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Simultaneous Determination of Rosuvastatin, Rosuvastatin-5 S-lactone, and N-desmethyl Rosuvastatin in Human Plasma by UPLC-MS/MS and Its Application to Clinical Study.
Bai, X, Wang, XP, He, GD, Zhang, B, Huang, M, Li, JL, Zhong, SL
Drug research. 2018;(6):328-334
Abstract
OBJECTIVE A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed and validated for the simultaneous quantification of rosuvastatin (RST), rosuvastatin-5 S-lactone (RSTL), and N-desmethyl rosuvastatin (DM-RST) in human plasma. METHODS Sample was prepared by liquid-liquid extraction with ethyl acetate from 100 μL acidulated buffered plasma. Then analytes were chromatographically separated using an Acquity UPLC HSS T3 column (3.0 mm×100 mm, 1.8 µm) by 0.1% formic acid and gradient acetonitrile at a flow rate of 0.30 mL/min. Three analytes and internal standards (carbamazepine) were eluted in 3.5 min. Mass spectrometry detection was performed through positive ion electrospray ionization (ESI). RESULTS The calibration curves for three analytes were linear (R≥0.9987, n=3) within the concentration range of 0.1-50 ng/mL for RST and RSTL, and 0.2-100 ng/mL for DM-RST. Mean extraction recoveries were enhanced by means of acidulated plasma using ammonium acetate of pH 4.0, which ranged within 75.3-98.8% for three analytes. Intra- and inter precision and accuracy were 88.2-96.4%. CONCLUSIONS This present method was lower LLOQ, less time consuming (3.5 min), less plasma consuming (100 µL) and simpler sample preparation. And it was successfully applied to determine steady state concentrations of RST, RSTL and DM-RST in a clinical study of RST for patients with coronary artery disease (CAD).
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Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children.
Conrad, MD, Bigira, V, Kapisi, J, Muhindo, M, Kamya, MR, Havlir, DV, Dorsey, G, Rosenthal, PJ
PloS one. 2014;(8):e105690
Abstract
The emergence of resistance to artemisinin derivatives in Southeast Asia, manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins, is a major concern. Recently, the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene (PF3D7_1343700) encoding kelch (K13) propeller domains, providing a molecular marker to monitor the spread of resistance. The P. falciparum cysteine protease falcipain-2 (FP2; PF3D7_1115700) has been shown to contribute to artemisinin action, as hemoglobin degradation is required for potent drug activity, and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance. Although delayed parasite clearance after artemisinin-based combination therapy (ACT) has not yet been noted in Uganda and ACTs remain highly efficacious, characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance. We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Uganda, including samples from 2006-7 (n = 49) and from 2010-12 (n = 175). Using 3D7 as the reference genome, we identified 5 non-synonymous polymorphisms in the K13-propeller domain (133 isolates) and 35 in FP2 (160 isolates); these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia. The prevalence of K13-propeller and FP2 polymorphisms did not increase over time, and was not associated with either time since prior receipt of an ACT or the persistence of parasites ≥2 days following treatment with an ACT. Thus, the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Uganda, and we did not see evidence for selection of polymorphisms in these genes.
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The efficacy of ginkgolide B in the acute treatment of migraine aura: an open preliminary trial.
Allais, G, D'Andrea, G, Maggio, M, Benedetto, C
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2013;:S161-3
Abstract
In this open trial we evaluated the possible efficacy of Ginkgolide B in the treatment of acute aura in a group of patients suffering from migraine with aura, considering in particular the effect of the treatment on aura duration. Twenty-five patients (16 females, 9 males, mean age 39.7 ± 13.5 years, range 18-65) suffering from migraine with aura were enrolled in the study. The diagnosis was made according to the diagnostic criteria of the international classification of headache disorders, second edition (ICHD-II), for typical aura with migraine headache (n = 19) or typical aura without headache (n = 6). Patients were asked to use a diary card to register the exact duration of the aura symptoms in two consecutive attacks of aura. In the first one, they only took note of the duration of neurological symptoms in minutes. In the following attack, they were instructed to take orally, immediately at the onset of the first symptoms of aura, two capsules of a combination of 60 mg Ginkgo biloba terpenes phytosome, 11 mg coenzyme Q 10 and 8.7 mg vitamin B2 (Migrasoll). Aura duration (expressed in minutes) was significantly (p < 0.001) reduced by Migrasoll intake, being 33.6 ± 11.5 in the first untreated attack and 21.9 ± 11.8 during the second attack. In general, there was a marked amelioration of the features of the neurological symptoms of aura in the treated attack. In four patients (18.1 %) suffering from typical aura with migraine, the pain phase disappeared. Among the patients who completed the study no serious adverse events were reported.
