Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.     

Antibodies to hepatitis C virus in autologous blood donors

Hepatitis C virus (HCV) is the major cause of posttransfusion hepatitis. Two anti-HCV enzyme immunoassay (EIA) kits and one recombinant immunoblot assay (RIBA) were used to test serum samples of 1476 donations from 692 autologous blood donors to assess the prevalence of anti-HCV and its relationship to transfusion history. Of all autologous blood donations, 23 (1.6%) reacted when tested with one EIA kit and 29 (2.0%) reacted when tested by the other EIA kit. Of the autologous donors, 12 (1.78%) reacted by the first EIA kit and 14 (2.02%) by the second. Discrepancies in the EIA results from different donations by the same donor were seen in seven donors. The RIBA was positive or indeterminate in 33 percent of the EIA-reactive donations and in 41 percent of EIA-reactive donors. All RIBA-positive and -indeterminate samples reacted with both EIA kits. There was no significant difference in the EIA-reactive rates of autologous and first-time homologous blood donors. Previously transfused autologous blood donors had a higher anti-HCV EIA-reactive rate than nontransfused autologous donors, but the difference was not significant. In regard to hepatitis C, the use of autologous blood for homologous transfusion appears to be as safe as the use of blood from first-time homologous donors. Universal testing of previously transfused patients for hepatitis C appears premature at this time. Discrepant anti-HCV EIA results from different donations from the same individual have implications regarding donor deferral.     

NEW INVESTIGATOR AWARD FINALISTSNIA0001Induction of differentiation in human preadipocytes may contribute to adipogenic effect of human adenovirus Ad-36

Human adenovirus Ad-36 causes adiposity in animal models and shows association with human obesity. The mechanism involved is unknown. We previously reported that Ad-36 enhances differentiation of 3T3-L1 preadipocytes and E4orf-1 gene of the virus is responsible for the adipogenic effect in the rodent cell line. We undertook a three-step approach to investigate the role of preadipocyte differentiation in adipogenic effect of Ad-36. First, we showed that the viral mRNA is expressed in adipose-derived stem cells (ASC) of animals experimentally infected with Ad-36. Infection of rats with Ad-36 resulted in increased epididymal fat pad weight and the expression of Ad-36 E4orf-1 mRNA was detected in ASC isolated from the fat pads. Next, we determined if humans naturally infected with Ad-36 will show greater preadipocyte differentiation. Subcutaneous adipose-tissue samples from 33 Pima Indian subjects were screened by nested-PCR specific for Ad-36 DNA. Nine subjects (27%) had Ad-36 DNA. A blinded comparison of their ASC showed greater differentiation to adipocytes for the Ad-36 DNA positive subjects ( P =  0.06) compared to the Ad-36 DNA negative group. Finally, we used a direct approach. Human-ASC when infected with Ad-36 showed spontaneous replication, differentiation, and lipid accumulation, which was significantly greater than the uninfected controls ( P  < 0.01). Ad-36 induced lipid accumulation in human-ASC increased in response to the viral load and the lipogenic response was observed regardless of the donor gender and over an age range of 22–57 years. These results suggest that ability of Ad-36 to induce preadipocyte differentiation may play a role in human adiposity.     

Anti-inflammatory activity of the leaf extacts of Gendarussa vulgaris Nees

Objective

To evaluate the anti-inflammatory property of the leaf exacts of Gendarussa vulgaris (G. vulgaris) Nees.

Methods

G. vulgaris Nees of the family Apocynaceae is a medium sized tree grown in semishade or no shade and is common in the Ernad and Nilambur taluks of Kerala.Various parts of this plant have been used in the treatment of ulcers, sores, inflammation, dyspepsia, healing of wounds, etc. The present study aimed at the evaluation of anti-inflammatory property of the aqueous and alcoholic extracts of the leaves by both in vitro and in vivo methods. In vitro method was estimated by human red blood cell membrane stabilisation (HRBC) method and in vivo method was estimated on the carrageenan induced paw oedima.

Results

Both the methods showed significant anti-inflammatory property of the different extracts tested.

Conclusions

The alcoholic extract at a concentration of 300 mg/mL showed potent activity on comparing with the standard drug diclofenac sodium.     

