Cost-effectiveness of weight-management pharmacotherapies in Canada: a societal perspective.

OBJECTIVES: This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg (NB-32), liraglutide 3.0 mg and semaglutide 2.4 mg as compared to the current standard of care (SoC). METHODS: Analyses were conducted using a cohort with a mean starting age 50 years, body mass index (BMI) 37.5 kg/m2, and 27.6% having type 2 diabetes. Using treatment-specific changes in surrogate endpoints from the STEP trials (BMI, glycemic, blood pressure, lipids), besides a network meta-analysis, the occurrence of weight-related complications, costs, and quality-adjusted life-years (QALYs) were projected over lifetime. RESULTS: From a societal perspective, at a willingness-to-pay (WTP) threshold of CAD 50 000 per QALY, semaglutide 2.4 mg was the most cost-effective treatment, at an incremental cost-utility ratio (ICUR) of CAD 31 243 and CAD 29 014 per QALY gained versus the next best alternative, i.e., orlistat, and SoC, respectively. Semaglutide 2.4 mg extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg and remained cost-effective both under a public and private payer perspective. Results were robust to sensitivity analyses varying post-treatment catch-up rates, longer treatment durations and using real-world cohort characteristics. Semaglutide 2.4 mg was the preferred intervention, with a likelihood of 70% at a WTP threshold of CAD 50 000 per QALY gained. However, when the modeled benefits of weight-loss on cancer, mortality, cardiovascular disease (CVD) or osteoarthritis surgeries were removed simultaneously, orlistat emerged as the best value for money compared with SoC, with an ICUR of CAD 35 723 per QALY gained. CONCLUSION: Semaglutide 2.4 mg was the most cost-effective treatment alternative compared with D&E or orlistat alone, and extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg. Results were sensitive to the inclusion of the combined benefits of mortality, cancer, CVD, and knee osteoarthritis.

Interactions of Body Weight Loss with Lipophilic Toxin Storage: Commentary.

A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.

Association of patient characteristics and insurance type with anti-obesity medications prescribing and fills.

AIM: To characterize factors associated with the receipt of anti-obesity medication (AOM) prescription and fill. MATERIALS AND METHODS: This retrospective cohort study used electronic health records from 1 January 2015 to 30 June 2023, in a large health system in Ohio and Florida. Adults with a body mass index ≥30 kg/m2 who attended ≥1 weight-management programme or had an initial AOM prescription between 1 July 2015 and 31 December 2022, were included. The main measures were a prescription for an AOM (naltrexone-bupropion, orlistat, phentermine-topiramate, liraglutide 3.0 mg and semaglutide 2.4 mg) and an AOM fill during the study follow-up. RESULTS: We identified 50 678 adults, with a mean body mass index of 38 ± 8 kg/m2 and follow-up of 4.7 ± 2.4 years. Only 8.0% of the cohort had AOM prescriptions and 4.4% had filled prescriptions. In the multivariable analyses, being a man, Black, Hispanic and other race/ethnicity (vs. White), Medicaid, traditional Medicare, Medicare Advantage, self-pay and other insurance types (vs. private insurance) and fourth quartile of the area deprivation index (vs. first quartile) were associated with lower odds of a new prescription. Hispanic ethnicity, being a man, Medicaid, traditional Medicare and Medicare Advantage insurance types, liraglutide and orlistat (vs. naltrexone-buproprion) were associated with lower odds of AOM fill, while phentermine-topiramate was associated with higher odds. Among privately insured individuals, the insurance carrier was associated with both the odds of AOM prescription and fill. CONCLUSIONS: Significant disparities exist in access to AOM both at the prescribing stage and getting the prescription filled based on patient characteristics and insurance type.

Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

Design, synthesis, biological evaluation and molecular docking of alkoxyaurones as potent pancreatic lipase inhibitors.

Aurones are a minor subgroup of flavonoids. Unlike other subgroups such as chalcones, flavones, and isoflavones, aurones have not been extensively explored as pancreatic lipase inhibitors. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. Thirty-six compounds belonging to four series (4,6-dihydroxyaurone, 6-hydroxyaurone, 4,6-dialkoxyaurone, and 6-alkoxyaurone) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbons) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC50 of 1.945 ± 0.520 µM) relative to quercetin (IC50 of 86.98 ± 3.859 µM) and orlistat (IC50 of 0.0334 ± 0.0015 µM). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed that 8 inhibited lipase through a competitive mechanism (Ki of 1.288 ± 0.282 µM). Molecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure.

