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Journal of Pharmacological and... 2016Even after removal of some stimulants, like fenproporex, amfepramone and mazindol, from Brazilian market, the use of these substances is still high, especially by...
INTRODUCTION
Even after removal of some stimulants, like fenproporex, amfepramone and mazindol, from Brazilian market, the use of these substances is still high, especially by drivers. Mazindol is the second most used anorectic agent in the world acting as an indirect sympathomimetic agonist, having stimulatory action on central nervous system. Plasma is a good matrix to monitor since it reflects the psychomotor effects of these drugs, but unlike urine has an invasive collection; drug levels and detection time are quite low.
METHOD
The method involved a liquid-liquid extraction of the samples and a LC-MS analysis was fully validated. Method was used to analyze samples of urine and plasma collected from health volunteers in a period of 24h. Metabolite of mazindol was synthesized using alkaline conditions.
RESULTS
After validation the method proved to be adequate to analyze samples collected from health volunteers. Method was linear in the concentration range of 0.1-10ng/mL (r=0.9982) for plasma and 5-50ng/mL (r=0.9973) for urine.
DISCUSSION
Analysis of the samples showed that mazindol can be detected after 1h of administration and that concentration levels in urine were always higher than in plasma. Mazindol metabolite was detected only in urine.
Topics: Central Nervous System Stimulants; Chromatography, Liquid; Humans; Liquid-Liquid Extraction; Mazindol; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 26718151
DOI: 10.1016/j.vascn.2015.12.003 -
Behavioural Brain Research Aug 2014Recent research has shown that pharmacological enhancement of dopaminergic function increases an optimism bias in humans. The present study investigated whether acute...
Recent research has shown that pharmacological enhancement of dopaminergic function increases an optimism bias in humans. The present study investigated whether acute dopaminergic system stimulation through the administration of two dopamine-mimetic drugs, cocaine and mazindol, have similar effects in rats. To accomplish this goal, after initial behavioural training, two groups of rats received single injections of either cocaine or mazindol and were subsequently tested with the ambiguous-cue interpretation (ACI) paradigm. Both drugs were administered in three doses using the fully randomised Latin square designs. Cocaine (1, 2 and 5mg/kg) had no significant effect on the interpretation of the ambiguous cue. Mazindol at all three doses (0.5, 1 and 2mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue. The results are discussed in relation to pharmacological and behaviourally evoked actions of tested compounds.
Topics: Animals; Cocaine; Cognition; Cues; Discrimination Learning; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Judgment; Male; Mazindol; Neuropsychological Tests; Rats; Rats, Sprague-Dawley
PubMed: 24859175
DOI: 10.1016/j.bbr.2014.05.026 -
Current Diabetes Reviews 2020Obesity shows a multifactorial disease and presents a serious public health problem, with an alarming epidemic character. According to NHANES (National Health and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Obesity shows a multifactorial disease and presents a serious public health problem, with an alarming epidemic character. According to NHANES (National Health and Nutrition Examination Survey) from 2015 to 2016, 39.6% of American adults and 18.5% of young people were obese and 7.7% of adults and 5.6% of young people had severe obesity. Brazil ranks fifth in the world ranking, with about 18 million people reaching up to 70 million overweight individuals. Despite shortterm weight loss with diet and exercise, weight regain continues to be a concern. Anti-obesity drugs, such as Sibutramine (SIB), Phentermine (PHEN), Fenproporex (FEN), Mazindol (MAZ), Amfepramone (AMFE) and Orlistat (ORL) may play a role in weight reduction in patients whose condition is refractory to non- and maintenance of weight loss.
OBJECTIVE
A systematic review followed by meta-analysis of randomized clinical trials over the past five years to explore the efficacy and safety of anorexigenic drugs for weight reduction and consequent treatment of obesity.