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Orlistat accentuates the fat-induced fall in blood pressure in older adults.
Tai, K, Gentilcore, D, Jones, KL, Banh, L, Gilja, OH, Hammond, AJ, Feinle-Bisset, C, Horowitz, M, Chapman, IM
The British journal of nutrition. 2011;(3):417-24
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Abstract
Postprandial hypotension may be influenced by the digestion of fat. The aim of the present study was to evaluate the hypothesis that products of fat digestion mediate the hypotensive response to fat. In part A of the study, nine healthy older subjects were studied on three separate occasions in randomised order. Blood pressure, heart rate (HR), plasma TAG and gastric emptying were measured following the ingestion of equivolaemic drinks: (1) 300 ml of high-fat drink (88 % fat); (2) fat drink mixed with 120 mg orlistat (lipase inhibitor); (3) water (control). In part B of the study, ten healthy older subjects were studied on two separate occasions. Blood pressure, HR, plasma TAG and superior mesenteric artery flow were measured during 90 min intraduodenal infusions of 10 % intralipid (2·7 ml/min), with and without 120 mg orlistat. Oral fat ingestion was associated with decreases in systolic and diastolic blood pressures (both P = 0·0001) that were greater when orlistat was co-administered (both P < 0·05), and an increase in HR (P = 0·0001) that was inhibited by orlistat co-administration (P < 0·03). Gastric emptying was slowed by oral fat digestion, and orlistat administration inhibited this slowing (P < 0·04). Intraduodenal fat infusion was not associated with changes in blood pressure but increased HR (P < 0·0001), an effect attenuated by orlistat (P < 0·05). In conclusion, orlistat potentiates the hypotensive response to oral fat in older adults, possibly as a result of faster gastric emptying of fat. The results do not support a role for fat digestion in lowering blood pressure.
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The effects of ezetimibe and/or orlistat on triglyceride-rich lipoprotein metabolism in obese hypercholesterolemic patients.
Nakou, ES, Filippatos, TD, Agouridis, AP, Kostara, C, Bairaktari, ET, Elisaf, MS
Lipids. 2010;(5):445-50
Abstract
We investigated the factors influencing triglycerides (TG) reduction during ezetimibe, alone or combined with orlistat, administration. Eighty-six obese hypercholesterolemic subjects were prescribed a low-fat diet and were randomized to ezetimibe (E group), orlistat (O group), or both (OE group) for 6 months. Plasma TG and apolipoprotein (apo) C-III reduction was significantly greater in the combination group compared with monotherapy. Multivariate analysis showed that in E group apoC-III reduction and baseline TG levels were independently positively correlated, whereas baseline apoC-II levels were negatively correlated, with TG lowering. In OE group apoC-III reduction was the only independent contributor to TG reduction.
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Influence of sibutramine, orlistat and Ispaghula in reducing body weight and total body fat content in obese individuals.
