NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine

Objective: Central counter‐regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK‐0557 potentiates sibutramine and orlistat weight loss effects. Research Methods and Procedures: Obese patients (497, BMI 30 to 43 kg/m²) were randomized to 1 of 5 treatment arms [placebo, n = 101; sibutramine 10 mg/d, n = 100; MK‐0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK‐0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all‐patients‐treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline. Results: The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK‐0557 + sibutramine, 69% in orlistat alone, and 76% in MK‐0557 + orlistat groups. Least squares (LS) mean difference [95% confidence interval (CI)] in weight change from baseline between MK‐0557 + sibutramine and sibutramine alone was ?0.1 (?1.6, 1.4) kg (p = 0.892) and between MK‐0557 + orlistat and orlistat alone was ?0.9 (?2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of ?5.9 (?6.9, ?4.9) kg vs. ?4.6 (?5.7, ?3.6) kg for orlistat (p = 0.097). There were no serious drug‐related adverse events and MK‐0557 was well tolerated. Discussion: Blockade of the NPY5R with the potent antagonist MK‐0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.     

Sibutramine use in pregnancy: report of two cases

BACKGROUND: Sibutramine is a drug used for the medical treatment of obesity. No data are available on sibutramine use in pregnancy. We report the fetal outcomes of two pregnant women exposed to sibutramine. CASES: The first woman was exposed to 10 mg/day of sibutramine during gestational weeks 4-6. The second woman was exposed to 10 mg/day of sibutramine during gestational weeks 5-8. At weeks 37 and 39, they delivered healthy infants. CONCLUSIONS: To our knowledge, this is the first report of sibutramine exposure in pregnancy. These cases may contribute to the knowledge about sibutramine use during pregnancy.     

Six‐Month Treatment of Obesity with Sibutramine 15 mg; A Double‐Blind,Placebo‐Controlled Monocenter Clinical Trial in a Hispanic Population

Objective: To evaluate the safety and efficacy of sibutramine 15 mg by mouth once per day in obese patients over a period of 6 months. Research Methods and Procedures: A monocenter, double‐blind, placebo controlled, parallel, prospective clinical trial was carried out. Sixty‐nine male and female obese patients (body mass index [BMI] > 30 kg/m²) aged 16 to 65 years entered the trial. Results: 22 of 35 patients in the sibutramine group and 9 of 34 patients in the placebo group completed the trial. The high dropout rate in the sibutramine group was due to adverse events in 3 cases, lack of efficacy (as judged by patients) in 7, loss to follow‐up in 2, and an orthopedic device being worn in 1; in the placebo group the dropouts were ascribed to lack of efficacy (as judged by patients) in 17 cases and to loss to follow‐up in 8 cases. Using the method of last observation carried forward, the weight loss in the sibutramine group was 10.27 kg (95% confidence intervals [95% CI] 7.66; 13.07) and 1.26 kg (95% CI 0.3; 2.23) in the placebo group. The BMI loss was 4.17 kg/m² (95% CI 3.11; 5.22) in the sibutramine group and 0.53 kg/m² (95% CI 0.13; 0.92) in the placebo group. The waist circumference reduction was 12.51 cm (95% CI 9.25; 15.77) in the sibutramine group and 3.26 cm (95% CI 1.38; 5.14) in the control group (p < 0.05 by paired Student's t test for all the intragroup comparisons). Twenty‐three sibutramine patients had 34 adverse events, the most frequent adverse events in the sibutramine group were upper respiratory tract infections (n = 6) and constipation (n = 6); 16 placebo patients had 21 adverse events. Three sibutramine patients withdrew their informed consent when they had adverse events. Discussion: The results show that sibutramine induces significant loss of body weight and waist circumference. Cardiovascular function was not significantly affected by sibutramine. Sibutramine was well tolerated by most of the patients.     

