Tesofensine

Authors:

Axel Lopez, Benjamin Arroyo, Claudia I Perez, Elvi Gil, Gilberto Castañeda-Hernández, Jorge Luis-Islas, Lievana Esmeralda Fonseca, Mario G Moreno, Omar Molina, Ranier Gutierrez, Xarenny Diaz

Findings:

Tesofensine induces greater weight loss in obese rats compared to lean rats, associated with differential modulation of neuronal ensembles and population activity in the Lateral Hypothalamus (LH). The study found that tesofensine inhibits a subset of LH GABAergic neurons in mice, reducing their ability to promote feeding, and chemogenetic silencing of these neurons enhanced tesofensine's food-suppressing effects. Unlike phentermine, tesofensine causes few, if any, head-weaving stereotypies at therapeutic doses, prolongs weight loss induced by 5-HTP, blocks body weight rebound, and its appetite-suppressant effects are independent of taste aversion or direct effects on sweetness perception.

Participants:

Animal model: Mice (Male and female adult VGAT-ChR2-EYFP mice, n=4, 20-30g; weaned Vgat-IRES-cre mice, n=27, after 21 postnatal day, groups of 3-5; Vgat-IRES-cre mice on High Fat Diet, n=5 for chemogenetic silencing; 2 Vgat-IRES-cre mice for electrophysiology with specific neuron counts). Animal model: Rats (Adult male Wistar rats; 33 rats on high-fat diet (HFD) or chow diet; 6 male rats for electrophysiology (3 HFD, 3 chow); 24 male rats, 330-370g, for locomotion/stereotypy experiments; 142 lean rats for isobologram studies; 4 male rats for sucrose detection task; Three-week-old, weight-matched male rats, 60-65g, divided into Chow-Saline (n=6), Chow-Tesofensine (n=7), HFD-Saline (n=6), HFD-Tesofensine (n=8) for diet-induced obesity model; lean male rats, n=6 per group, for chronic treatment with tesofensine and 5-HTP/CB).

Dosage:

Tesofensine: 2 mg/kg and 6 mg/kg (s.c.) in mice for open-loop task; 2 mg/kg (s.c.) in mice for electrophysiology and chemogenetic silencing. In rats: 2 mg/kg (s.c.) daily for 15 days for diet-induced obesity model; 1 mg/kg and 2 mg/kg (s.c.) daily for 15 days in combination with 5-HTP/CB; ED30 of 2.11 ± 0.81 mg/kg for isobologram assay; 2 mg/kg (s.c.) for sucrose detection task; 2 mg/kg and 6 mg/kg for locomotion/stereotypy. 5-HTP: 31 mg/kg (i.p.) with Carbidopa (CB) 75 mg/kg (i.p.) in rats. Clozapine-N-Oxide (CNO): 3 mg/kg (i.p.) in mice. Phentermine: 20 mg/kg (i.p.) in rats.

Study Quality Assessment:

Study design elements mentioned: behavioral tasks (e.g., open-loop task, sucrose detection task, open acrylic box, homegustometer), DeepLabCut videotaped analysis, electrophysiological ensemble recordings (multichannel recordings, optrode recordings), optogenetic activation/identification, chemogenetic silencing, stereotaxic surgery, histology, isobolographic analysis. Specific methods: t-distributed Stochastic Neighbor Embedding (t-SNE), hierarchical clustering analysis. Statistical analyses mentioned: Chi-square test, ANOVA (One-way, Repeated Measures), Tukey’s post hoc test, Dunnett’s test, linear regression, modified Student’s t-test. Sample sizes (n=X) are reported for various experiments. Ethical approval: 'The Institutional Animal Care and Use Committee (CINVESTAV) approved all procedures.' Publication status: 'This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.' Competing interests: 'RG is soliciting a patent for the homegustometer behavioral equipment.' Funding: Supported by 'Productos Medix 3247, Cátedra Marcos Moshinsky, fundación Miguel Aleman Valdes, CONACyT Fronteras de la Ciencia CF-2023-G-518 (R.G.).' Funding transparency: 'The sponsors play NO role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.' Acknowledged limitation: 'A caveat of our study is that we did not measure the release of these neurotransmitters.' Study timeline: 'Received 2023 Sep 4; Accepted 2024 Feb 26; Collection date 2024.'