The effect of orlistat in the treatment of non-alcoholic fatty liver in adolescents with overweight and obese.

Nonalcoholic fatty liver disease (NAFLD), which can manifest as nonalcoholic steatohepatitis (NASH) or severe fibrosis, is the most prevalent chronic liver disease in children and adolescents. However, there is no proven cure for it so far. This study was conducted to determine whether adolescents with NAFLD would improve with treatment intervention with orlistat. This study is a randomized controlled trial (RCT). Fifty-three adolescents with overweight/obese as well as with NAFLD randomly allocated to receive orlistat (n = 27) or placebo as control (n = 26) for 12 weeks. In addition, NAFLD activity score, anthropometric factors, biochemical parameters including serum levels of lipid profiles, liver enzyme, and glucose metabolism taken from subjects at baseline and end of the study were investigated. The findings of our article indicated that orlistat improves liver enzymes (alanine transaminase and aspartate transaminase) (P = < 0.001), steatosis score (P = 0.001), NAFLD activity score (P = < 0.001), weight (P = < 0.001), body mass index (BMI) (P = < 0.001), waist circumferences (WC) (P = < 0.001), BMI-Z score (P = < 0.001), glucose metabolism (P = 0.001), total cholesterol (TC) (P = 0.009), low density lipoprotein-cholesterol (LDL) (P = < 0.001), and high density lipoprotein-cholesterol HDL levels (P = 0.014) compared to the control group after adjusting for possible confounders for 12 weeks. However, no significant changes were observed on triglyceride (TG) following intake of orlistat compared to placebo after adjusting for confounders. CONCLUSION: The findings of our study reported that orlistat improved NAFLD-related factors and metabolic syndrome-related factors compared to placebo for 12 weeks. TRIAL REGISTRATION: (Clinical trial registry number: IRCT20220409054467N2, with a registration date of 2022-05-13). WHAT IS KNOWN: • Among the interventions of interest for the management of pediatric NAFLD, we can mention lifestyle and pharmaceutical measures. WHAT IS NEW: • This study was conducted to determine whether adolescents with NAFLD would improve with treatment intervention with orlistat. • The findings of our study reported that orlistat improved NAFLD-related factors and metabolic syndrome-related factors compared to placebo for 12 weeks.

Efficacy and safety of orlistat in male patients with overweight/obesity and hyperuricemia: results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Obesity is associated with elevated serum uric acid (SUA) levels and frequent gout flares. Losing weight can reduce the SUA level and gout flares. The effect of orlistat on SUA levels and gout flares in patients with overweight/obesity and hyperuricemia (HUA) has not been extensively studied. This study investigated the effects of orlistat on SUA levels and gout flares compared to placebo in overweight and obese patients with HUA. METHODS: A total of 72 Chinese patients with overweight/obesity and HUA were randomly divided into a placebo group (35, 48.6%) and an orlistat group (37, 51.4%); the trial lasted 12 weeks. The primary endpoints were the relative changes in body weight, the SUA level, and gout flares in the per-protocol population. RESULTS: Orlistat reduced the proportion of patients with gout flares (log-rank P = 0.023, hazard ratio = 0.31, 95% confidence interval 0.11-0.85). There was no significant difference in SUA level between the two groups. The average weight loss of the orlistat group was 2.85 kg, and the average weight loss of the placebo group was 0.76 kg. The weight loss in the orlistat group was significantly greater than that in the control group (P < 0.05). CONCLUSIONS: This study is the first to demonstrate that orlistat has no significant effect on SUA levels in patients with overweight/obesity and HUA. The utility of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized. TRIAL REGISTRATION: Clinicaltrials.gov NCT05496075.

Orlistat for the treatment of antipsychotic-induced weight gain: an eight-week multicenter, randomized, placebo-controlled, double-blind trial.