Hepatitis B vaccine safety monitoring in the chimpanzee: interpretation of results

In September, 1983, a group of French and American experts met at the French National Health Laboratory to discuss their experience in monitoring for the safety of a hepatitis B vaccine in 42 chimpanzees. The observations made, conclusions reached, and recommendations for future studies are presented.     

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses’ Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.     

The value of juvenile animal studies: a pediatric clinical perspective

With the emphasis of US American and European legislators on consideration of children in the drug development process regulatory authorities ask increasingly for additional non-clinical data to elucidate the safety of a given drug in development in future pediatric use. Juvenile animal studies are increasingly requested. These requests should never be tick box requests. Companies, academic toxicologists, clinicians, and regulatory authorities need a dialogue to differentiate between the perceived need to do "something" and the request for studies that have clinically meaningful results.     

Nematode parasitism in sheep in North-East England: The epidemiology of Ostertagia species

This investigation was undertaken to determine the epidemiology of a single parasite genus, Ostertagia, in natural parasite populations in sheep raised under intensive conditions in North-East England.Over the 2 years of study, striking differences were found in the overall level of parasitism which were related to different climatic conditions, specifically rainfall. Despite the low source of infection derived from the ewes grazing on clean pasture in 1973 the overall level of parasitism in the lamb crop was high, this was attributed to the ideal climatic conditions for parasite translation during Spring and Summer. Ostertagia spp. was found to survive well over Winter and to initiate early infections in the young lambs in the following year. Despite the two sources of egg contamination, from the ewes and lambs, unusually dry conditions were experienced from March to June which resulted in much lower levels of infection in the second year of investigation.Regulation of the parasite population within the lambs was clearly demonstrated. Inhibition of Ostertagia was recorded somewhat earlier in the season than had been hitherto reported and was considered to be induced by a multiplicity of factors.     

广西的蛇类资源与蛇伤调查

报道作者在广西壮族自治区 (中国的一个省 )进行蛇类资源和蛇咬伤情况的调查结果。至今为止发现栖息在广西境内的蛇类有 7科 4 2属 96种 ,其中盲蛇科( Typhloidae)、 1种、蟒科 ( Boidae) 1种、闪鳞蛇科( Xenopheltidae) 1种、游蛇科 ( Colubridae) 71种、眼镜蛇科 ( Elapidae) 6种、海蛇科 ( Hydrophiidae) 7种、蝰科( Viperidae) 9种 ,其中有毒蛇 33种。经蛇伤流行病学调查推算 ,广西每年蛇伤病人约 376 0 0例 ,其中约 1 0 1 9例死亡 ,而蛇伤死亡率最高为眼镜王蛇咬伤 ( 5 7.1 % ) ;其次为银环蛇 ,由于抗蛇毒血清供应不足 ,很多边远地区病人因不能及时接受抗蛇毒血清治疗是造成死亡的主要原因之一。     

A decade of malaria during pregnancy in Brazil: what has been done concerning prevention and management

In Brazil, malaria remains a disease of major epidemiological importance because ofthe high number of cases in the Amazonian Region. Plasmodium spp infections duringpregnancy are a significant public health problem with substantial risks for thepregnant woman, the foetus and the newborn child. In Brazil, the control of malariaduring pregnancy is primarily achieved by prompt and effective treatment of the acuteepisodes. Thus, to assure rapid diagnosis and treatment for pregnant women withmalaria, one of the recommended strategy for low transmission areas by World HealthOrganization and as part of a strategy by the Ministry of Health, the NationalMalaria Control Program has focused on integrative measures with woman andreproductive health. Here, we discuss the approach for the prevention and managementof malaria during pregnancy in Brazil over the last 10 years (2003-2012) usingmorbidity data from Malaria Health Information System. Improving the efficiency andquality of healthcare and education and the consolidation of prevention programmeswill be challenges in the control of malaria during pregnancy in the next decade.     

