The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

Safety of a Novel Weight Loss Combination Product Containing Orlistat and Acarbose.

The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.

Analysis of 2,4-Dinitrophenol in Postmortem Blood and Urine by Gas Chromatography-Mass Spectrometry: Method Development and Validation and Report of Three Fatalities in the United States.

2,4-dinitrophenol (2,4-DNP) is a compound used in the early 1900s as a weight-loss drug but later prohibited due to its severe adverse effects, including death. It has however been attracting interest, due to its weight-loss properties, and appears to be re-emerging in forensic casework. As 2,4-DNP is available for use in industry and as a pesticide and easily accessible online, the dissemination of this drug can be fast. The compound exerts its effects through inhibition of ATP synthesis, and corresponding thermogenic energy loss which can be fatal. A method for qualitative and quantitative analysis of 2,4-DNP in blood and urine specimens using GC-MS with hydrogen as carrier gas is described. The method was validated and displayed acceptable performance parameters with linearity (R2 higher than 0.998), inter-assay imprecision (lower than 10.6%), intra-assay imprecision (lower than 10.7%), and extraction efficiency (92.1%). Stability of 2,4-DNP in blood and urine was studied, and the drug was stable up to 30 days refrigeration or frozen. Six cases in United States suspected to be related to 2,4-DNP were analyzed. Three cases were found to be positive for 2,4-DNP. Concentrations of 2,4-DNP were in the range of 61.6-220 mg/L in urine and <3-114 mg/L in blood. Based on our findings, we suggest that medical examiners and forensic toxicologists be aware of the reappearance of 2,4-DNP, including this compound as a target in death investigations related to weight-loss drugs.

Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents.

AIM: To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). METHODS: The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. RESULTS: ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. CONCLUSIONS: ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.

The effect of obesity and repeated exposure on pharmacokinetic response to grape polyphenols in humans.

SCOPE: Evidence suggests that dietary pattern may affect polyphenol absorption and/or metabolism. Further, obesity is associated with lower circulating nutrients, though the reason is unclear. We investigated the pharmacokinetic (PK) response of polyphenols in obese/overweight versus lean individuals before and after repeated dosing of grape polyphenols. METHODS AND RESULTS: A pilot study was conducted in which PK challenges were administered before and after 10 days of repeated dosing with polyphenols. Volunteers (6 lean, 6 overweight/obese) consumed resveratrol, grape seed extract, and grape juice (2125 mg total polyphenols) daily. On days 1 and 11, blood samples were collected for 6 h after the polyphenol dose and analyzed for deconjugated catechin, epicatechin, resveratrol, and quercetin. Area under the plasma polyphenol mass by time curves (AUCs) were greater for catechin, epicatechin, and quercetin on day 11 versus day 1 for low BMI individuals (p = 0.039) but not high BMI individuals. Further, AUCs were greater for epicatechin and resveratrol for low versus high BMI individuals (p = 0.041), with a similar trend for catechin (p = 0.065), on day 11 but not day 1. CONCLUSION: These results suggest that that obesity and repeated exposure may modify polyphenol absorption and/or metabolism in humans.

Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity.

Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood-brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin-P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin-P85 conjugates: one, Lep(ss)-P85(L), containing one P85 chain and another, Lep(ss)-P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)-P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)-P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.

Histidine supplementation alleviates inflammation in the adipose tissue of high-fat diet-induced obese rats via the NF-κB- and PPARγ-involved pathways.