BACKGROUND: Weight gain and metabolic disorders are commonly induced by antipsychotics. Orlistat is a lipase inhibitor used for weight control. The effect of orlistat on weight gain and metabolic disturbances in people (especially women) treated with antipsychotics has not been sufficiently studied. This study aimed to investigate the efficacy of orlistat in mitigating antipsychotic-induced weight gain and abnormal glycolipid metabolism. METHODS: Patients with schizophrenia or bipolar disorder with a weight gain ≥ 7% after taking antipsychotics were recruited. Participants were randomly allocated to two groups: one received eight weeks of orlistat (360 mg/day) and the other received a placebo. Anthropometric and fasting serum biochemical parameters were measured at baseline, week 4 and week 8. RESULTS: Sixty individuals (orlistat:placebo = 32:28) participated in the study. After controlling for the study center, the eight-week changes in body mass index (BMI), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-CH) and low-density lipoprotein cholesterol (LDL-CH) were significantly different between the groups. According to the mixed linear models, CHOL and LDL-CH were significantly lower in the orlistat group than in the control group at week 8. The week 0-to-8 slopes of BMI, CHOL and LDL-CH were also significantly lower in the orlistat group. CONCLUSIONS: These findings suggested that orlistat is an effective intervention for attenuating weight gain and serum lipid disturbances in antipsychotic-treated patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03451734.

The evaluations of the inhibition of orlistat on Clostridium perfringens sialidase (NanI) activity by in†vitro and in silico approaches.

Clostridium perfringens (C. perfringens) is a bacterium that causes serious problems in humans and animals such as food poisoning, gas gangrene and infections. C. perfringens has three sialidases (NanH, NanI, NanJ) and inhibition of NanI constitutes an approach in the treatment of C. perfringens since NanI provides the carbohydrate source necessary for the growth of bacteria. In our study, the inhibition effect of some drugs belonging to different drug groups on NanI activity was investigated. Among these drugs, orlistat (0.21±0.05 µM) was determined to have a lower IC50 value than the positive control quercetin (15.58±1.59 µM). It was determined in vitro by spectrofluorometric method. Additionally, NanI molecular docking studies with orlistatand quercetin were performed using iGemdock, DockThor and SwissDock. Orlistat (-93.93, -8.649 and -10.03 kcal/mol, respectively) was found to have a higher binding affinity than quercetin (-92.68, -7.491 and -8.70 kcal/mol, respectively), and the results were in line with in vitro studies. The results may suggest that orlistat is a molecule with drug potential for C. perfringens because it inhibits the drug target NanI, and that the inhibition efficiency can be increased by studies with orlistat derivatives.

Medications for Obesity: A Review.

Importance: Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia. Observations: AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16 964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants). Conclusion and Relevance: Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.

White Tea Consumption Alleviates Anthropometric and Metabolic Parameters in Obese Patients.

Background and Objectives: Obesity and related disorders are an increasing global health problem. Achieving and maintaining long-term weight loss through lifestyle changes and/or pharmacological interventions have not met expectations. Dietary supplements and alternative treatments have also shown limited effectiveness in this regard. The consumption of green tea in general has been shown to benefit obese patients, with effects attributed to caffeine, catechins, polyphenols and other components. However, the potential of white tea to prevent and treat the negative effects of obesity has not been addressed so far. In this study, the effect of white tea (WT) consumption in obese individuals was anthropometrically and biochemically investigated. Materials and Methods: Based on anthropometric and biochemical assessments, the patients were assigned to the control, orlistat, metformin and WT groups. Patients were given a diet and exercise program and one of either orlistat, metformin or WT for 12 weeks. At the end of the 12th week, the anthropometric and biochemical measurements were reassessed. Results: Body weight, waist circumference and BMI parameters decreased significantly in all groups. TNF-α, IL-6, IL-1ß and MMP-9 levels decreased significantly in the WT group. In addition, contrary to a significant elevation in HDL-C, the serum cholesterol, LDL-C and TG levels decreased significantly. Furthermore, leptin, ghrelin and asprosin levels decreased significantly. Serum glucose levels decreased significantly in all groups except for the control. In the WT group, while there was a significant decrease in the levels of serum PL MDA and 8-OHdG, the opposite was true for GSH. Conclusions: The oral consumption of WT, its availability and its potency in obesity treatment and prevention pave the way for further delineation of the mechanisms of actions of its bioactive compounds at the cellular and endocrinological levels.

AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Anticancer Activity of Nano-formulated Orlistat-Dopamine Conjugates Through Self-Assembly.