All Effects:

Authors:

Young Jin Tak

Findings:

This review provides a comprehensive overview of anti-obesity medications (AOMs), covering lipase inhibitors (orlistat, cetilistat), GLP-1 receptor agonists (exenatide, liraglutide, semaglutide), leptin analogs (metreleptin), and MC4R agonists (setmelanotide). It discusses their mechanisms of action, clinical trial data on efficacy (e.g., semaglutide showed greater weight loss than liraglutide), FDA-approved indications, contraindications, and serious side effects. The review highlights that while some AOMs are for general obesity, others like metreleptin and setmelanotide target specific genetic causes, and emphasizes the importance of AOMs as adjuncts to lifestyle modifications.

Participants:

The review covers studies on various populations including: adults with obesity (BMI ≥30) or overweight (BMI ≥27) with weight-related comorbidities; children and adolescents (aged ≥12, or ≥6 for setmelanotide) with obesity (e.g., BMI ≥95th percentile for age and sex for children for semaglutide); patients with type 2 diabetes mellitus (T2DM); and individuals with specific genetic obesity conditions like generalized lipodystrophy, Bardet-Biedl syndrome, or deficiencies in proopiomelanocortin (POMC), proprotein subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR).

Dosage:

Orlistat (Xenical®): Oral, one 120-mg capsule three times a day with each main meal containing fat. Cetilistat: A phase 2 trial used doses of 40, 80, and 120 mg three times a day. Liraglutide (Saxenda®): Subcutaneous injection, 3 mg once daily, with dose increased gradually from 0.6 mg to 3 mg over 5 weeks. Semaglutide (Wegovy®): Subcutaneous injection, 2.4 mg once weekly, with dose increased gradually from 0.25 mg to 2.4 mg over 16 weeks. (Ozempic® for T2DM: 0.5, 1.0, and 2.0 mg doses once weekly). Metreleptin (Myalept®): Subcutaneous injection; body weight ≤40 kg: starting dose 0.06 mg/kg/day, max 0.13 mg/kg/day; males >40 kg: starting dose 2.5 mg/day, max 10 mg/day; females >40 kg: starting dose 5 mg/day, max 10 mg/day. Setmelanotide (Imcivree®): Subcutaneous injection once daily; Adults and pediatric patients ≥12 years: starting 2 mg (0.2 mL) for two weeks; Pediatric patients 6 to <12 years: starting 1 mg (0.1 mL) for two weeks. Recommended target dosage for adults and pediatric patients ≥6 years is 3 mg (0.3 mL) once daily. Text also mentions starting dose of 1.0 mg for adults and 0.5 mg for children, increased by 0.5 mg every two weeks up to max 3.0 mg.

Study Quality Assessment:

The article is a review published in Cureus (2023 Oct 7;15(10):e46623). It is an open access article distributed under the terms of the Creative Commons Attribution License. The review discusses various clinical trials, including randomized, placebo-controlled studies (e.g., for cetilistat), phase 2 trials (e.g., for cetilistat, semaglutide vs liraglutide), and phase 3 trials (e.g., for liraglutide, semaglutide, setmelanotide), some of which are described as single-arm, open-label, or multicenter. The XENDOS clinical study for orlistat is mentioned. Authors declared no competing interests and detailed author contributions. The text includes a PMC Copyright Notice and Disclaimer stating inclusion in an NLM database does not imply endorsement.

All Effects:

Authors:

EunJin Ahn, Hyun Kang

Findings:

This article provides an introduction for clinicians on performing and understanding systematic reviews and meta-analyses. It highlights that these methods combine data from various studies and are powerful tools, but can yield misleading results if studies with biases or improperly assessed quality are included, or if methodology is not strictly applied. The article emphasizes the importance of standardized guidelines and critical appraisal when interpreting meta-analysis results, as indiscriminate acceptance can be dangerous.

Study Quality Assessment:

The article describes methodologies for conducting trustworthy systematic reviews and meta-analyses. These include: using randomized controlled trials (RCTs) as a high level of evidence; following guidelines like QUORUM and PRISMA for standardization and quality improvement; pre-registering protocols (e.g., PROSPERO); defining clear inclusion/exclusion criteria; comprehensive literature searches (e.g., Medline, Embase, CENTRAL) with study selection by at least two investigators; assessing quality of evidence (e.g., Newcastle-Ottawa Scale, GRADE system); evaluating risk of bias using tools like the Cochrane "risk of bias" method (covering random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases); data extraction by two investigators; appropriate statistical methods for data analysis (e.g., fixed-effect models, random-effect models, Mantel-Haenszel, Inverse variance, Peto methods); testing for heterogeneity (forest plot, Cochrane’s Q test, Higgins I2 statistics); subgroup analysis or meta-regression for heterogeneity; and assessing/addressing publication bias (funnel plot, Begg and Mazumdar’s rank correlation test, Egger’s test, trim-and-fill method).