腹腔镜膀胱癌根治加回肠膀胱术

目的:总结腹腔镜下膀胱癌根治加回肠膀胱术的手术方法及临床疗效。方法:2003年6月～2007年5月共行25例腹腔镜下根治性全膀胱切除、双侧盆腔淋巴结清扫加回肠膀胱术,患者平均年龄68岁,全膀胱切除和盆腔淋巴结清扫均在腹腔镜下完成,标本自下腹部小切口取出后,体外切取末端回肠10～15cm,近端闭合并与双侧输尿管吻合,远端造口于右下腹壁。结果:所有手术均顺利完成,手术时间210～320min,平均270min。术中出血220～1000ml,平均460ml。平均每例清扫淋巴结数10个,淋巴结阳性率16.2%,手术切缘均阴性。术后3～5天肠道功能恢复,1例因粘连性肠梗阻于术后1周再行手术探查松解粘连。术后2～3周拔除单J管,无肠漏及尿漏并发症发生。随访2～30个月,1例死于原发病转移,无腹壁造口狭窄发生,3例术后B超或造影显示单侧轻度肾积水和轻度输尿管扩张。结论:腹腔镜膀胱癌根治术具有创伤小,恢复快等优点,但手术难度较大,手术技术要求较高。回肠膀胱术手术操作相对简单,并发症少,可作为腹腔镜膀胱癌根治术后尿流改道可选方式之一。     

Evaluation of myocardial perfusion in patients with hypertrophic cardiomyopathy in comparison with clinical and echocardiographic data

AIM: To study peculiarities of myocardial perfusion in patients with hypertrophic cardiomyopathy (HCMP) in correlation with clinical and echocardiographic data. MATERIAL AND METHODS: 62 patients with HCMP (23 females and 39 males, mean age 44.4 +/- 11.2 years, the disease duration 13.0 +/- 10.4 years) have undergone ECG, 24-h ECG monitoring, echocardiography, perfusion scintigraphy of the myocardium with 99m-TcMIBI at rest and in combination with bicycle ergometry. The patients were divided into two groups: 35 patients of group 1 had moderate left ventricular hypertrophy (the septal thickness in diastole under 20 mm; 27 patients of group 2 had severe hypertrophy (the thickness was over 20 mm). RESULTS: Dyspnea and syncopal states occurred more frequently in patients from group 2. They also had a higher functional class of heart failure (2.0 +/- 0.8 and 1.2 +/- 0.7 for group 1 and 2, respectively, p < 0.05). Cardiac performance was significantly higher in patients of group 1. The size of the left atrium, left ventricular myocardium mass, the septal thickness and thickness of posterior wall of the left ventricle, gradient of pressure in the outflow tract of the left ventricle proved higher in patients of group 2. Deep stable defects of myocardial perfusion were detected in 5 (15%) patients of group 1 and 10 (37%) patients of group 2. Transient defects of myocardial perfusion were found in 9 (26%) patients of group 1 and 12 (44%) patients of group 2. The index of myocardial ischemia in group 1 patients was significantly lower than in patients of group 2 (3.5 +/- 2.2 and 8.3 +/- 2.5, respectively, p < 0.05). CONCLUSION: Patients with severe hypertrophy of the left ventricle had severe clinical picture, low exercise tolerance, marked hemodynamic changes, more frequent defects of left ventricular perfusion defects compared to patients with moderate hypertrophy of the left ventricular myocardium.     

Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGFβ) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.Key words: pancreatic cancer, xenograft mouse models, cyclin-dependent kinases, SCH727965, dinaciclib, cell cycle, translational research     

高位胸段硬膜外麻醉下清醒病人的冠状动脉搭桥手术

目的　了解在高位胸段硬膜外麻醉下避免全麻行非体外循环心脏跳动下冠状动脉搭桥手术的可行性。方法　硬膜外麻醉下对 2 5例清醒病人行非体外循环心脏跳动下冠状动脉搭桥手术 ,没有气管插管全麻 ,所有病人在手术前晚行硬膜外置管。结果　总共搭桥 71支 (1支 11例 ,2支 5例 ,3支 6例 ,4支 3例 )。除 1例因为术中出现室颤转为全麻和体外循环外 ,2 4例在硬外麻作为唯一麻醉下完成非体外循环心脏跳动下冠状动脉搭桥手术。除 2例行左胸小切口外其余行正中切口 ;其中 6例为再次手术 ;平均每例搭桥2 8支 ,没有手术死亡。术后在复苏室和病房住院时间分别为 (16 2± 4 2 )h和 (3 2 4± 1 2 )d。结论　本组的早期经验提示在没有气管插管全麻、病人清醒下可以行多支冠状动脉搭桥术