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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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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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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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Effect of Orlistat in obese patients with heart failure: a pilot study.
Beck-da-Silva, L, Higginson, L, Fraser, M, Williams, K, Haddad, H
Congestive heart failure (Greenwich, Conn.). 2005;(3):118-23
Abstract
Heart failure is the leading cause of hospitalization. Obesity is increasingly common and is a major public health problem. The aim of this study is to assess whether obese patients with heart failure can benefit from losing weight via an orlistat-assisted diet. This randomized clinical trial included obese patients with ejection fractions < or =40%. Orlistat and diet counseling were compared with diet counseling alone. Twenty-one consecutive obese patients with heart failure were recruited. Significant improvement in 6-minute walk test (45.8 m; 95% confidence interval, 5.2-86.4 m; p=0.031), functional class (-0.6+/-0.5, p=0.014), weight loss (-8.55 kg; 95% confidence interval, -13.0 to -4.1 kg; p<0.001) and also significant decreases in total cholesterol (p=0.017), low-density lipoprotein cholesterol (p=0.03), and triglycerides (p=0.036) were observed in the orlistat group. Orlistat can promote significant weight loss and symptoms of relief in obese patients with heart failure, as measured by 6-minute walk test and functional capacity. The lipid profile improved. Orlistat was safe and well tolerated.
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Exercise training as an adjunct to orlistat therapy reduces oxidative stress in obese subjects.
Ozcelik, O, Ozkan, Y, Karatas, F, Kelestimur, H
The Tohoku journal of experimental medicine. 2005;(4):313-8
Abstract
The anti-obesity drug orlistat promotes weight loss and improves obesity-related risk factors, but its effect on oxidative stress is not clear yet. Orlistat reduces dietary fat absorption, which may have effects on fat soluble vitamins especially the antioxidant vitamins A and E. The aim of this study was to determine and compare the effects of weight loss achieved by orlistat therapy and a combination of orlistat with aerobic exercise training on lipid peroxidation and antioxidative defense in obese subjects. Total of 24 obese subjects were randomly assigned to receive 12-week treatment with hypocaloric diet-orlistat (120 mg three times daily) (DO group) or diet-orlistat-exercise (DOE group). Serum levels of malondialdehyde (MDA), a marker for lipid peroxidation, and vitamins A and E were measured by high performance liquid chromatography at baseline and at the end of the treatment. Body weight and fat mass were significantly reduced in the two groups (p < 0.001). In the DO group, the MDA levels remained unchanged (p = 0.59), while vitamins A (p < 0.01) and E (p < 0.001) were significantly decreased. In contrast, the subjects treated with DOE exhibited marked decreases in MDA (p = 0.002) and a small but significant decrease in vitamins A (p = 0.003) and E (p = 0.003). Thus, orlistat therapy alone caused a significant reduction in antioxidative capacity without affecting oxidative stress, whereas orlistat in combination with exercise training provided a significant decrease in MDA levels. The beneficial effect of aerobic exercise as an adjunct to the orlistat therapy is of importance with regard to the obesity-associated risk factors.
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Influence of a lipase inhibitor on gastric sensitivity and accommodation to an orally ingested meal.
Demarchi, B, Vos, R, Deprez, P, Janssens, J, Tack, J
Alimentary pharmacology & therapeutics. 2004;(12):1261-8
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BACKGROUND Intraduodenal administration of lipids, through lipid digestion and release of cholecystokinin (CCK), induces viscero-visceral reflexes that affect gastric tone and sensitivity. It is unclear whether the same mechanisms control gastric function after an orally ingested meal. AIM: To evaluate the effect of orlistat, a selective lipase inhibitor, on gastric response to an orally administered meal. METHODS Eighteen healthy volunteers participated in this study. They were treated for 5 days with orlistat (120 mg) or placebo t.d.s. in a double-blind randomized crossover design. During treatment, all subjects underwent a gastric barostat study, measurement of plasma CCK levels and a satiety drinking test. RESULTS Although CCK plasma levels were significantly decreased, pre-treatment with orlistat failed to affect gastric compliance (72 +/- 6 mL/mm Hg and 64 +/- 6 mL/mm Hg, NS), gastric sensitivity (discomfort threshold 12.2 +/- 0.6 mm Hg vs. 10.9 +/- 0.6 mm Hg above minimal distending pressure, NS) or gastric accommodation (172 +/- 41 mL vs. 206 +/- 49 mL, NS) to an orally ingested meal. Furthermore, orlistat pre-treatment had no significant effect on the amount of calories ingested during a satiety drinking test (1329 +/- 88 kcal vs. 1217 +/- 115 kcal, NS). CONCLUSION Administration of a lipase inhibitor does not affect gastric compliance, sensitivity to distension and accommodation to an orally ingested meal, and does not influence meal-induced satiety.
