib. Cumulatively, the data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of lapatinib and cetuximab/Herceptin is a promising strategy in ESCC.


aspirin

clopidogrel

aspirin

Preoperative platelet aggregation predicts perioperative blood loss and rethoracotomy for bleeding in patients receiving dual antiplatelet treatment prior to coronary surgery. Patients scheduled for coronary artery bypass graft surgery (CABG) are commonly treated with clopidogrel. We sought to assess the relation between preoperative platelet aggregation and bleeds in CABG patients on clopidogrel. ### Material And Methods In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy . Platelet aggregation induced by 10μmol/l adenosine di-phosphate (ADP) in platelet-rich plasma was measured in subjects on clopidogrel within 5days prior to surgery. ADP-induced aggregation of ≥50% was used to define subjects with satisfactory inhibition of platelet reactivity. ### results In 29 patients with preoperative ADP-induced aggregation ≥50%, compared with 23 subjects with aggregation <50%, lower chest-tube drainage volumes (after 6h, p=0.002; and 12h, p=0.001) and fewer rethoracotomies were observed (p=0.03). The former group was characterized with lower transfusion rates of packed red blood cells (p=0.009), platelet concentrate (p=0.04) and fresh frozen plasma (p=0.001). Patients with ADP-induced aggregation ≥50% did not differ from untreated controls regarding the postoperative drainage, transfusions and rethoracotomy. The incidence of thromboembolic events and death during perioperative period were similar in all groups. Multivariate logistic regression identified ADP-induced aggregation <50% as the only independent predictor of rethoracotomy (OR=2.94 [1.12-7.75], p=0.029). ### conclusions Patients on aspirin and clopidogrel <5days before CABG who had preoperative ADP-induced platelet aggregation ≥50% have bleeding risk similar to those receiving aspirin monotherapy. Reduced platelet reactivity to ADP can predict postoperative bleeding in CABG patients on dual antiplatelet therapy.


levofloxacin

erythromycin

rifampin

Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila. The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin . In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin.


Ketanserin

tropisetron

Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor. In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. ketotifen (3 to 100 mumol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect . Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)


zidovudine

oxazepam

Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient.  This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam . Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. zidovudine concentrations were determined by radioimmunoassay. oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


amiloride

isoprenaline

Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis. In cystic fibrosis (CF), the clinical condition of patients correlates poorly with genotype. One possible explanation is that clinical status is influenced by net preserved chloride secretion rather than the CF mutation. We tested the relationships between residual chloride secretion, as measured by nasal potential difference (PD) and the type of mutation (genotypes expressing apical cystic fibrosis transmembrane conductance regulator (CFTR) protein versus those that do not) and clinical status. Twenty two CF patients (mean age 25.7 yrs, 11 females and 11 males, mean forced expiratory volume in one second (FEV1) 53.1% of predicted) with defined genotypes were recruited. Nasal PD was measured using a standard protocol involving the perfusion of the nasal epithelium with a sodium channel blocker (amiloride), followed by a solution of low chloride and finally with isoprenaline. Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) . There was no correlation between mutation type and clinical condition. When these patients were recategorized as "high" (> 10 mV amiloride to isoprenaline response) or "low" (10 mV or less) chloride secretors, we found that the former group had a significantly higher FEV1 (67.7 versus 48.3% pred) and a better pulmonary radiological score (4.14 versus 7.07, by Northern scoring system). These results suggest that some cystic fibrosis patients, regardless of genotype, have an ability to secrete chloride when stimulated with chloride secretatagogues, and this is correlated with a better lung function. These results also have implications for the use of potential difference measurements in novel cystic fibrosis transmembrane conductance regulator replacement trials.


ketoconazole

abiraterone

enzalutamide

docetaxel

Factors influencing treatment of veterans with advanced prostate cancer. Treatments for metastatic castration-resistant prostate cancer (CRPC) differ in toxicity, administration, and evidence. In this study, clinical and nonclinical factors associated with the first-line treatment for CRPC in a national delivery system were evaluated. ### methods National electronic laboratory and clinical data from the Veterans Health Administration were used to identify patients with CRPC (ie, rising prostate-specific antigen [PSA] on androgen deprivation) who received abiraterone, enzalutamide, docetaxel, or ketoconazole from 2010 through 2017. It was determined whether clinical (eg, PSA) and nonclinical factors (eg, race, facility) were associated with the first-line treatment selection using multilevel, multinomial logistic regression. The average marginal effects (AMEs) were calculated of patient, disease, and facility characteristics on ketoconazole versus more appropriate CRPC therapy. ### results There were 4998 patients identified with CRPC who received first-line ketoconazole, docetaxel, abiraterone, or enzalutamide. After adjustment, increasing age was associated with receipt of abiraterone (adjusted odds ratio [aOR], 1.07; 95% credible interval [CrI], 1.06-1.09) or enzalutamide (aOR, 1.10; 95% CrI, 1.08-1.11) versus docetaxel. Greater preexisting comorbidity was associated with enzalutamide versus abiraterone (aOR, 1.53; 95% CrI, 1.23-1.91). Patients with higher PSA values at the start of treatment were more likely to receive docetaxel than oral agents and less likely to receive ketoconazole than other oral agents. African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) . This effect was attenuated when adjusting for facility characteristics (AME, 1.9%; 95% CI, -0.4% to 4.1%). ### conclusions Clinical factors had an expected effect on the first-line treatment selection. Race may be associated with the receipt of a guideline-discordant first-line treatment.


