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Pharmacology, Biochemistry, and Behavior Feb 1976The ability of the intravenous administration of mazindol (SaH 42-548) to act as a reinforcer in monkeys previously conditioned to self-administer cocaine was...
The ability of the intravenous administration of mazindol (SaH 42-548) to act as a reinforcer in monkeys previously conditioned to self-administer cocaine was ascertained. Unit dosages i.e. dosage per injection, of 50 and 100 mug/kg resulted in self-administration rates significantly greater than that which occurred with saline. An inverse relationship existed between unit dosage and frequency of self-administration over the unit dosage range 50-200 mug/kg. The total mazindol dosage self-administration per session was however independent of unit dosage. Approximately 2-3 mg/kg was self-administered by each animal during a 4 hr session at each of the 3 unit dosages. This tends to indicate that the 200 mug/kg unit dosage was also reinforcing even though the self-administration rate was similar to that of saline. This study indicates that mazindol can serve as a reinforcer and that the relationship between total session intake, unit dosage, and self-administration frequency of mazindol are similar to these seen with other reinforcing psychomotor stimulant drugs.
Topics: Animals; Cocaine; Conditioning, Classical; Dose-Response Relationship, Drug; Haplorhini; Indoles; Injections, Intravenous; Macaca mulatta; Male; Mazindol; Reinforcement Schedule
PubMed: 817301
DOI: 10.1016/0091-3057(76)90017-4 -
Drug and Alcohol Dependence Nov 2020Stimulant (cocaine and/or methamphetamine) use has increased among people with opioid use disorder. We conducted a systematic review of medications for stimulant use... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stimulant (cocaine and/or methamphetamine) use has increased among people with opioid use disorder. We conducted a systematic review of medications for stimulant use disorders in this population.
METHODS
We searched for randomized controlled trials in multiple databases through April 2019, and dual-screened studies using pre-specified inclusion criteria. Primary outcomes were abstinence defined as stimulant-negative urine screens for ≥3 consecutive weeks; overall use as the proportion of stimulant-negative urine specimens; and retention as the proportion of participants who completed treatment. We rated strength of evidence using established criteria and conducted meta-analyses of comparable interventions and outcomes.
RESULTS
Thirty-four trials of 22 medications focused on cocaine use disorder in patients with opioid use disorder. Most studies enrolled participants stabilized on opioid maintenence therapy, generally methadone. None of the six studies that assessed abstinence found significant differences between groups. We found moderate-strength evidence that antidepressants (desipramine, bupropion, and fluoxetine) worsened retention. There was moderate-strength evidence that disulfiram worsened treatment retention (N = 605, RR 0.86, 95 % CI 0.77 to 0.95). We found low-strength evidence that psychostimulants (mazindol and dexamphetamine) may reduce cocaine use, though the difference was not statistically significant (standard mean difference 0.35 [95 % CI -0.05 to 0.74]). There was only 1 trial for methamphetamine use disorder, which showed insufficient-strength evidence for naltrexone.
CONCLUSIONS
Co-occurring stimulant/opioid use disorder is an important problem for targeting future research. Medication trials for methamphetamine use disorder are lacking in this population. Most of the medications studied for cocaine use were ineffective, although psychostimulants warrant further study.
Topics: Analgesics, Opioid; Antidepressive Agents; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Female; Humans; Methadone; Naltrexone; Opioid-Related Disorders
PubMed: 32861136
DOI: 10.1016/j.drugalcdep.2020.108193 -
Obesity Research Jul 1999The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed...
Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine.
OBJECTIVE
The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed at 5%-30%. We studied 86 patients who had echocardiograms before treatment with appetite suppressants to determine the incidence of new cases and to evaluate the clinical implication of the echocardiographic findings.
RESEARCH METHODS AND PROCEDURES
We studied 69 men [Mean+/-Standard Deviation (S) age 49+/-8] and 17 women (mean+/-S age 50+/-7) who had 233 echocardiograms before, during, and after a weight-loss program that used predominantly fenfluramine (or dexfenfluramine) with mazindol (or phentermine). Mean drug exposure was 17 months. Blinded echocardiographic readings were performed to identify and grade aortic regurgitation (AR) or mitral regurgitation (MR).
