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Abstract
Obesity is considered a chronic disease requiring treatment. The effect of sibutramine combined with hypocaloric diet and exercise on body weight, body fat mass, lipids, glycemic control, insulin secretion and insulin resistance was evaluated in a randomized, controlled, open-label study. A total of 44 obese type 2 diabetic patients (aged 45.2±5.2 years, BMI 33.62±2.2 kg/m2) and 49 obese nondiabetic subjects (aged 41.9±5.7 years, BMI 34.3±2.6 kg/m2) were treated with sibutramine for 3 months. Moreover, 39 age-matched obese type 2 diabetic patients and 41 obese nondiabetic subjects only on hypocaloric diet and exercise served as control groups. Insulin secretion was estimated during intravenous glucose tolerance test; insulin resistance was assessed by the HOMA index. There was a significant reduction in body weight in both sibutramine-treated diabetic patients (7.1%) and nondiabetic subjects (9.1%), accompanied by a significant reduction in body fat mass. HbA1c decreased significantly in the diabetic patients after sibutramine treatment. There was a significant improvement of lipid parameters in the two groups. Insulin resistance decreased by 21.9% in the sibutramine-treated diabetic patients and by 38.5% in the nondiabetic group. Weight loss was accompanied by an increase of 43.8% in first phase insulin secretion in the sibutramine-treated diabetic group; in the treated nondiabetic subjects there was a decrease in first and second phase insulin secretion and the area under the curve for total insulin secretion. In conclusion, sibutramine leads to a significant reduction in body weight, body fat mass and waist and hip circumferences; it improves insulin sensitivity, insulin secretion, glycaemic control and lipid parameters in both diabetic and nondiabetic obese subjects. 相似文献
3.
Warren Kati Gennadiy Koev Michelle Irvin Jill Beyer Yaya Liu Preethi Krishnan Thomas Reisch Rubina Mondal Rolf Wagner Akhteruzzaman Molla Clarence Maring Christine Collins 《Antimicrobial agents and chemotherapy》2015,59(3):1505-1511
Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections. 相似文献
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N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin
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J P Cobb C Natanson W D Hoffman R F Lodato S Banks C A Koev M A Solomon R J Elin J M Hosseini R L Danner 《The Journal of experimental medicine》1992,176(4):1175-1182
Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both. 相似文献
6.
Lu L Dekhtyar T Masse S Pithawalla R Krishnan P He W Ng T Koev G Stewart K Larson D Bosse T Wagner R Pilot-Matias T Mo H Molla A 《Antiviral research》2007,76(1):93-97
Compound A-837093, a non-nucleoside HCV RNA-dependent RNA polymerase inhibitor, displayed nanomolar potencies against HCV genotypes 1a and 1b replicons. It also exhibited an excellent metabolic profile and achieved high plasma and liver concentrations in animals. In order to characterize the development of resistance to this anti-HCV agent, HCV subgenomic 1b strain N replicon cells were cultured in the presence of A-837093 with G418. Mutations S368A, Y448H, G554D, Y555C, and D559G in the NS5B polymerase gene were identified that led to substantial decreases in the susceptibilities of 1b genotype replicons to the inhibitor A-837093. However, the resistant mutants remained susceptible to HCV protease inhibitor BILN-2061 and alpha interferon as well as to a different class of non-nucleoside HCV polymerase inhibitor. In addition, each single resistant mutation identified significantly reduced the replication capacity of mutant compared to wild-type replicon. These findings provide a strategic guide for the future development of non-nucleoside inhibitors of HCV NS5B polymerase. 相似文献
7.
Antiviral interactions of an HCV polymerase inhibitor with an HCV protease inhibitor or interferon in vitro 总被引:4,自引:0,他引:4
The combinations of Abbott Hepatitis C virus (HCV) polymerase A-782759 with either Boehringer Ingelheim HCV NS3 protease inhibitor BILN-2061 or interferon (IFN) displayed additive to synergistic relationships over a range of concentrations of two-drug combination. Treatment of HCV replicon with A-782759, IFN or BILN-2061 for about 16 days resulted in dramatic reductions in HCV RNA (5.1, 3.0 and 3.9 log10 RNA copies, respectively). However, none of the compounds tested alone lead to replicon RNA reduction to undetectable levels. Ongoing replication in the presence of A-782759 or BILN-2061 was associated with the appearance of resistant mutations M414T in NS5B and D168V in NS3, respectively. In contrast, a combination of A-782759 with BILN-2061 resulted in greater than 7 logs RNA reduction leading to undetectable replicon RNA after 16 days of treatment. Our findings suggest that a monotherapy with either drug alone is likely to result in development of resistant mutants. However, a combination therapy with polymerase inhibitor has the potential to improve the efficacy of IFN or a protease inhibitor alone in vivo, due to the lower likelihood of resistance development. 相似文献
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9.
Koev Krassimir Bojkov Stefan 《Documenta ophthalmologica. Advances in ophthalmology》1997,93(3):211-221
This article discusses the possibility of application of 15% medical gelatin solution compared to 10% medical gelatin solution
in the anterior chamber and in the posterior eye segment as a viscosubstance in the viscosurgery. The experimental investigations
were performed on 24 Chinchilla rabbits, divided in two groups consisting of 12 each. 0.5 ml of 10% and 15% of medical gelatin
were injected in the anterior chamber and 2 ml of 10% and 15% medical gelatin were injected in the vitreous body of the tested
eyes. 2% methyl cellulose and 0.89% Sodium Chloride were injected in the vitreous body of the control eyes. Clinical, biomicroscopical,
ophthalmoscopical, tonometrical, histological and electron-microscopical examinations were performed. It was established that
when the eyes were injected with 10% and 15% medical gelatin, as well as with 0.89% Sodium Chloride, the intraocular pressure
was not increased but when the eyes were injected with methyl cellulose the intraocular pressure was increased. We also found
that 15% of medical gelatin has longer effect than 10% medical gelatin. Toxoallergic and inflammatory changes were not observed
in the eyes injected with 10% and 15% medical gelatin. In the same eyes, histologically and by electron microscopy, were not
found any changes in the layers of the cornea and retina. These substances could be used as viscosubstances and as instruments
in surgical interventions of the anterior eye segment and in the posterior eye segment (vitrectomy). 相似文献
10.
Tankova T Koev D Dakovska L Kirilov G 《International journal of clinical practice》2002,56(8):578-581
The aim of the present study was to evaluate the effect of metformin in very obese subjects with acanthosis nigricans. Five patients (two obese children, mean age 14.4 +/- 0.6 yr, mean BMI 35.2 +/- 1.9 kg/m2 and normal glucose tolerance, and three newly diagnosed obese type 2 diabetic patients, mean age 37.7 +/- 3.2 yr, mean BMI 37.7 +/- 2.9 kg/m2) were enrolled in the study Insulin secretion was measured during oral glucose tolerance (OGT) and intravenous glucose tolerance (IVGT) tests. Insulin resistance was assessed by the homoeostasis model assessment (HOMA) index. All the patients were treated with metformin at a mean daily dose of 2.23 +/- 0.45 g. Six months after initiation of therapy we found a significant reduction in AUC for insulin secretion during OGTT (p < 0.05), due to reduction in both basal and stimulated insulin secretion (p<0.05). Body weight was reduced by mean 4.7 +/- 1.9% and body fat mass by 8.95 +/- 3.7%. We have demonstrated a significant decrease of 36.3% in insulin resistance (p < 0.01). Our results demonstrate that metformin reduces hyperinsulinaemia, body weight and fat mass and improves insulin sensitivity in patients with insulin resistance and acanthosis nigricans. 相似文献