Orlistat, an FDA-approved fatty acid inhibitor for obesity treatment, demonstrates certain low and greatly varied anticancer abilities. In a previous study, we revealed a synergistic effect between orlistat and dopamine in cancer treatment. Here, orlistat-dopamine conjugates (ODCs) with defined chemical structures were synthesized. The ODC by design underwent polymerization and self-assembly in the presence of oxygen to form nano-sized particles (Nano-ODCs) spontaneously. The resulted Nano-ODCs of partial crystalline structures demonstrated good water dispersion to form stable Nano-ODC suspensions. Because of the bioadhesive property of the catechol moieties, once administered, Nano-ODCs were quickly accumulated on cell surfaces and efficiently uptaken by cancer cells. In the cytoplasm, Nano-ODC experienced biphasic dissolution followed by spontaneous hydrolysis to release intact orlistat and dopamine. Besides elevated levels of intracellular reactive oxygen species (ROS), the co-localized dopamine also induced mitochondrial dysfunctions through monoamine oxidases (MAOs)-catalyzed dopamine oxidation. The strong synergistic effects between orlistat and dopamine determined a good cytotoxicity activity and a unique cell lysis mechanism, explaining the distinguished activity of Nano-ODC to drug-sensitive and -resistant cancer cells. This new technology-enabled orlistat repurposing will contribute to overcoming drug resistance and the improvement of cancer chemotherapy.

Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug.

Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of p-nitrophenol acetate, a common substrate of the major drug-metabolizing hydrolases, carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), in vitro. The aim of this study was to examine whether orlistat affects the pharmacokinetics of drug(s) metabolized by hydrolases in vivo after evaluating its inhibitory potencies against CES1, CES2, and AADAC in vitro. Orlistat potently inhibited the hydrolysis of acebutolol, a specific substrate of CES2, in a non-competitive manner (inhibition constant, K i = 2.95 ± 0.16 nM), whereas it slightly inhibited the hydrolysis of temocapril and eslicarbazepine acetate, specific substrates of CES1 and AADAC, respectively (IC50 >100 nM). The in vivo DDI potential was elucidated using mice, in which orlistat showed strong inhibition against acebutolol hydrolase activities in the liver and intestinal microsomes, similar to humans. The area under the curve (AUC) of acebutolol was increased by 43%, whereas the AUC of acetolol, a hydrolyzed metabolite of acebutolol, was decreased by 47% by co-administration of orlistat. The ratio of the K i value to the maximum unbound plasma concentration of orlistat (<0.012) is lower than the risk criteria for DDI in the liver defined by the US Food and Drug Administration guideline (>0.02), whereas the ratio of the K i value to the estimated intestinal luminal concentration (3.3 × 105) is considerably higher than the risk criteria in the intestine (>10). Therefore, this suggests that orlistat causes DDI by inhibiting hydrolases in the intestine. SIGNIFICANCE STATEMENT: This study demonstrated that orlistat, an anti-obesity drug, causes drug-drug interactions in vivo by potently inhibiting carboxylesterase 2 in the intestine. This is the first evidence that inhibition of hydrolases causes drug-drug interactions.

Orlistat mouth rinse: Using the tongue to deliver antiobesity medication in a double-blind randomized crossover pilot trial.

AIM: To investigate the effects of an orlistat mouth rinse on the intake of a high-fat meal. METHODS: A double-blind, balanced order, crossover study was conducted in participants (n = 10, body mass index 25-30 kg/m2 ) assigned to receive placebo or orlistat (24 mg/mL) prior to a high-fat meal. Participants were divided into low- or high-fat consumers based on calories consumed from fat following placebo administration. RESULTS: The orlistat mouth rinse decreased total and fat calories consumed during the high-fat meal in high-fat consumers, and did not alter calories consumed in low-fat consumers (P < 0.05). CONCLUSIONS: Orlistat decreases long-chain fatty acid (LCFA) absorption by inhibiting lipases that breakdown triglycerides. Orlistat mouth rinse decreased fat intake in high-fat consumers, suggesting that orlistat inhibited the detection of LCFAs from the high-fat test meal. Lingual delivery of orlistat is predicted to eliminate the risk of oil incontinence and promote weight loss in individuals who prefer fat.