Confirmation studies of Soviet research on immunological effects of microwaves: Russian immunology results

This paper presents the results of a replication study performed to investigate earlier Soviet studies conducted between 1974 and 1991 that showed immunological and reproductive effects of long‐term low‐level exposure of rats to radiofrequency (RF) electromagnetic fields. The early studies were used, in part, for developing exposure standards for the USSR population and thus it was necessary to confirm the Russian findings. In the present study, the conditions of RF exposure were made as similar as possible to those in the earlier experiments: Wistar rats were exposed in the far field to 2450 MHz continuous wave RF fields with an incident power density in the cages of 5 W/m² for 7 h/day, 5 days/week for a total of 30 days, resulting in a whole‐body SAR of 0.16 W/kg. Effects of the exposure on immunological parameters in the brain and liver of rats were evaluated using the complement fixation test (CFT), as in the original studies, and an additional test, the more modern ELISA test. Our results, using CFT and ELISA, partly confirmed the findings of the early studies and indicated possible effects from non‐thermal RF exposure on autoimmune processes. The RF exposure resulted in minor increases in formation of antibodies in brain tissue extract and the exposure did not appear to be pathological. In addition, a study was conducted to replicate a previous Soviet study on effects from the injection of blood serum from RF‐exposed rats on pregnancy and foetal and offspring development of rats, using a similar animal model and protocol. Our results showed the same general trends as the earlier study, suggesting possible adverse effects of the blood serum from exposed rats on pregnancy and foetal development of intact rats, however, application of these results in developing exposure standards is limited. Bioelectromagnetics 31:589–602, 2010. © 2010 Wiley‐Liss, Inc.     

The choice of amniotic fluid in metabolomics for the monitoring of fetus health - update

Introduction: In recent years, several studies have highlighted the promising role of metabolomics in the analysis of amniotic fluid (AF), to describe and characterize the interactions occurring between the mother and the fetus during prenatal development.

Among the available biological fluids, AF represents an ideal substrate to provide dynamic information regarding fetal organogenesis and metabolism through pregnancy, since it originates from both maternal and fetal tissues and contains substances derived from placenta, fetal skin, lungs, gastric fluid, and fetal urine.

Areas covered: In this paper, we provide an update reporting the most recent results on AF metabolomics in the assessment of feto-maternal health, regarding physiological pregnancies but even fields such as prematurity, bronchopulmonary dysplasia, fetal malformations, chromosomopathies, maternal diseases, placental inflammation or infections, maternal diet or exposure to exogenous substances, according to the literature found on MEDLINE since 2015.

Expert opinion: Metabolomics shows a promising role in describing both physiology and disease; the goal would be the identification of biomarkers able to precociously and efficaciously detect pathological conditions, allowing the identification of complicated pregnancy and improving their management. However, this field is under development and its reliability still needs to be clarified, especially through more numerous and accurate studies.     

妊娠期抗癫痫药物的药代动力学变化及胎盘转运特征

癫痫是一种常见的神经系统慢性疾病,多数患者妊娠期需继续应用抗癫痫药物(AEDs)治疗,以控制癫痫发作。但妊娠期妇女体 内一系列生理变化可改变 AEDs 的药代动力学行为,导致癫痫发作并危及胎儿的生长发育。基于此,综述妊娠期 AEDs 的药代动力学变化 及胎盘转运特征,为妊娠期癫痫患者的精准合理用药提供参考。     

Quality and content of abstracts in papers reporting about drug exposures during pregnancy