Kazmi, SA, Khan, M, Mashori, GR, Saleem, A, Akhtar, N, Jahangeer, A
Journal of Ayub Medical College, Abbottabad : JAMC. 2009;(2):45-8
Abstract
BACKGROUND The correlations between combined body fat parameters and risk factors of obesity explained a portion of the variation in the weight, BMI and waist circumference, the average number of categorical metabolic risk factors increases progressively with increasing total body fat content. There is currently no data available in which influence of drugs can be assessed on total body fat content. This was a non-randomized, prospective, open-label, parallel group study was conducted to compare the effectiveness of sibutramine, orlistat and ispahgula in reducing body weight and percentage of total body fat content in obese individuals. METHODS A nonrandomized, open label, prospective, intention to treat clinical trial was conducted from July 2008 to March 2009 in JPMC, Karachi, Pakistan. The study was based on three arms A (ispahgula), B (orlistat) and C (sibutramine) comprising 40 patients in each. The selection criteria has included patients from either sex with age 18 years or more with BMI > or =30 as obese with or without associated risk factors and BMI > or = 27 < 30 as over weight only if any significant risk factor is present. Compliance on diet chart and instruction for life style modification were assessed monthly. RESULTS The comparison of mean difference in percentage of total body fat content between the groups and within the groups at day 150 is (p-value) 0.029 and difference in body weight is (p-value) 0.042 which is statistically significant. CONCLUSION Sibutramine is more effective than ispahgula and orlistat in reducing body weight and percentage of total body fat content in obese patients.
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Effects of orlistat therapy on plasma concentrations of oxygenated and hydrocarbon carotenoids.
Sundl, I, Pail, E, Mellitzer, K, Toplak, H, Winklhofer-Roob, BM
Lipids. 2006;(2):113-8
Abstract
Orlistat is a lipase inhibitor that is applied for treating obesity. Lipases are required for digestion and absorption of dietary lipids and fat-soluble vitamins and carotenoids. The aim of this study was to compare the effects of orlistat therapy on plasma concentrations of oxygenated (beta-cryptoxanthin, lutein/zeaxanthin) and hydrocarbon (alpha-, beta-carotene, lycopene) carotenoids. Six patients with a body mass index (BMI) > or = 30 kg/m2 received 360 mg/d orlistat over 4.5 mon. Plasma carotenoid concentrations were determined at baseline (T0) and after 3 (T3) and 4.5 mon (T4.5) along with anthropometric, dietary, and biochemical indices, including plasma lipids, retinol, (alpha- and gamma-tocopherols, and FA. Baseline BMI was 32.7 +/- 1.97 kg/m2. Five of six patients lost weight; the average weight loss was 3.6 +/- 2.4% (P = 0.47). There were no significant changes in dietary carotenoid intakes. In contrast, plasma alpha- and beta-carotene concentrations decreased significantly from T0 to T4.5 by 45% (P = 0.006) and 32% (P = 0.013), respectively. Plasma lycopene decreased from T0 to T3 but increased again from T3 to T4.5, while beta-cryptoxanthin and lutein/zeaxanthin concentrations did not change. There were no significant alterations in tocopherol, retinol, and FA concentrations. In conclusion, even though weight loss was not significant, orlistat therapy was associated with significant decreases in plasma concentrations of the highly lipophilic hydrocarbon carotenoids, alpha- and beta-carotene.
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Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial.
Chanoine, JP, Hampl, S, Jensen, C, Boldrin, M, Hauptman, J
JAMA. 2005;(23):2873-83
Abstract
CONTEXT The prevalence of overweight and obesity in children and adolescents is increasing rapidly. In this population, behavioral therapy alone has had limited success in providing meaningful, sustained weight reduction, and pharmacological treatment has not been extensively studied. OBJECTIVE To determine the efficacy and safety of orlistat in weight management of adolescents. DESIGN, SETTING, AND PATIENTS Multicenter, 54-week (August 2000-October 2002), randomized, double-blind study of 539 obese adolescents (aged 12-16 years; body mass index [BMI] >or=2 units above the 95th percentile) at 32 centers in the United States and Canada. INTERVENTIONS A 120-mg dose of orlistat (n = 357) or placebo (n = 182) 3 times daily for 1 year, plus a mildly hypocaloric diet (30% fat calories), exercise, and behavioral therapy. MAIN OUTCOME MEASURES Change in BMI; secondary measures included changes in waist and hip circumference, weight loss, lipid measurements, and glucose and insulin responses to oral glucose challenge. RESULTS There was a decrease in BMI in both treatment groups up to week 12, thereafter stabilizing with orlistat but increasing beyond baseline with placebo. At the end of the study, BMI had decreased by 0.55 with orlistat but increased by 0.31 with placebo (P = .001). Compared with 15.7% of the placebo group, 26.5% of participants taking orlistat had a 5% or higher decrease in BMI (P = .005); 4.5% and 13.3%, respectively, had a 10% or higher decrease in BMI (P = .002). At study end, weight had increased 0.53 kg with orlistat and 3.14 kg with placebo (P<.001). Dual-energy x-ray absorptiometry showed that this difference was explained by changes in fat mass. Waist circumference decreased in the orlistat group but increased in the placebo group (-1.33 cm vs +0.12 cm; P<.05). Generally mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group. CONCLUSIONS In combination with diet, exercise, and behavioral modification, orlistat statistically significantly improved weight management in obese adolescents compared with placebo. The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events were more common in the orlistat group.
