Effects of acute low-dose combined treatment with rimonabant and sibutramine on appetite and weight gain in rats

In view of its potential advantages, drug polytherapy is currently attracting significant interest in the field of obesity research. In this context, concurrent manipulation of serotonergic and cannabinoid pathways in rodents has been found to reduce food and fluid intake in both an additive or synergistic manner. To further assess the value of this polytherapeutic approach, the current study examined the acute effects of low-dose combinations of the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.5 mg/kg) and the dual serotonin- and noradrenaline-reuptake inhibitor sibutramine (0.125 and 0.25 mg/kg) in male rats. Ethological analysis was used to generate comprehensive behavioural profiles, including the behavioural satiety sequence (BSS). Findings confirmed that, although neither drug given alone significantly altered food intake, feeding behaviour or weight gain, rimonabant per se tended to reduce consumption and time spent feeding while significantly increasing scratching and grooming responses. However, none of these effects of the CB1 receptor antagonist/inverse agonist was significantly altered by the presence of either dose of sibutramine. In striking contrast to recent reports of acute low-dose interactions (enhanced appetite suppression and reduced side-effects) between rimonabant and naloxone, present results would not appear to support the clinical potential of rimonabant/sibutramine polytherapy for obesity.     

Anticonvulsant drugs in monotherapy. Effect on the fetus

We describe a material of 577 infants born of epileptic women treated with anticonvulsants in monotherapy during early pregnancy and collected from France, Italy, and Sweden. The incidence of major malformations is increased compared with the general population but no definite difference in risk can be demonstrated between the various anticonvulsants, but valproic acid was associated with a doubling of the average risk. The increased risk for facial clefts and for cardiac malformations, described from most studies on epilepsy during pregnancy, cannot be seen in this material. Unusually many cases of penis abnormalities (micropenis, hypospadias) were noted. An effect on fetal growth can be demonstrated and is apparently more pronounced for carbamazepine than for the other drugs. It results in a reduced birth weight in spite of normal gestational length, reduced body length and head circumference. The possible biological significance of this finding is discussed.Corresponding author.     

Long-term glycaemic control with pioglitazone in patients with type 2 diabetes

Patients with type 2 diabetes have dual defects: insulin resistance and beta-cell dysfunction. Thiazolidinediones (TZDs), a new class of oral drugs used for the treatment of type 2 diabetes, reduce insulin resistance via an action on peroxisome proliferator-activated receptors. There is also growing evidence that TZDs may preserve beta-cell function. Pioglitazone is a TZD that provides appropriate monotherapy or combination treatment for patients with type 2 diabetes. Studies of up to 32-week duration have shown that pioglitazone significantly reduces HbA1c and fasting plasma glucose when used alone or in combination with another glucose-lowering agent. Four recently published 52-week clinical trials, involving over 3700 patients with type 2 diabetes, show that pioglitazone is an effective long-term treatment, both as monotherapy and in combination with metformin or sulphonylurea. As well as maintaining glycaemic control over the long term, pioglitazone also confers benefits in terms of improvements in fasting insulin, lipid parameters, C-peptide and 32,33-split proinsulin (independent predictors of cardiovascular risk) and hypoglycaemia compared with other monotherapies or combination therapies. It is well tolerated, with a low incidence of adverse events. These long-term data support the concept that pioglitazone should be used earlier in the treatment of type 2 diabetes, either as monotherapy or as add-on therapy.     

Anti–Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today?

Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse–human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy‐refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitumumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti‐EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti‐EGFR monotherapy is an effective treatment modality for patients with chemotherapy‐refractory advanced CRC.     

多重耐药鲍曼不动杆菌治疗药物的研究进展

随着广谱抗菌药物的广泛应用,多重耐药鲍曼不动杆菌不断出现,并已成为现代医疗体系的重大挑战。碳青霉烯类抗生素是治疗鲍曼不动杆菌感染最有效的药物之一。但碳青霉烯类耐药鲍曼不动杆菌也逐渐增多,使治疗药物的选择非常局限。联合用药在体外研究中显示出不同程度的协同作用,新型药物的开发也显得格外重要。     

多西紫杉醇与多西紫杉醇联合卡铂治疗老年晚期非小细胞肺癌的疗效观察

目的比较单药多西紫杉醇（Docetaxel,TXT）和TXT联合卡铂（Carboplatin,CBP）即TC方案治疗老年晚期非小细胞肺癌(Non-small cell lung cancer,NSCLC)的疗效及不良反应的差异。方法46例晚期NSCLC老年患者,随机分为两组: TXT组给予TXT 50mg/m²,第1天,每2周重复;TC组给予TXT 40mg/m²,第1天, CBP 300mg/m²,第1天,每2周重复。结果两组有效率(36.4% vs 41.7%, P=0.77)和中位生存期(9.2月 vs 7.9月,P=0.13)差异均无统计学意义。TXT组患者生活质量改善优于TC组（77.3% vs 45.8%,P=0.03）,且Ⅲ+Ⅳ度白细胞减少发生率明显低于TC组（18.2% vs 54.2%, P=0.02）。两组非血液学毒性较温和,耐受性良好。结论与TC方案相比,TXT单药2周方案治疗老年NSCLC疗效相当,耐受性及生活质量更好,值得临床进一步观察研究。     

吉西他滨单药化疗联合适形放疗治疗老年局限晚期非小细胞肺癌的疗效分析

目的探讨吉西他滨单药化疗联合适形放疗治疗老年局限晚期非小细胞肺癌(NSCL)的临床控制率(CCR)及毒副反应。方法选择2005年6月~2009年1月收治的Ⅲa～Ⅲb老年局限非小细胞肺癌患者40例,随机分为对照组及实验组,每组20例。对照组组采用吉西他滨单药化疗4周期,实验组吉西他滨单药化疗2周期后进行适形放疗。治疗结束后比较两组患者肿瘤控制率及毒副反应差异。方法实验组总有效率(ORR)为85.0%,对照组ORR值为35.0%,实验组ORR高于对照组,差异有统计学意义(P<0.05)。实验组化疗毒副反应发生等级低于对照组,差异有统计学意义(P<0.05),实验组中有7例出现放射性肺炎,12例出现放射性食管炎。结论采用吉西他滨单药化疗联合适形放疗治疗老年晚期非小细胞肺癌能提高肿瘤临床控制率,合理控制放疗剂量,能够避免严重放射性损伤风险,适合老年非小细胞肺癌患者应用。     

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer

BackgroundProgrammed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC.Patients and MethodsEligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed.ResultsSeventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS.ConclusionAtezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.     

吉西他滨治疗老年晚期非小细胞肺癌的临床观察研究

目的探讨吉西他滨单药治疗老年晚期非小细胞肺癌的临床疗效和安全性。方法选择初治的经病理证实不能手术的老年晚期(Ⅲb～Ⅳ期)非小细胞肺癌患者42例,给予吉西单滨1000mg/m2,第1、8、15天,每4周重复。2周期后评价疗效。结果近期疗效:全组42例患者中PR12例,SD14例,PD10例,RR为29.1%,DCR为74.2%。生活质量变化:KPS评分改善33.33%(14/42),稳定45.23%(19/42),下降21.43%(9/42)。不良反应主要为骨髓抑制和消化道反应,大多数患者不良反应轻微,为Ⅰ～Ⅱ级。结论单药吉西他滨方案治疗老年晚期非小细胞肺癌安全有效。