BACKGROUND: Most clinicians read only the abstract of papers in scientific journals. Therefore, it is very important that abstracts contain as much information as possible, to summarize the data succinctly. Our objectives were to evaluate the quality of information in abstracts reporting human fetal outcomes following drug exposure during pregnancy. METHODS: We developed quality criteria based on previous work, modifying them for use with pregnancy outcomes. Quality scores were calculated as present/absent for all of the equally weighted criteria, then expressed as percentages (present/[present + absent]). We examined a random sample of 100 abstracts obtained through searches of MEDLINE, EMBASE, and the Web of Science databases from 1990 to 2005. Average quality scores were compared across designs (cohort, case-control, meta-analysis, and mixed design) Using Kruskal-Wallis ANOVA and structured/unstructured formats using Student's t test. RESULTS: The overall average quality was 59.2% +/- 14% (median, 61.5%; range, 15.4-83.3%). Quality was not significantly different across designs (P = .16) or between structured and unstructured abstracts (P = .44). Quality scores increased over time (Rho = 0.23, P = .02). Most frequently absent were baseline risk (94%), drug dose (91%), nonsignificant P values (72%), confounders (69%), significant P values (57%), and risk difference (48%). CONCLUSIONS: Abstracts provide insufficient information, particularly baseline risk values, for readers to make evidence-based decisions regarding drug use during pregnancy. Efforts need to be made to improve the quality of abstracts and include critical information such as baseline risk.     

Weighted regression analysis to correct for informative monitoring times and confounders in longitudinal studies

We address estimation of the marginal effect of a time‐varying binary treatment on a continuous longitudinal outcome in the context of observational studies using electronic health records, when the relationship of interest is confounded, mediated, and further distorted by an informative visit process. We allow the longitudinal outcome to be recorded only sporadically and assume that its monitoring timing is informed by patients' characteristics. We propose two novel estimators based on linear models for the mean outcome that incorporate an adjustment for confounding and informative monitoring process through generalized inverse probability of treatment weights and a proportional intensity model, respectively. We allow for a flexible modeling of the intercept function as a function of time. Our estimators have closed‐form solutions, and their asymptotic distributions can be derived. Extensive simulation studies show that both estimators outperform standard methods such as the ordinary least squares estimator or estimators that only account for informative monitoring or confounders. We illustrate our methods using data from the Add Health study, assessing the effect of depressive mood on weight in adolescents.     

Myrrh and trematodoses in Egypt: An overview of safety, efficacy and effectiveness profiles

Myrrh is an herbal product that has been used since ancient ages for traditional medication and other purposes. The revolution of myrrh as an antiparasitic agent in Egypt began in the 1990s through scientific evidence-based research. The human trematode infections in Egypt were the main focus of research with stories of success and disagreement, at times. The present paper reviewed the antiparasitary activity of myrrh with stress on its possible mode of action, its safety, efficacy and effectiveness on trematode infections in experimental studies and clinical trials in Egypt as well as its molluscicidal effects on the intermediate hosts of trematodes.     

Associations between intensive diabetes therapy and NMR-determined lipoprotein subclass profiles in type 1 diabetes

Our objective is to define differences in circulating lipoprotein subclasses between intensive versus conventional management of type 1 diabetes during the randomization phase of the Diabetes Control and Complications Trial (DCCT). NMR-determined lipoprotein subclass profiles (NMR-LSPs), which estimate molar subclass concentrations and mean particle diameters, were determined in 1,294 DCCT subjects after a median of 5 years (interquartile range: 4–6 years) of randomization to intensive or conventional diabetes management. In cross-sectional analyses, we compared standard lipids and NMR-LSPs between treatment groups. Standard total, LDL, and HDL cholesterol levels were similar between randomization groups, while triglyceride levels were lower in the intensively treated group. NMR-LSPs showed that intensive therapy was associated with larger LDL diameter (20.7 vs. 20.6 nm, P = 0.01) and lower levels of small LDL (median: 465 vs. 552 nmol/l, P = 0.007), total IDL/LDL (mean: 1,000 vs. 1,053 nmol/l, P = 0.01), and small HDL (mean: 17.3 vs. 18.6 μmol/l, P < 0.0001), the latter accounting for reduced total HDL (mean: 33.8 vs. 34.8 μmol/l, P = 0.01). In conclusion, intensive diabetes therapy was associated with potentially favorable changes in LDL and HDL subclasses in sera. Further research will determine whether these changes contribute to the beneficial effects of intensive diabetes management on vascular complications.