RESULTS
Seven of 86 patients (8%) had pre-existing regurgitation with five (6%) meeting our case definition. Thirteen (16.5%) of initially normal patients developed valvular regurgitation and were new cases. Of the new cases, 12 were grade I/IV AR and one was both grade II/III MR and II/IV AR. All 13 patients were asymptomatic, and only two aortic insufficiency murmurs could be auscultated. There was significantly greater risk for developing valvulopathy for those who took medications longer than 6 months (p = 0.03), and no new cases were observed in patients exposed for less than 8 months. No increased risk associated with age, presence of hypertension, or exposure to fenfluramine-phentermine combination was demonstrated. Although there was a higher incidence of new regurgitation in women (31% vs. 13% for men), this was not statistically significant (p = 0.093).
DISCUSSION
Some patients who had normal echocardiograms at baseline developed cardiac valvular regurgitation after exposure to fenfluramine or dexfenfluramine with mazindol or phentermine. The development of valvulopathy was significantly correlated with duration of exposure. The clinical implications of echocardiographically demonstrated regurgitation are uncertain, since there were only two audible murmurs and no other clinically relevant signs or symptoms among the patients.
Topics: Aortic Valve Insufficiency; Appetite Depressants; Body Mass Index; Counseling; Dexfenfluramine; Drug Therapy, Combination; Echocardiography; Female; Fenfluramine; Humans; Incidence; Male; Mazindol; Middle Aged; Mitral Valve Insufficiency; Obesity; Observer Variation; Phentermine; Prevalence; Weight Loss
PubMed: 10440587
DOI: 10.1002/j.1550-8528.1999.tb00414.x -
Biological & Pharmaceutical Bulletin Mar 2008We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the...
We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Brain; Catalysis; Cloning, Molecular; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Enzyme Inhibitors; Humans; Hydroxylation; Microsomes; Pregnanolone; Progesterone; Psychotropic Drugs; Rats; Recombinant Proteins; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 18310890
DOI: 10.1248/bpb.31.348 -
Obesity Research Nov 1999Dropouts from clinical trials decrease quality and increase costs. Free participation, paid participation, and contingency contracting are three study retention methods.... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
OBJECTIVE
Dropouts from clinical trials decrease quality and increase costs. Free participation, paid participation, and contingency contracting are three study retention methods. Contingency contracting, or depositing a fee to be refunded contingent upon attendance in a clinical trial, has been reported to decrease dropouts without affecting weight loss. These three methods of retention were compared with a commercial weight loss clinic's practice of charging nonrefundable fees.
METHODS AND PROCEDURES
Dropouts were compared in two studies testing mazindol, with one study using free care and the other using contingency contracting; two studies testing phenylpropanolamine, one using free care and the other using contingency contracting; and in studies with phenylpropanolamine on file with Thompson Medical Company using free care, paid participation, and contingency contracting.
RESULTS
The dropout rate was 50% at 8 weeks in a trial of mazindol with free care vs. 7% for contingency contracting (p<0.001). The two phenylpropanolamine studies gave the same weight losses, but the dropouts were 37% at 8 weeks for free care vs. 11% for contingency contracting (p<0.001). The studies of phenylpropanolamine on file at the Thompson Medical Company had 28% dropouts at 8 weeks using free care vs. 19% for paid participation (p<0.001), and 11% for contingency contracting (p<0.005). Dropouts with contingency contracting (11%) were not different from the commercial weight loss program (13%).
DISCUSSION
Contingency contracting can decrease dropouts, improve quality, and decrease costs without affecting weight loss in clinical trials for obesity.
Topics: Appetite Depressants; Double-Blind Method; Humans; Mazindol; Patient Dropouts; Patient Selection; Phenylpropanolamine; Placebos; Weight Loss
PubMed: 10574519
DOI: 10.1002/j.1550-8528.1999.tb00719.x -
Yakugaku Zasshi : Journal of the... 2014With the prefectural governments' aid of the purchase, the Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences (NIHS)... (Review)
Review
[Analysis and identification of illegal constituents in health food products implicitly advertizing tonic or slimming effect in the National Institute of Health Sciences in Japan].
With the prefectural governments' aid of the purchase, the Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences (NIHS) successively has surveyed illegal constituents in health food products implicitly advertizing tonic or slimming effect since the fiscal year of 2002 (slimming type) or 2003 (tonic type). The average numbers of the analyzed products per year are about 100 (slimming type) and 150 (tonic type), respectively. We also continuously distribute standards of authentic samples of several illegal components such as N-nitrosofenfluramine (NFF) and sildenafil (SIL) to prefectural institutes and the average gross number per year is about 140. In the case of slimming type, the fact that the products containing NFF were widely sold in Japanese markets in 2002 is well known. In addition, phenolphthalein, fenfluramine, sibtramine, desdimethylsibtramine, orlistat, mazindol, Rhubarb, Senna Leaf, etc. have been found as illegal constituents. In the tonic type products, we have identified more than 20 synthetic compounds relating to the erectile dysfunction (ED) treatment drugs, SIL, vardenafil and tadalafil (TDF). Since 2005, their synthetic intermediates and the patented but non-approved PDE5 inhibitors also have been found. It should be noted that TDF was found in the shells of capsule in 2009 and that mutaprodenafil was found as pro-drug type illegal component in 2010. In this report identification method of these illegal constituents is briefly described and then analytical trend in this decade is reviewed.