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Lipase inhibition by orlistat: effects on gall-bladder kinetics and cholecystokinin release in obesity.
Mathus-Vliegen, EM, Van Ierland-Van Leeuwen, ML, Terpstra, A
Alimentary pharmacology & therapeutics. 2004;(5):601-11
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BACKGROUND Obese subjects are at risk of developing gallstones as a result of the obese state and during weight reduction. AIM: To study whether orlistat, by lipase inhibition, impairs gall-bladder emptying, thus further predisposing weight-losing obese subjects to gallstone formation. METHODS Patients entering a randomized clinical trial of 1 month of diet, followed by treatment with placebo, 3 x 60 mg orlistat or 3 x 120 mg orlistat, underwent gall-bladder emptying studies measured by ultrasound. Meal-induced cholecystokinin release and gall-bladder emptying were investigated at the start, at randomization and after 1 and 12 months. RESULTS One month of dieting did not change gall-bladder emptying and cholecystokinin release. After 1 month, placebo treatment resulted in a decreased fasting volume of 11%, compared with increases of 26% and 47% with 60 and 120 mg orlistat, respectively. Gall-bladder emptying increased by 9% with placebo and decreased by 15% and 53% with 60 and 120 mg orlistat, respectively. Fasting cholecystokinin values and cholecystokinin release decreased significantly in the orlistat group. After 1 year, a persistent but attenuated effect of orlistat on gall-bladder emptying and cholecystokinin release remained. Three of 40 patients developed gallstones, two on placebo with major weight loss and one on 60 mg orlistat. CONCLUSIONS One month of lipase inhibition by orlistat significantly impaired gall-bladder motility, which persisted to some extent after 1 year. Obese subjects with diabetes or hyperlipidaemia, who are more at risk of gallstones, should be followed carefully.
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Cholesterol lowering effect of dietary weight loss and orlistat treatment--efficacy and limitations.
Erdmann, J, Lippl, F, Klose, G, Schusdziarra, V
Alimentary pharmacology & therapeutics. 2004;(11):1173-9
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BACKGROUND Orlistat reduces energy uptake by the impairment of fat digestion and some evidence indicates it also lowers plasma cholesterol. AIM: To examine total, low-density lipoprotein- and high-density lipoprotein cholesterol during a weight reducing regimen, and assess the effect of orlistat in lowering cholesterol levels independent of its weight reducing efficacy. METHODS A total of 448 patients with elevated cholesterol according to cardiovascular risk factors entered a 2 week single-blind run-in period on a hypocaloric diet. Of 384 patients were subsequently assigned double-blind treatment with orlistat (3 x 120 mg/day) or placebo for 6 months in conjunction with the hypocaloric diet. RESULTS Weight loss in the orlistat group was 7.4 kg vs. 4.9 kg with placebo. Total and low-density lipoprotein cholesterol decreased by 25-30 mg/dL vs. 10-15 mg/dL with placebo. Reduction of cholesterol with orlistat was significantly greater than anticipated from weight loss alone. In patients with cardiovascular risk factors entering the study with lower cholesterol values orlistat was also superior to placebo. On the contrary, reduction of cholesterol concentrations never exceeded 20%. CONCLUSION Orlistat has a cholesterol lowering efficacy independent of its weight reducing effect. Because of the limited therapeutic effectiveness, patients at high cardiovascular risk should receive rather early additional cholesterol lowering medication during weight loss programmes.