Obesity is considered to be accompanied by a chronic low-grade inflammatory state that contributes to the occurrence of many chronic diseases. Our previous study has demonstrated that histidine supplementation significantly ameliorates inflammation and oxidative stress in obese women. However, the in vivo potential mechanisms are not known. The present study was conducted to investigate the mechanisms underlying the effects of histidine on inflammation in a high-fat diet (HFD)-induced female obese rat model. An obese model was established in female Sprague-Dawley rats by HFD feeding for 8 weeks and followed by histidine supplementation for another 4 weeks. The results revealed that HFD-increased body weight and HFD-lowered serum histidine concentrations were significantly reversed by histidine supplementation (P< 0·05). In addition, the serum concentrations of TNF-α, IL-6, C-reactive protein (CRP) and malondialdehyde were significantly reduced and those of superoxide dismutase (SOD) were significantly increased by histidine supplementation when compared with those in obese rats (P< 0·05). Correspondingly, the mRNA expressions of TNF-α, IL-6 and CRP in the adipose tissue were significantly down-regulated and that of CuZnSOD was significantly up-regulated by histidine supplementation (P< 0·05). Histidine supplementation significantly reduced the HFD-induced translocation of NF-κB p65 into the nucleus (P= 0·032) by reducing the phosphorylation of the inhibitor of κBα in the adipose tissue. The results also revealed that the expression of adiponectin was markedly increased both in the serum and in the adipose tissue after histidine supplementation, accompanied by the activation of PPARγ (P= 0·021). These findings indicate that histidine is an effective candidate for ameliorating inflammation and oxidative stress in obese individuals via the NF-κB- and PPARγ-involved pathways.

Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET.

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]ßCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E(max) model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

Lorcaserin: a review of its use in chronic weight management.

Oral lorcaserin (BELVIQ(®)), a selective serotonin 5-HT2C receptor agonist, is indicated in the US as an adjunct to diet and exercise in the chronic weight management of obese adults, or overweight adults with at least one weight-related comorbidity (e.g. dyslipidaemia, hypertension, type 2 diabetes). This article reviews the pharmacological properties, therapeutic efficacy and tolerability of oral lorcaserin in this patient population. In three large randomized, double-blind, multicentre studies, oral lorcaserin was more effective than placebo in the management of obese and overweight adults with or without type 2 diabetes mellitus. Following 12 months' therapy, significantly higher proportions of lorcaserin than placebo recipients achieved a ≥5 and ≥10 % reduction from baseline in their bodyweight and a significant between-group difference favouring lorcaserin over placebo was observed for the change from baseline in bodyweight. Moreover, among patients who had achieved a ≥5 % reduction in their bodyweight after 12 months' therapy with lorcaserin, a significantly higher proportion who received lorcaserin for a further 12 months than those who switched to placebo maintained ≥5 % weight loss at 24 months. In general, oral lorcaserin was well tolerated in clinical studies, with hypoglycaemia and headache the most frequently reported adverse events in those with or without type 2 diabetes, respectively. According to a pooled analysis, the risk of US-FDA-defined valvulopathy with lorcaserin is generally low and not statistically significantly different from placebo. From these and other data, the FDA has concluded that lorcaserin is unlikely to elevate the risk of valvulopathy.

Differentiation and quantification of endogenous and recombinant-methionyl human leptin in clinical plasma samples by immunocapture/mass spectrometry.

Therapeutic recombinant-methionyl human leptin (r-metHu-Leptin, Mr 16155) shares an identical amino acid sequence with endogenous leptin (endo-leptin, Mr 16024), with the addition of an N-terminal methionyl incorporated during recombinant expression in Escherichia coli. Current immunochemistry-based assays do not allow discrimination between the drug and endo-leptin because of cross reactivity. Using the immunoassay, the total plasma concentration measured in some clinical study subjects receiving r-metHu-Leptin can reach supra-physiological levels. To determine which leptin species contributes to the elevated concentrations detected in some subjects, a mass spectrometry-based method allowing discrimination and quantification of both leptin species was developed. Endo-leptin and r-metHu-Leptin were enriched from plasma matrix proteins by immuno capture, and subsequently injected onto a reversed phase analytical column coupled to an API 4000 Q-TRAP LC-MS/MS system. Multiple charge state ions and specific MRMs were monitored to provide unambiguous differentiation between endo-leptin and r-metHu-Leptin. A "top down" assay distinguishing the two forms of leptin was successfully developed and had a linear range from 15.63 to 1000 ng/ml, low limit of quantification of 15.63 ng/ml. The method was applied to selected clinical samples and revealed that the elevated leptin concentrations observed in some subjects reflected accumulation of r-metHu-Leptin. An LC-MS/MS method was developed for unambiguous differentiation of r-metHu-Leptin from endogenous leptin in human plasma. Using this method, specific quantitative information was obtained for pharmacokinetic studies in a clinical trial. The method should prove useful in quantifying this investigational drug against endo-leptin background in future clinical studies.