Topics: Dietary Supplements; Fenfluramine; Food Analysis; Food, Organic; Government Agencies; Illicit Drugs; Japan; Piperazines; Purines; Sildenafil Citrate; Sulfones
PubMed: 24492223
DOI: 10.1248/yakushi.13-00230-1 -
Obesity Research May 1997Anorectic drugs such as mazindol bind to a class of low-affinity, sodium-sensitive sites in the brain which are affected by ambient glucose concentrations and a...
Anorectic drugs such as mazindol bind to a class of low-affinity, sodium-sensitive sites in the brain which are affected by ambient glucose concentrations and a predisposition to develop diet-induced obesity (DIO). This study used quantitative autoradiography of 10 nM 3H-mazindol binding to identify the cellular location of these putative anorectic binding sites in the brain and to assess the way in which the development of DIO affected their binding. We previously showed that chow-fed, obesity-prone rats have widespread increases in brain 3H-mazindol binding to these low-affinity sites as compared with diet-resistant (DR) rats. Here, low-affinity 3H-mazindol binding was assessed in the brains of eight rats which developed DIO vs. eight which were DR after three months on a high-energy diet. DIO rats gained 89% more weight and had 117% higher plasma insulin levels but no difference in plasma glucose levels compared with DR rats. Along with these differences, low-affinity 3H-mazindol binding in DIO rats was identical to that in DR rats in all of the 23 brain areas assessed. This suggested that this binding was downregulated by the development of obesity in DIO rats. In other chow-fed rats, stereotaxic injections of 5,7-dihydroxytryptamine and 6-hydroxydopamine (6OHDA) to ablate serotonin and catecholamine nerve terminals in the ventromedial nucleus of the hypothalamus (VMN) had no effect on 3H-mazindol binding. However, ibotenic acid injected into the VMN, substantia nigra, pars reticulata, and pars compacta destroyed intrinsic neurons and/or their local processes and decreased low-affinity 3H-mazindol binding by 13%-22%. Destruction of dopamine neurons in the substantia nigra, pars compacta, and noradrenergic neurons in the locus ceruleus with 6OHDA also reduced 3H-mazindol binding in those areas by 9% and 12%, respectively. This suggested that up to 22% of putative anorectic binding sites may be located on the cell bodies of dopamine, norepinephrine, and other neurons, but not on serotonin or catecholamine nerve terminals in the brain. Binding to these sites may be downregulated by the development of DIO, possibly as a result of the concomitant hyperinsulinemia.
Topics: Animals; Appetite Depressants; Autoradiography; Binding Sites; Brain; Diet; Male; Mazindol; Obesity; Rats; Rats, Sprague-Dawley
PubMed: 9192394
DOI: 10.1002/j.1550-8528.1997.tb00294.x -
The Journal of Clinical Investigation Apr 1981Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central...
Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central nervous system glucoprivation were investigated by administering 20-min i.v. infusions of 2-deoxy-d-glucose (50 mg/kg), a competitive inhibitor of glucose utilization, or normal saline (sham), to 24 normal volunteers. Some of the infusions were administered in combination with neuropharmacological blocking agents (placebo). The behavioral, physiological, metabolic, and hormonal correlates of 2-deoxy-d-glucose (2DG)-induced gluco-privation and AVP secretion were studied in a group (n = 5) pretreated for 1 wk with either mazindol (1 mg per os three times per day), a potent norepinephrine and dopamine-reuptake blocker, or placebo. A second group (n = 5) received either propranolol (3 mg/3 min followed by 80 mug/min) or normal saline infusion before and during 2DG administration. With 2DG alone, plasma AVP levels increased from 1.3+/-0.3 pg/ml at base line to a peak of 4.5+/-1.4 pg/ml at 60 min and remained elevated for 150 min. From 30 to 180 min after 2DG administration, the 2DG-infused volunteers increased their water intake in comparison with sham-infused volunteers. Marked increases in epinephrine and slight increases in norepinephrine were associated with increases in plasma glucose and renin activity and decreases in plasma potassium. Plasma sodium and osmolality increased transiently and mean arterial pressure (MAP) fell. These changes, however, were small and inconstant and could not account for the observed increases in thirst and AVP levels. Pretreatment with mazindol prevented the decrease in MAP and the increase in plasma renin activity (PRA) following 2DG infusions without modifying increased thirst, water intake, or AVP responses to glucoprivation. Pretreatment with propranolol effectively blocked beta-adrenoreceptors as evidenced by increased MAP and plasma epinephrine, and abolition of the RPA increases during 2DG-induced glycoprivation, but did not suppress AVP and thirst responses. A cervical cord-sectioned patient lacking descending sympathetic out-flow had a potentiated thirst response to 2DG-induced glucoprivation in the absence of increases in sodium, catecholamines, and PRA. Thus 2DG administration activates mechanisms for increased thirst and AVP which are unrelated to changes in peripheral catecholamines, MAP, PRA, and osmolality.