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Double-blind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry.
Jackson, ID, Heidemann, BH, Wilson, J, Power, I, Brown, RD
British journal of anaesthesia. 2004;(5):675-80
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BACKGROUND Rofecoxib, a selective cyclooxygenase-2 inhibitor, and dexketoprofen trometamol, a single isomer non-steroidal anti-inflammatory drug (NSAID), are available for the treatment of acute pain. Both are claimed to have fewer adverse effects than traditional NSAIDs. We have compared them in a clinical setting. METHODS We performed a double-blind randomized controlled trial involving 120 patients undergoing surgical removal of a single mandibular third molar at the Edinburgh Dental Institute. Those who developed moderate pain within 4 h of the procedure were allocated to one of three groups: rofecoxib 50 mg (Group RO, n=37); dexketoprofen trometamol 25 mg (Group DE, n=42); or placebo (Group PL, n=41). Participants monitored pain intensity and pain relief for 24 h using visual analogue scales (VAS) and verbal rating scales (VRS). The summed, time-weighted pain relief score to 8 h derived from the VRS (TOTPAR 8) was used as the primary outcome variable. RESULTS No significant difference was demonstrated between Groups RO and DE using TOTPAR 8 as the primary outcome variable. Both drugs were significantly different compared with placebo. Rescue analgesia during the trial period was required by only 15 out of 37 subjects in Group RO, but 35 out of 42 subjects in Group DE. The median times to use of rescue medication were 150 (Group PL), 398 (Group DE) and 1440 min (Group RO). Both drugs were well tolerated and adverse events reported were mild to moderate in severity. CONCLUSIONS Rofecoxib and dexketoprofen trometamol are effective treatments for acute pain using a dental pain model and are well tolerated. Rofecoxib has a longer duration of action as a single dose and gave adequate analgesia for over half of that study group; patients in the dexketoprofen trometamol group needed more rescue analgesia.
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Effects of short-period exercise training and orlistat therapy on body composition and maximal power production capacity in obese patients.
Colak, R, Ozcelik, O
Physiological research. 2004;(1):53-60
Abstract
We examined the effects of weight loss induced by diet-orlistat (DO) and diet-orlistat combined with exercise (DOE) on maximal work rate production (Wmax) capacity in obese patients. Total of 24 obese patients were involved in this study. Twelve of them were subjected to DO therapy only and the remaining 12 patients participated in a regular aerobic exercise-training program in addition to DO therapy (DOE). Each patient performed two incremental ramp exercise tests up to exhaustion using an electromagnetically-braked cycle ergometer: one at the onset and one at the end of the 4th week. DOE therapy caused a significant decrease in total body weight: 101.5+/-17.4 kg (basal) vs 96.3+/-17.3 kg (4 wk) associated with a significant decrease in body fat mass: 45.0+/-10.5 kg (basal) vs 40.9+/-9.8 kg (4 wk). DO therapy also resulted in a significant decrease of total body weight 94.9+/-14.9 kg (basal) vs 91.6+/-13.5 kg (4 wk) associated with small but significant decreases in body fat mass: 37.7+/-5.6 kg (basal) to 36.0+/-6.2 kg (4 wk). Weight reduction achieved during DO therapy was not associated with increased Wmax capacity: 106+/-32 W (basal) vs 106+/-33 W (4 wk), while DOE therapy resulted in a markedly increased Wmax capacity: 109+/-39 W (basal) vs 138+/-30 W (4 wk). DO therapy combined with aerobic exercise training resulted in a significant reduction of fat mass tissue and markedly improved the aerobic fitness and Wmax capacities of obese patients. Considering this improvement within such a short period, physicians should consider applying an aerobic exercise-training program to sedentary obese patients for improving their physical fitness and thereby reduce the negative outcomes of obesity.