vorinostat

exemestane

ibuprofen

Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. ### methods Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. ### results Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. ### conclusion UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen .


everolimus

erlotinib

Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active β-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3β (p-GSK3β) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active β-catenin, GATA-6 and p-GSK3β were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition . Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients.


dexmedetomidine

bupivacaine

Value of Adding Dexmedetomidine in Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis for Treatment of Pancreatic Cancer-Associated Pain. Abdominal and back pain is present in up to 80% of patients with pancreatic cancer and represents a significant cause of morbidity. Celiac plexus neurolysis (CPN) demonstrated good results in relief of pain of upper abdominal malignancy. Dexmedetomidine is alpha-2 adrenoceptor highly selective agonist approved for procedural sedation use. ### Patients And Methods Fifty patients divided in two groups with locally advanced pancreatic cancer-associated abdominal pain underwent endoscopic ultrasound (EUS)-guided CPN using bupivacaine 0.5% alone with alcohol for the first group and bupivacaine 0.5% plus dexmedetomidine in the second. Patients scored their pain according to the Numeric Rating Scale (NRS-11) before, 2, 4, 6, 8, 12, 16, and 24 week after the procedure. ### results The study has included 50 patient in two groups. There was no significant difference between the two groups as regards medical, laboratory, or tumor characters. The median pain score decreases from 8.32 ± 0.75 before the procedure to 3.75 ± 3.72 24 week after the procedure in group 1 and from 8.08 ± 0.86 before to 1.67 ± 2.3 24 week after the procedure in group 2. However, there was no significant difference between the two groups in the median pain score during the first 4 weeks. There was no statistically significant difference between the two groups as regards the median survival time. ### conclusion The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival .


gefitinib

gefitinib

meloxicam

meloxicam

Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis. To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. ### Materials And Methods The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. ### results The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) . The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. ### conclusion Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.


ziconotide

morphine

ropivacaine

clonidine

Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. ### objective To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. ### Study Design Observational cohort study. ### setting Three French cancer centers. ### methods Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine . ### results Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7  (9%) including 5  (6%) for whom a causal role for ziconotide was highly likely; among them 4  (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity  (by 48%) in response to intrathecal analgesic therapy that included ziconotide. ### limitations Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. ### conclusions The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration.


adalimumab

etanercept

methotrexate

A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. ### Data Sources Electronic databases were searched up to February 2005. ### Review Methods Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. ### results Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (<or=3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage . etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around pound30,000 per quality-adjusted life-year (QALY) in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is pound24,000 per QALY, substantially lower than for adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY). First line use as monotherapy generates ICERs around pound50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. ### conclusions adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.


gemcitabine

doxorubicin

paclitaxel

Evaluation of a gemcitabine-doxorubicin-paclitaxel combination schedule through flow cytometry assessment of apoptosis extent induced in human breast cancer cell lines.  Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer . We compared the potential of various schedules of GAT to induce apoptosis on MDA-MB-231, MCF7, and T47D human breast cancer cell lines. The extent of apoptotic induction was analyzed by flow cytometry with 7-aminoactinomycin D (7AAD) staining. Differences between various schedules in terms of apoptotic induction were statistically significant (P < 0.05). The most effective apoptotic induction regimen was achieved by the sequence: Dox for 16 h followed by Pac + Gem. Schedules employing a 16-h interval between drug administrations induced higher levels of apoptosis in human breast cancer cell lines compared with schedules using a 4-h interval. The therapeutic efficacy of the experimental results shown in this paper has been clinically corroborated in a phase II trial in metastatic breast cancer patients.