All Effects:

Authors:

Pradeep J Nathan

Findings:

This review found that centrally acting antiobesity drugs exhibit varied neuropsychiatric adverse event profiles. Drugs targeting monoamine systems (e.g., sibutramine, bupropion, tesofensine) most commonly caused insomnia but also showed some positive effects on mood and anxiety. Sedation and tiredness were common with drugs targeting m-opioid receptors (e.g., naltrexone) and combination therapies like Contrave™. Antiepileptic drugs (topiramate, zonisamide) were frequently associated with cognitive impairments, consistent with their sedative properties. Drugs targeting the cannabinoid system (rimonabant, taranabant) and the D1/D5 antagonist ecopipam were consistently linked to anxiety, depression, and reports of suicidal ideation.

Participants:

This review covers studies on various centrally acting antiobesity drugs, with participant populations including obese or overweight individuals, some with comorbidities (e.g., depression, anxiety, Parkinson's, Alzheimer's, type 2 diabetes, binge eating disorder), healthy subjects, individuals with substance use disorders (alcoholics, opiate addicts), and animal models (rats, mice).

Dosage:

The review mentions various dosages for different drugs, including: Sibutramine (e.g., 10 mg, 15 mg daily), Bupropion (e.g., 200 mg for 8 weeks, 300-400 mg SR for 24 weeks), Tesofensine (e.g., 0.25–1 mg for 24 weeks), Naltrexone (e.g., 50 mg, 300 mg for 8 weeks), Rimonabant (e.g., 20 mg), Topiramate (e.g., 64–384 mg/day, 96–256 mg/day), Zonisamide (e.g., dose escalated from 100 to 600 mg/day), Contrave™ (bupropion 360 mg/day SR and naltrexone 32 mg/day SR).

Study Quality Assessment:

This paper is a review of neuropsychiatric adverse effects of antiobesity drugs. It discusses findings from various study types including open-label studies, controlled trials (some placebo-controlled, double-blind), large observational cohort studies, prescription event monitoring, Phase I, II and III clinical trials, and meta-analyses. Methodological aspects mentioned include the use of assessment scales (e.g., HAM-D, BDI, VAMS, POMS, HAD scale, PHQ-9) and acknowledges limitations in some reviewed studies, such as the use of insensitive measures (e.g., VAMS), lack of comprehensive neuropsychiatric assessment in early drug development, and potential underreporting of adverse events.

All Effects:

Findings:

A population pharmacokinetic model for NS2330 (tesofensine) and its major metabolite M1 was successfully developed using data from 320 Alzheimer's disease patients. Both NS2330 and M1 pharmacokinetics were best described by one-compartment models with first-order elimination and long half-lives (234h for NS2330, 374h for M1). Sex and creatinine clearance (CLCR) were identified as significant covariates influencing steady-state plasma concentrations; simulations showed that females with impaired renal function (CLCR 35.6 ml min−1) had a 62% increased exposure to NS2330 compared to males with normal renal function.

Participants:

N=320 patients with mild to moderate dementia of Alzheimer's type. Age range: 40–85 years (median 76 years, mean 75 years, 5th–95th percentile 59–86 years). Sex distribution: 119 males (37.2%) and 201 females (62.8%).

Dosage:

Multiple oral dosing of NS2330 (tesofensine) or placebo as tablets, one tablet daily for 14 weeks. Doses studied: 0.25 mg, 0.5 mg, and 1 mg. Simulations for covariate effects assumed a dosing regimen of 1 mg NS2330 administered orally once daily.

Study Quality Assessment:

Double-blind, randomized, placebo-controlled proof of concept study (clinical phase II). N=320. Conducted in accordance with the Declaration of Helsinki (1996 Version), ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP), and appropriate regulatory requirements. Written informed consent was obtained from each patient. Pharmacokinetic modeling performed using NONMEM. Model robustness and accuracy demonstrated by internal and external dataset validation. Limitations acknowledged: influence of CYP3A4 inhibitors needs further investigation as less than 6% of plasma samples were from patients on these drugs; high interindividual variability in nonmetabolic clearance of NS2330 remained, suggesting undiscovered covariates. Funding source: Boehringer Ingelheim Pharma GmbH & Co KG.

All Effects: