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Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist.
Iepsen, EW, Zhang, J, Thomsen, HS, Hansen, EL, Hollensted, M, Madsbad, S, Hansen, T, Holst, JJ, Holm, JC, Torekov, SS
Cell metabolism. 2018;(1):23-32.e3
Abstract
Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6.8 kg ± 1.8 kg in individuals with pathogenic MC4R mutations and by 6.1 kg ± 1.2 kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity.
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2.
Safety and clinical pharmacokinetics of nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and multiple oral doses.
Guo, B, Wu, X, Zhang, Y, Shi, Y, Yu, J, Cao, G, Zhang, J
Clinical drug investigation. 2012;(7):475-86
Abstract
BACKGROUND Nemonoxacin, a novel C-8-methoxy non-fluorinated quinolone, is currently being developed in oral and intravenous formulations. It exhibits potent antibacterial activities against Gram-positive, Gram-negative and atypical pathogens, especially methicillin-resistant Staphylococcus aureus. The first-in-human study of a nemonoxacin capsule was conducted in a Western population. This current study was the first investigation on the clinical pharmacokinetics (PK) of nemonoxacin in a Chinese population, and was designed to determine PK data in a Chinese population and investigate the dose regimen for future clinical use. OBJECTIVE The objective of this study was to evaluate the PK profile of nemonoxacin as well as its safety and tolerability in healthy Chinese volunteers following single and multiple oral doses. METHODS The first part of the study was a double-blind, placebo-controlled, sequential ascending single-dose safety and tolerability study. In each cohort, two subjects received a placebo and six received single oral doses of nemonoxacin 125, 250, 500, 750 or 1000 mg. In the second part, the single-dose PK study, three dose levels (250, 500 and 750 mg) of nemonoxacin were administered orally to 12 healthy Chinese volunteers (male : female = 1 : 1) under fasting conditions in a crossover manner. The same volunteers received orally an additional dose of 500 mg under fed conditions after a 7-day washout. In the third part, the multiple-dose PK study, 24 subjects received 500 or 750 mg of nemonoxacin orally once daily for 10 consecutive days. Within each cohort, 12 subjects (male : female = 1 : 1) received the same dose level of nemonoxacin under fasting conditions. The PK profiles, safety and tolerability, and food and sex effects were evaluated. RESULTS No severe or serious adverse events (AEs) occurred in this study, and no clinically significant abnormalities were noted in the vital signs or on physical examination. Notable AEs, mainly nausea and rash with or without pruritus, were mild and resolved spontaneously. Most laboratory AEs were mild and transient and the subjects recovered without treatment. Nemonoxacin was found to be rapidly absorbed, with peak plasma concentrations (C(max)) attained 1-2 hours after administration. The C(max) and area under the concentration-time curve from time zero to infinity (AUC(∞)) were dose-proportional after single oral doses. The elimination half-life was 10-12 hours. Nemonoxacin was excreted primarily in urine, with a recovery of intact nemonoxacin of 60-70% of the dose over 72 hours. Food had a significant effect on the rate and extent of absorption (p < 0.001), increasing the time to reach C(max) from 1.14 to 3.64 hours and reducing C(max) by 34% and AUC(∞) by 18%, while a sex effect was not found. C(max) and AUC(∞) were similar between the single-dose and multiple-dose PK studies. The multiple-dose PK data suggested no drug accumulation in healthy subjects. CONCLUSION Nemonoxacin exhibited a linear PK profile in the 250-750 mg dose range with moderate food effects. There was no accumulation following consecutive administration for 10 days. The PK and safety profiles of nemonoxacin in Chinese subjects support evaluation of once-daily dosing in the future development of this agent.
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[Clinical observation on effect of shaogen decoction for the prevention and treatment of acute radiation esophagitis].