adriamycin

mitomycin-C

bleomycin

etoposide

Overcoming of cross-resistance to the cell-killing activity of oxygen radicals in VCR-resistant hematologic cell lines with cyclosporin-A.  Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals . Since vincristine (VCR)-resistant cells show cross-resistance to oxygen radicals, this study was designed to study whether the combined effects of oxygen radicals derived from hypoxanthine-xanthine oxidase plus enhancers of anti-cancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxygen radicals in VCR-resistant human leukemia/lymphoma cell lines. We found that 3 micrograms/mL Cy-A enhances the cidal effect of oxygen radicals on two of five types of wild type and two of five VCR-resistant cell lines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cidal activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms from those of Ver or Dip, and Cy-A may be useful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment.


isepamicin

amikacin

The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections . This multicentre, randomised, open-label, parallel group study compared the efficacy and safety of isepamicin (15 mg/kg once daily) and amikacin (7.5 mg/kg twice daily) when given intravenously in combination with metronidazole to 267 hospitalised adults with intra-abdominal infections. Clinical cure or improvement was achieved in 96.3% (130/135) evaluable patients (efficacy population) in the isepamicin group and 94.3% (66/70) patients in the amikacin group. Bacteriological elimination occurred in 93.3% (126/135) evaluable isepamicin patients and 95.7% (67/170) amikacin patients. there was not statistically significant differences between the groups. Adverse events were reported by 9% of patients in the isepamicin group (16/178) and 10% of patients in the amikacin group (9/89). Events considered to be related to treatment occurred in 6% of patients in both groups. The most frequent adverse events were diarrhoea, nausea and vomiting. Renal problems caused three patients (2 isepamicin, 1 amikacin) to withdraw from the study. Ototoxicity (detected by audiometric testing) occurred in one patient (treated with isepamicin). In conclusion, isepamicin at a dose of 15 mg/kg once daily was shown to be as effective as amikacin (7.5 mg/kg twice daily) in the treatment of intra-abdominal infections in hospitalised adults also treated with metronidazole. Both treatments were well tolerated.


Imipenem

nafcillin

penicillin

gentamicin

Imipenem therapy of experimental Staphylococcus aureus and Streptococcus faecalis endocarditis. imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively . The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data.


paclitaxel

cisplatin

etoposide

Paclitaxel, cisplatin, etoposide combination chemotherapy: a multifractionated bolus dose schedule for non-small cell lung cancer. In this phase II study, paclitaxel was added to the combination of cisplatin and etoposide (TPE regimen), in 37 patients with advanced non-small cell lung cancer, using a multifractionated dosing schedule. The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days . 15 patients had stage III A or B disease and 22 stage IV disease. 32 patients were evaluable for toxicity and 37 for response. Neutropenia was the most prominent toxicity. Grade 3 or grade 4 neutropenia was observed in 12 (38%) and 9 (25%) of the patients, respectively and 11 patients required hospitalisation. 3 patients died secondary to chemotherapy related sepsis. Diarrhoea (grade 3, 3 patients; grade 4, 2 patients) was the only other significant non-haematological acute toxicity. The optimal dose rate for this multifractionated regimen was paclitaxel 35 or 40 mg/m2/fraction; cisplatin 15 mg/m2/fraction; etoposide 35 or 40 mg/m2/fraction. Responses were observed in 28 of 37 evaluable patients (3 complete response; 25 partial responses [76%]. 22 patients are alive; 8 with stage III B disease received radiation or surgery (3 had minimal or no tumour in the pathology specimen). TPE is a highly active regimen for non-small cell lung cancer and multifractionated dose scheduling is a feasible and well tolerated system.


lenvatinib

pembrolizumab

lenvatinib

everolimus

sunitinib

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. ### methods In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) . The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. ### results A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. ### conclusions lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).


ACNU

vincristine

methotrexate

A long surviving case of recurrent medulloblastoma displaying effectiveness of ACNU/vincristine chemotherapy. A favorable case of recurrent medulloblastoma, in which 19 years has elapsed with combination therapy due to surgery, radiation and chemotherapy since the initial operation, is reported. The case was a male of age 12 who was admitted due to medulloblastoma of the classical type. Tumor recurrences were observed 3 times within 7 years after the initial operation and radiation treatment. At the 3rd recurrence, a large tumor was found in the cerebellar vermis and left cerebellar hemisphere on CT with CSF dissemination and a high NSE level in the CSF (62 ng/ml). Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time . The tumor image and gait disturbance with radicular pain disappeared completely and the NSE level in the CSF improved to within the normal range (5.4 ng/ml). The patient continues in complete remission, with a Karnovsky performance status of 100% at 4 years after the 3rd recurrence. We report full details of this case in which active treatments consisting mainly of chemotherapy proved to be effective for recurrent medulloblastoma, even though its prognosis is generally very unfavorable.