Topics: Arginine Vasopressin; Central Nervous System; Deoxy Sugars; Deoxyglucose; Glucose; Humans; Male; Mazindol; Propranolol; Spinal Cord Injuries; Thirst
PubMed: 7204569
DOI: 10.1172/jci110121 -
British Journal of Pharmacology Nov 19761 Anorexia in rats following injections of mazindol (0.1-8 mg/kg i.p.) could be antagonized by pretreatment with a dopamine receptor blocker (primozide) but not by...
1 Anorexia in rats following injections of mazindol (0.1-8 mg/kg i.p.) could be antagonized by pretreatment with a dopamine receptor blocker (primozide) but not by pretreatment with an alpha-adrenoceptor blocker (phenoxybenzamine), a beta-adrenoceptor blocker ((-)-propranolol), or a 5-hydroxytryptamine receptor blocker (methergoline). 2 In rats with a unilateral lesion in the substantia nigra made by stereotaxic injection of 6-hydroxydopamine, mazindol caused a dose-dependent turning towards the lesioned side, indicating an indirect mechanism of action. This effect could be antagonized by pretreatment with a dopamine receptor blocker. 3 In rats pretreated with reserpine and alpha-methyl-p-tyrosine, mazindol did not have any motor stimulant action. 4 In vitro studies with synaptosomes prepared from rat brain, indicated that mazindol blocks uptake and causes release of dopamine. 5 It is concluded that the anorectic action of mazindol is mediated by a dopaminergic mechanism.
Topics: Animals; Appetite Depressants; Behavior, Animal; Corpus Striatum; Dopamine; Feeding Behavior; Hydroxydopamines; In Vitro Techniques; Indoles; Male; Mazindol; Methyltyrosines; Rats; Reserpine; Substantia Nigra; Synaptosomes; Time Factors
PubMed: 990591
DOI: No ID Found -
PloS One 2012The increasing number of people suffering from metabolic syndrome and obesity is becoming a serious problem not only in developed countries, but also in developing...
The increasing number of people suffering from metabolic syndrome and obesity is becoming a serious problem not only in developed countries, but also in developing countries. However, there are few agents currently approved for the treatment of obesity. Those that are available are mainly appetite suppressants and gastrointestinal fat blockers. We have developed a simple and rapid method for the measurement of the feeding volume of Danio rerio (zebrafish). This assay can be used to screen appetite suppressants and enhancers. In this study, zebrafish were fed viable paramecia that were fluorescently-labeled, and feeding volume was measured using a 96-well microplate reader. Gene expression analysis of brain-derived neurotrophic factor (bdnf), knockdown of appetite-regulating genes (neuropeptide Y, preproinsulin, melanocortin 4 receptor, agouti related protein, and cannabinoid receptor 1), and the administration of clinical appetite suppressants (fluoxetine, sibutramine, mazindol, phentermine, and rimonabant) revealed the similarity among mechanisms regulating appetite in zebrafish and mammals. In combination with behavioral analysis, we were able to evaluate adverse effects on locomotor activities from gene knockdown and chemical treatments. In conclusion, we have developed an assay that uses zebrafish, which can be applied to high-throughput screening and target gene discovery for appetite suppressants and enhancers.
Topics: Animal Feed; Animals; Appetite Depressants; Appetite Regulation; Cyclobutanes; Drug Evaluation, Preclinical; Feeding Behavior; Fluorescent Dyes; Fluoxetine; Gene Expression Regulation; Gene Knockdown Techniques; High-Throughput Screening Assays; Humans; Larva; Paramecium; Zebrafish
PubMed: 23300705
DOI: 10.1371/journal.pone.0052549