Effect of Orlistat on anthropometrics and metabolic indices in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Childhood obesity is one of the main concerns of public health. Considering its long-term adverse health effect, various studies investigated the effect of drug therapy on anthropometric parameters and provided mixed results. In this systematic review and meta-analysis, we aimed to determine the effect of Orlistat on anthropometrics and biochemical parameters in children and adolescents. MATERIALS AND METHODS: The databases of PubMed, Scopus, and Web of Science were searched until September 2022. Experimental and semi-experimental studies were included if they evaluated the effect of Orlistat on obesity-related parameters in children and reported the before and after anthropometric values. A revised Cochrane risk-of-bias (Rob2) was used to evaluate the methodological quality. STATA software version 16.0 was used for the meta-analysis of the random-effect model. RESULTS: Of 810 articles retrieved in the initial search, four experimental and two semi-experimental studies were selected for systematic review. The result of the meta-analysis of experimental studies indicated the significant effect of Orlistat on waist circumference (SMD: -0.27, 95% CI: -0.47, -0.07) and serum insulin level (SMD: -0.89, 95% CI: -1.52, 0.26). However, there were no significant effects of orlistat on body weight, body mass index, lipid profile, and serum glucose level. CONCLUSION: The present meta-analysis showed the significant effect of Orlistat on the reduction of waist circumference and insulin level in overweight and obese adolescents. However, due to the paucity of studies included in the meta-analysis, more prospective studies with longer duration and more sample sizes will be needed in this age group.

Necessity, Role, and Outcomes of Fasciotomy in Patients with Acute Limb Ischemia.

BACKGROUND: The incidence of compartment syndrome in patients with acute lower limb ischemia (ALLI) and the effects of fasciotomy on outcomes are largely undefined. This study aimed to define the incidence of compartment syndrome in patients with ALLI and to examine whether different fasciotomy strategies are associated with specific patient outcomes. METHODS: A single-center retrospective study of patients who had ALLI between April 2016 and October 2020 at a tertiary care center. Patients were categorized into groups as having received early and late therapeutic fasciotomy (TF), early prophylactic fasciotomy (PF), early exploratory fasciotomy, and no fasciotomy. Primary outcome was 30-day amputation rate. Secondary outcomes were 30-day and 1-year mortality, 1-year amputation rate, and length of stay. Groups were compared using descriptive statistics to assess the association of fasciotomy approach with outcomes. RESULTS: During the study period, 266 patients were treated for ALLI, and 62 patients (23%) underwent 66 fasciotomies. A total of 41 TF, 23 PF, and 2 exploratory fasciotomies were done. There were 58 early fasciotomies performed (88% of 66 limbs): 33 (57%) early TF, 23 (40%) PF, and 2 (3%) exploratory. There were 8 patients who developed compartment syndrome after their revascularization operation and received delayed TF (12% of 66 limbs). The total number of TF was 41, which was 15% of all ALLI patients. The mean ± SD time to fasciotomy closure was 6.7 ± 5.7 days, which did not differ between PF and TF groups. Significantly more patients in the TF group had an amputation at 30 days (11 [29%] vs. 1 [5%]; P = 0.03) and at 1 year (6 [18%] vs. 2 [9%]; P = 0.02) than those in the PF group. Length of stay was increased in both TF (16 days) and PF (19 days) patients compared to nonfasciotomy patients (10 days; P < 0.01) but did not differ between the 2 fasciotomy groups (P = 0.4). Thirty-day limb loss was highest in patients who underwent early TF (10/33, 33%), intermediate in those with delayed TF (1/8, 13%), and lowest in PF (1/23, 5%; P = 0.03). CONCLUSIONS: Approximately 15% of patients with ALLI in our cohort required a TF for compartment syndrome. Close postoperative monitoring of ALLI patients who did not undergo early fasciotomy did detect delayed compartment syndrome; however, this approach did not prevent limb loss. To optimize limb salvage, physicians treating patients with ALLI should be experienced in how to recognize and treat compartment syndrome.

A Flavonoid-rich Zuccagnia punctata Extract Prevents High Fat Diet-induced Normal Weight Obesity in a Rabbit Model.