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Influence of intense multidisciplinary follow-up and orlistat on weight reduction in a primary care setting.
Feigenbaum, A, Pasternak, S, Zusk, E, Sarid, M, Vinker, S
BMC family practice. 2005;(1):5
Abstract
BACKGROUND Obesity is the most common health problem in developed countries. Recently, several physicians' organizations have issued recommendations for treating obesity to family physicians, including instructions in nutrition, physical activity and medications. The aim of this study was to examine if effective weight-reducing treatment can be given by a family physician. It compares regular treatment with intensive treatment that include close follow-up and orlistat treatment. METHODS The study was conducted in three primary care clinics. 225 patients were divided into three groups according to their choice. Group A received a personal diet with fortnightly meetings with the family physician and dietitian and orlistat treatment. Group B received a general diet, monthly meetings with the family physician only and orlistat treatment. Group C received a personal diet, monthly meetings with the dietitian only and no drug treatment. The primary endpoint was reduction of at least 5% of the initial weight during the study period. RESULTS A greater percentage of patients in group A achieved their weight reduction goals than in other groups (51%, 13% and 9% in groups A, B and C, respectively, p < 0.001). There was a significant reduction in triglycerides in all groups, a significant reduction of low density lipids (LDL) in groups A and B and no significant difference in high density lipids (HDL) in any group. CONCLUSIONS Significant weight reduction was obtained in a family physician setting. Further research is needed to evaluate if, by providing the family physician with the proper tools, similar success can be achieved in more clinics.
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10.
[Efficacy and safety of a short-time orlistat treatment in obese subjects].
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Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna. 2005;(2):90-6
Abstract
Obesity is frequently associated with a high cardiovascular risk. The aim of this study was to assess safety, tolerability and efficacy of orlistat treatment in comparison with placebo in the reduction of body weight in obese subjects and the related cardiovascular risk factors. For such a purpose, 146 obese patients were randomly assigned to two treatments over a period of 27 weeks: 1) hypocaloric diet, exercise and placebo (n = 72); 2) hypocaloric diet, exercise and orlistat 120 mg twice/day (n = 74). The side effects observed were similar for the two treatment groups, with exception of gastrointestinal symptoms, which were significantly more frequent in the orlistat group than in the placebo group. Nevertheless, the side effects were limited and resolved. In fact, none of the patients dropped-out. During the observation period a significantly higher reduction in body weight (-6.9 kg, p < 0.001), systolic blood pressure (-4.9 mmHg, p < 0.001), diastolic blood pressure (-2.9 mmHg, p < 0.001), LDL cholesterol (12.8%, p < 0.001) was observed in the orlistat group than in the placebo group (-4.1 kg, 3.2 mmHg, 1.8 mmHg and 5.1%, respectively). By using a validated questionnaire, in the orlistat group a significantly higher motivation (p < 0.01) to continue diet and exercise than in the placebo group was observed. In addition, at the end of the study, patients receiving orlistat treatment gave a better evaluation of their own image than patients receiving placebo (p < 0.01).