nivolumab

ipilimumab

sunitinib

A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma. The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib . The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. ### Materials And Methods A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. ### results The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. ### conclusion Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. ### Implications For Practice This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients.


docetaxel

paclitaxel

Preclinical pharmacology of the taxanes: implications of the differences. Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to beta-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux . Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons.


olanzapine

risperidone

clozapine

Comparative study of sexual dysfunction and serum prolactin level associated with olanzapine, risperidone, and clozapine in patients with remitted schizophrenia. Sexual dysfunctions have been a major side effect of the second generation anti-psychotic drugs which often affects treatment compliance in patients with schizophrenia. There is no/few systematic review or research addressing sexual dysfunction and their effect on serum prolactin level among different atypical antipsychotics in India. ### aims To determine and compare the frequency of sexual dysfunction associated with olanzapine, risperidone, and clozapine and their effect on serum prolactin level in remitted patients with schizophrenia. ### Settings And Design Cross-sectional hospital-based study. Recruitment by purposive sampling. Estimation of serum prolactin was done using enzyme-linked immunosorbent assay technique. ### Materials And Methods The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls . A Brief Psychiatric Rating Scale, Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and Sexual Functioning Questionnaire were administered. Analysis of variance was used to compare clinical variables. Chi-square test was used to identify the frequency of sexual dysfunction. Kruskal-Wallis test was used to compare UKU side effect, sexual dysfunction, and blood parameters across the study groups. ### Results And Conclusion Eighty-six percentage reported sexual dysfunction in one or more domains of sexual functioning in risperidone group as compared to 48.3% in olanzapine and 31% in clozapine groups, respectively. Prolactin level elevation was statistically significant in risperidone group followed by clozapine and olanzapine groups, respectively.


ropivacaine

bupivacaine

ropivacaine

levobupivacaine

levobupivacaine

bupivacaine

Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacaine for intrathecal labor analgesia. Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. ### methods Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. ### results The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine . There were significant trends (P bupivacaine and levobupivacaine. ### conclusions This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine.


Lapatinib

paclitaxel

A novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro.  Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial . In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with ¹H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.


bevacizumab

irinotecan

temozolomide

vincristine

Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease. ### methods We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, ± temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125-150 mg/m(2) irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m(2) orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days . ### results Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea. ### conclusions The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy.


acamprosate

naltrexone

Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study. The COMBINE study evaluated the effects of acamprosate, naltrexone, and the Combined Behavioral Intervention (CBI). In secondary analyses, our goals were to identify trajectories of any drinking prior to randomization, to characterize subjects in these trajectories, and to assess whether prerandomization trajectories predict drinking outcomes and moderate treatment response. ### methods We analyzed daily indicators of any drinking in 90 days prior to randomization using a trajectory-based approach. General linear models and generalized logistic regression assessed main and interactive effects of prerandomization drinking trajectories and treatment on summary drinking measures during active treatment. ### results We identified five trajectories of any drinking prior to randomization: "T1: frequent drinkers", "T2: very frequent drinkers", "T3: nearly daily drinkers", "T4: consistent daily drinkers", and "T5: daily drinkers stopping early". During treatment, "T3: nearly daily drinkers" and "T4: consistent daily drinkers" had significantly worse drinking outcomes than "T1: frequent drinkers", while "T5: daily drinkers stopping early" had comparable drinking outcomes to "T1: frequent drinkers". acamprosate significantly increased the chance of abstinence from heavy drinking for the "T2: very frequent drinking" trajectory but decreased the chance of abstinence from heavy drinking for "T5: daily drinkers stopping early". naltrexone differentially improved rates of continuous abstinence for very frequent drinkers. ### conclusions acamprosate benefited very frequent drinkers and contrary to expectations was associated with poorer response compared to placebo for consistent daily drinkers who had longer durations of pretreatment abstinence (e.g., ≥14 days). Baseline drinking trajectories also moderated naltrexone effects. These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial .


doxorubicin

vinorelbine

Multicenter phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. ### Patients And Methods From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks . ### results The median age of the patients in this trial was 68 years (range 60-82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0-1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. ### conclusion The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment.


simvastatin

exemestane

Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells. Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells . The anti-proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF-7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF-7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF-7 estrogen receptor-positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein apoptotic pathway and the mitogen-activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone-dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials.


Omeprazole

Praziquantel

Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms . Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. ### methodology We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. ### Principal Findings We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. ### conclusions Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.


aztreonam

cefepime

Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to β-lactams in ICU patients: A pilot study. Resistance to all β-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. ### Material And Methods Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all β-lactams and treated with the association of at least aztreonam plus cefepime . Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. ### results Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. ### discussion These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all β-lactams with a clinical efficacy rate of 69%.