Zhang, J, Zhang, L, Wang, J
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2010;(12):1272-4
Abstract
OBJECTIVE To observe the effect of Shaogen Decoction (SGD) for the prevention and treatment of acute radiation esophagitis (ARE). METHODS Sixty patients with breast tumor receiving chemo/radiotherapy were assigned to two groups, the SGD group and the control group. The patients in the SGD group were administered with SGD, a Chinese preparation consisted of Radix Sophorae tonkinensis 10 g, Radix Paeoniae Alba 30 g, Radix Scrophulariae 15 g, Rhizoma Bletillae 15 g, Radix Notoginseng 3 g, etc., starting from the initial day of radiotherapy, 10 mL, thrice a day, while in case of 2nd or over 2nd grade ARE occurred, it was changed to 10 mL, every 2 h, medicated by keeping in mouth and slowly swallowed followed with 5-min forbiddance of food and water. The patients in the control group were treated, in case of 2nd or over 2nd grade ARE occurred, with antibiotic drugs (such as cefuroxime 4.5 g) and hormone (dexamethasone 5 mg) by intravenous infusion for 7 days. The incidence, happening time, and retaining time of ARE, therapeutic effect on it, as well as the proportion of patients for whom antibiotics and hormone were used in the two groups were observed. RESULTS The incidence of 2nd or over 2nd grade ARE in the SGD group and the control group was 33.33% and 63.33%, respectively, that in the former was significantly lower (chi2 = 5.406, P<0.05). Different degrees of acute esophageal toxic response occurred in both groups, initially presenting at 19.8 +/- 7.4 days in the SGD group and at 20.2 +/- 9.6 days in the control group after radiotherapy, that was delayed in the former (t=2.130, P<0.05). Clinical symptom of ARE retained for 56.4 +/- 19.5 days and 58.2 +/- 15.0 days in the two groups, respectively, it was shorter in the SGD groups (t=2.441, P<0.05). Moreover, the proportion of patients for whom antibiotics and hormone were used in the SGD group was less. CONCLUSION SGD acted, in coordinating with chemo-radiotherapy, to reduce the incidence, retard the happening and shorten the retaining time of 2nd or over 2nd grade ARE, and reduce the proportion of patients needing antibiotics and hormone treatment as well, showing equivalent efficacy in treating ARE as Western drugs.
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Intensive cholesterol-lowering therapy improves large artery elasticity in acute myocardial infarction patients.
Jia, X, Wei, M, Fu, X, Gu, X, Fan, W, Zhang, J, Xue, L
Heart and vessels. 2009;(5):340-6
Abstract
This study was aimed at probing the effects of intensive cholesterol-lowering therapy with simvastatin on the large artery elasticity of acute myocardial infarction patients. A total of 72 cases of acute myocardial infarction patients were divided into a normocholesterol group (n = 37) and a hypercholesterol group (n = 35) according to their serum low-density lipoprotein. All patients were given oral simvastatin 40 mg/day for 6 months, and their pulse-wave velocity (PWV) of different artery segments and ankle-brachial index (ABI) were measured before and after the therapy. The low-density lipoprotein cholesterol level in both groups decreased significantly (2.13 +/- 0.32 vs 1.56 +/- 0.28, 3.43 +/- 0.80 vs 2.28 +/- 0.47 mmol/l, P < 0.01). The PWV of each artery segment in both the normocholesterol group and the hypercholesterol group decreased significantly (P < 0.05). Pulse-wave velocity in the hypercholesterol group was lowered much more than that of the normocholesterol group (P < 0.05). There were no differences among each artery segment in each group. Ankle-brachial index increased significantly in both groups (1.12 +/- 0.16 to 1.22 +/- 0.12, P < 0.05 in the normocholesterol group, and 1.03 +/- 0.22 to 1.23 +/- 0.16, P < 0.01 in the hypercholesterol group), but ABI increased much more in the hypercholesterol group than in the normocholesterol group (0.21 + 0.15 vs 0.11 + 0.09 P = 0.02). Intensive cholesterol-lowering therapy with simvastatin for acute myocardial infarction patients can significantly improve their large artery elasticity and regress their atherosclerosis. Hypercholesterol patients benefit more from this therapy.
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5.
Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population.
Zheng, Y, Li, H, Qin, W, Chen, W, Duan, Y, Xiao, Y, Li, C, Zhang, J, Li, X, Feng, G, et al
Biochemical and biophysical research communications. 2005;(4):809-15
Abstract
Several independent linkage studies have demonstrated that the 1q22 region is likely to harbor candidate schizophrenia susceptibility genes. Recently, some genetic variants within CAPON have been reported as exhibiting significant linkage disequilibrium to schizophrenia in Canadian familial-schizophrenia pedigrees. We examined nine single nucleotide polymorphisms (SNPs), which span an approximately 236-kb region of CAPON, in 664 schizophrenia cases and 941 controls in the Chinese Han population. We detected a significant difference in allele distributions of SNP rs348624 (P = 0.000017). Moreover, the overall frequency of haplotypes constructed from three SNPs including rs348624 showed significant difference between cases and controls (P = 0.000025). Our findings indicate that CAPON gene may be a candidate susceptibility gene for schizophrenia in Chinese Han population, and also provide further support for the potential importance of NMDAR-mediated glutamatergic transmission in the etiology of schizophrenia.