Determination of a novel TAZ modulator, 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H imidazo[4,5-b]pyridine] (TM-25659) in rat plasma by liquid chromatography-tandem mass spectrometry.

TM-25659 compound, a novel TAZ modulator, is developed for the control of bone loss and obesity. TAZ is known to bind to a variety of transcription factors to control cell differentiation and organ development. A selective and sensitive method was developed for the determination of TM-25659 concentrations in rat plasma. The drug was measured by liquid chromatography-tandem mass spectrometry after liquid-liquid extraction with ethyl acetate. TM-25659 and the internal standard imipramine were separated on a Hypersil GOLD C18 column with a mixture of acetonitrile-ammonium formate (10 mM) (90:10, v/v) as the mobile phase. The ions m/z 501.2→207.2 for TM-25659 and m/z 281.0→86.0 for imipramine in multiple reaction monitoring mode were used for the quantitation. The calibration range was 0.1-100 µg/ml with a correlation coefficient greater than 0.99. The lower limit of quantitation of TM-25659 in rat plasma was 0.1 µg/ml. The percent recoveries of TM-25659 and imipramine were 98.6% and 95.7% from rat plasma, respectively. The intra- and inter-batch precisions were 3.17-15.95% and the relative error was 0.38-10.82%. The developed assay was successfully applied to a pharmacokinetic study of TM-25659 administered intravenously (10 mg/kg) to rats.

Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients.

MK-5046 is an orally active, potent, selective agonist of the orphan G protein-coupled receptor bombesin receptor subtype-3 (BRS-3) that is under evaluation for treatment of obesity. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (T(max)) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS-3 in reproductive physiology. Oral administration of MK-5046 achieves plasma concentrations that are projected to activate BRS-3 and therefore should be suitable for exploring its biological role in humans.

Vaspin in obesity and diabetes: pathophysiological and clinical significance.

Vaspin (visceral adipose tissue-derived serpin; serpinA12) was originally identified as an adipokine, which is predominantly secreted from visceral adipose tissue in Otsuka Long-Evans Tokushima fatty (OLETF), an animal model of obesity and type 2 diabetes. Consistent with that higher vaspin serum concentrations and increased vaspin mRNA expression in human adipose tissue were found to be associated with obesity, insulin resistance, and type 2 diabetes in humans. However, the mechanisms how vaspin secretion may be linked to deterioration of glucose metabolism and insulin sensitivity are not entirely understood. Vaspin serum concentrations show a food intake-related diurnal variation. Vaspin is also expressed in the skin, hypothalamus, pancreatic islets, and stomach. Administration of vaspin to obese mice improves glucose tolerance, insulin sensitivity, and reduces food intake. Until now molecular target(s) of vaspin and its mode of action are unknown. Thus, identification of the proteases, which are inhibited by vaspin may lead to the development of novel strategies in the treatment of obesity, diabetes and insulin resistance. This review discusses the clinical relevance of vaspin in the pathophysiology of obesity and type 2 diabetes.

[Simultaneous determination of 15 anti-obesity drugs in blood by high performance liquid chromatography-tandem mass spectrometry].

An analytical method for the simultaneous determination of 15 anti-obesity drugs (caffeine, sibutramine, phenformin, etc.) in blood sample was developed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). After a simple protein precipitation step, the HPLC separation was performed on an UltimateXB-C18 column with methanol and 20 mmol/L ammonium acetate (containing 0.1% (v/v) of glacial acetic acid) as the mobile phases in a gradient elution mode. The MS/MS detection was achieved by electrospray ionization in both positive and negative modes by rapid switching with selective reaction monitoring (SRM). The results showed that the limits of quantification of all anti-obesity drugs were in the range of 0.001 -0.05 mg/L. The calibration curves of all anti-obesity drugs showed good linearity and the correlation coefficients were more than 0.99. The recoveries of all antiobesity drugs at 3 spiked levels were in the range of 77.3% - 110.8% with the intra-day and inter-day precisions less than 12.3%. The mass spectrum characterizations of 15 anti-obesity drugs were studied. The method is sensitive and reproducible for the detection of the 15 anti-obesity drugs in blood, and can also be applied to the determination of the anti-obesity drugs in pharmaceuticals or foods.

Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats.

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid ß-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid ß-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.