Oral administration of rich in flavonoids hydroalcoholic extract from Zuccagnia punctata (ZpE) improves lipid profile and prevents vascular dysfunction in hypercholesterolemic rabbits. This study aimed to evaluate the ability of ZpE to prevent metabolic and vascular alterations induced by high fat diet (HFD) on a metabolically obese and normal weight rabbit model. The major components of ZpE were analyzed by HPLC method. Rabbits were separated into six groups: 1-fed on standard chow (CD); 2-fed on HFD; 3, 4, 5- fed on HFD and orally administrated 2.5 mg, 5 mg or 10 mg GAE/day of ZpE, respectively (ZpE- HFD); 6- fed on HFD and orally administered 30 mg orlistat/day (Or-HFD). All diets were administrated by 6 weeks. The major compounds of ZpE identified were chalcones: 2',4'-dihydroxy-3'-methoxychalcone and 2',4'-dihydroxychalcone. Oral treatment with ZpE 5 mg GAE/day as well as orlistat prevented the HFD-induced increase of triglycerides, fasting glucose, intraperitoneal glucose test, white cells, and TyG index. Acetylcholine relaxation was reduced in arteries from HFD group and oral administration of ZpE reached this response to CD values. Contractile response to angiotensin II was lower in arteries from rabbits fed on HFD treated with ZpE 5 and 10 mg GAE/day than those of untreated rabbits. Moreover, ZpE could inhibit the activity of pancreatic lipase in vitro and in vivo. In conclusion the ZpE may prevent normal weight obesity by inhibiting the pancreatic lipase. Thus, the use of ZpE as a natural product in the prevention of metabolic syndrome and endothelial dysfunction is very promising.

FASN inhibition sensitizes metastatic OSCC cells to cisplatin and paclitaxel by downregulating cyclin B1.

OBJECTIVES: To investigate the potential effect of fatty acid synthase (FASN) inhibitor orlistat to enhance the effectiveness of chemotherapy drugs widely used to treat oral squamous cell carcinomas (OSCC), such as 5-fluorouracil, cisplatin, and paclitaxel. METHODS: The OSCC SCC-9 LN-1 metastatic cell line, which expresses high levels of FASN, was used for drug combination experiments. Cell viability was analyzed by crystal violet staining and automatic cell counting. Apoptosis and cell cycle were analyzed by flow cytometry with Annexin-V/7-AAD and propidium iodide staining, respectively. Cyclin B1, Cdc25C, Cdk1, FASN, and ERBB2 levels were assessed by Western blotting. Finally, cell scratch and transwell assays were performed to assess cell migration and invasion. RESULTS: Inhibition of FASN with orlistat sensitized SCC-9 LN-1 cells to the cytotoxic effects of paclitaxel and cisplatin, but not 5-fluorouracil, which was accompanied by a significant reduction in cyclin B1. The suppression of proliferation, migration, and invasion of SCC-9 LN-1 cells induced by orlistat plus cisplatin or paclitaxel was not superior to the effects of chemotherapy drugs alone. CONCLUSION: Our results suggest that orlistat enhances the chemosensitivity of SCC-9 LN-1 cells to cisplatin and paclitaxel by downregulating cyclin B1.

In vitro and in vivo local tolerability of a synergistic anti-tuberculosis drug combination intended for pulmonary delivery.

A drug combination, vancomycin (VAN) plus tetrahydrolipstatin (THL), has demonstrated an effective synergistic action in vitro against Mycobacterium tuberculosis (Mtb). The poor oral bioavailability of VAN and THL and the predominant tropism of Mtb infection to the lungs make their pulmonary administration very attractive. To evaluate their local tolerability, bronchial cells, alveolar cells and monocytes were exposed to concentrations around and above their minimal inhibitory concentration (MIC). The VAN had no inhibitory activity on the tested human cell lines, even at a concentration 125 times higher than its MIC, whereas the THL, alone or in combination with VAN, presented a cytostatic action. Monolayer epithelium showed no significant irreversible damage at concentrations up to 100 times the combination MIC. BALB/cAnNRj mice exposed to concentration of 50 times the combination MIC delivered endotracheally 3 times a week for 3 weeks showed no clinical signs or significant weight loss. The increase of proinflammatory biomarkers (i.e., IL-1, IL-6, TNF-α and proportion of inflammatory cells) and cytotoxicity in bronchoalveolar lavage fluid (BALF) were non-significant. Lung histopathology did not show significant tissue damage. The VAN/THL combination at doses up to 50 times the combination MIC is found to be thus well tolerated by pulmonary route. This study is a promising result and encouraging further investigations of pulmonary administration of VAN/THL combination as dry powder for anti-tuberculosis treatment.