A potential role for 5-androstene-3ß,7ß,17ß-triol in obesity and metabolic syndrome.

Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients. Androstene-3ß,7ß,17ß-triol (ß-AET) an anti-inflammatory metabolite of DHEA, also exhibits GC-opposing and immune-modulating activity when administered to rodents. We hypothesized a role for ß-AET in obesity. We now report that plasma levels of ß-AET positively correlate with BMI in healthy men and women. Together with previous studies, the observations reported here may suggest a compensatory role for ß-AET in preventing the development of metabolic syndrome. The ß-AET structural core may provide the basis for novel pharmaceuticals to treat this disease.

Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: physicochemical characterization and pharmacokinetics in beagle dogs.

To develop a novel sibutramine base-loaded solid dispersion with enhanced solubility and bioavailability, various solid dispersions were prepared using a spray drying technique with hydrophilic polymers such as gelatin, HPMC and citric acid. Their solubility, thermal characteristics and crystallinity were investigated. The dissolution and pharmacokinetics of the sibutramine base-loaded solid dispersion were then compared with a sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The solid dispersions prepared with gelatin gave higher drug solubility than those prepared without gelatin, irrespective of the amount of polymer. The sibutramine base-loaded solid dispersions containing hydrophilic polymer and citric acid showed higher drug solubility compared to sibutramine base and sibutramine hydrochloride monohydrate. Among the formulations tested, the solid dispersion composed of sibutramine base/gelatin/HPMC/citric acid at the weight ratio of 1/0.8/0.2/0.5 gave the highest solubility of 5.03+/-0.24 mg/ml. Our DSC and powder X-ray diffraction results showed that the drug was present in an altered amorphous form in this solid dispersion. The difference factor (f(1)) values between solid dispersion and commercial product were 2.82, 6.65 and 6.31 at pH 1.2, 4.0 and 6.8, respectively. Furthermore, they had the similarity factor (f(2)) value of 65.68, 53.43 and 58.97 at pH 1.2, 4.0 and 6.8, respectively. Our results suggested that the solid dispersion and commercial product produced a similar correlation of dissolution profiles at all pH ranges. The AUC, C(max) and T(max) of the parent drug and metabolite I and II from the solid dispersion were not significantly different from those of the commercial product, suggesting that the solid dispersion might be bioequivalent to the commercial product in beagle dogs. Thus, the sibutramine base-loaded solid dispersion prepared with gelatin, HPMC and citric acid is a promising candidate for improving the solubility and bioavailability of the poorly water-soluble sibutramine base.

Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review.

CONTEXT: Thyroid hormone therapy to enhance weight loss in obesity during caloric deprivation and to improve morbidity and mortality in adults with nonthyroidal illnesses remains controversial. OBJECTIVE: The aim of this study was to conduct a systematic review evaluating effectiveness and risks of T(3) and/or T(4) therapy in these populations. DATA SOURCES: Electronic databases and reference lists were searched. STUDY SELECTION: Studies with comparable control groups comparing T(3) and/or T(4) therapy to placebo in randomized controlled trials (RCTs) or prospective observational studies were selected. DATA EXTRACTION: Three reviewers performed serial abstraction. DATA SYNTHESIS: During caloric deprivation of obese subjects, T(3) therapy decreased serum TSH and T(4) concentrations. Consistent effects of T(3) or T(4) on weight loss, protein breakdown, metabolic rate, and heart rate could not be established. In euthyroid cardiac patients, T(3) decreased TSH and free T(4) levels, without consistent effects of T(3) or T(4) on heart rate, cardiac output, or systemic vascular resistance. Mortality increased 3.3-fold with T(4) therapy in acute renal failure patients, whereas an effect in cardiac, critically ill, and burn patients could not be established. Equivalence testing indicated that larger RCTs are required to determine whether thyroid hormone therapy alters end-points in obesity or nonthyroidal illnesses. LIMITATIONS: Numbers of usable unique studies were small, numbers of patients in each study were inadequate, end-points were variable, few RCTs were performed, and study quality of non-RCTs was poor. CONCLUSIONS: Available data are inconclusive regarding effectiveness of thyroid hormone therapy in treating obesity or nonthyroidal illnesses, whereas data support that such therapy induces subclinical hyperthyroidism.