METHODS
The search strategy in MEDLINE / Pubmed, Web of Science, ScienceDirect Journals (Elsevier), Scopus (Elsevier), OneFile (Gale) is as follows : - search for mesh terms (Sibutramine, Phentermine, Fenproporex, Mazindol, Amfepramone , Orlistat, Weight loss, Safety), and the use of booleans "and" between mesh terms and "or" among historical findings.
RESULTS
It was observed that in the last five years of randomized studies no significant general complications were found, with only 5.7%. The mean overall weight loss was 6.18 (± 2.8) kg in the mean time of 12 months. The overall success rate among these drugs was 80.18%. The p-value values did not present a significant statistical difference, being p <0.05 within each drug group analyzed, for both weight and success rates.
CONCLUSION
The scientific findings of randomized studies on the use of anorexigenic drugs to treat obesity have shown safety and efficiency in the last five years, with a reasonable weight loss and no significant complications.
Topics: Appetite Depressants; Humans; Obesity; Randomized Controlled Trials as Topic; Weight Loss
PubMed: 31729302
DOI: 10.2174/1573399815666191113125247 -
Critical Reviews in Analytical Chemistry 2016Norepinephrine reuptake inhibitors (NRIs) are a class of antidepressant drugs that act as reuptake inhibitors for the neurotransmitters norepinephrine and epinephrine.... (Review)
Review
Norepinephrine reuptake inhibitors (NRIs) are a class of antidepressant drugs that act as reuptake inhibitors for the neurotransmitters norepinephrine and epinephrine. The present review provides an account of analytical methods published in recent years for the determination of NRI drugs. NRIs are atomoxetine, reboxetine, viloxazine and maprotiline. NRIs with less activity at other sites are mazindol, bupropion, tapentadol, and teniloxazine. This review focuses on the analytical methods including chromatographic, spectrophotometric, electroanalytical, and electrophoresis techniques for NRI analysis from pharmaceutical formulations and biological samples. Among all of the published methods, liquid chromatography with UV-vis or MS-MS detection is the most popular technique. The most the common sample preparation techniques in the analytical methods for NRIs include liquid-liquid extraction and solid-phase extraction. Besides the analytical methods for single components, some of the simultaneous determinations are also included in this review.
Topics: Antidepressive Agents; Chromatography, High Pressure Liquid; Electrochemical Techniques; Humans; Luminescent Measurements; Mass Spectrometry; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 26857446
DOI: 10.1080/10408347.2014.948679 -
Clinics (Sao Paulo, Brazil) Mar 2018[This corrects the article doi: 10.6061/clinics/2017(05)10].
[This corrects the article doi: 10.6061/clinics/2017(05)10].
PubMed: 29561929
DOI: 10.6061/clinics/2018/e1err -
CNS Drugs Mar 2018Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel... (Randomized Controlled Trial)
Randomized Controlled Trial
A Double-Blind, Placebo-Controlled, Phase II Study to Determine the Efficacy, Safety, Tolerability and Pharmacokinetics of a Controlled Release (CR) Formulation of Mazindol in Adults with DSM-5 Attention-Deficit/Hyperactivity Disorder (ADHD).
BACKGROUND
Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) formulation of mazindol was developed to allow once-daily dosing.
OBJECTIVE
The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD.
DESIGN
We conducted a randomized, double-blind, placebo-controlled 6-week trial.
METHODS
Subjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1-3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression-Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed.
RESULTS
Eighty-five participants were randomized (n = 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active-placebo) of - 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR.
CONCLUSION
Mazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III. (Clinicaltrials.gov Registration No. NCT02808104).
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Mazindol; Middle Aged; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult
PubMed: 29557078
DOI: 10.1007/s40263-018-0503-y -
Journal of Pain Research 2017The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the...
Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.
BACKGROUND
The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund's adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined.
METHODS
Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15-day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography.
RESULTS
Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints.
CONCLUSION
Results suggest that mazindol via D2-like receptors has an antinociceptive role in mice with CFA-induced knee arthritis without modifying the bone health negatively.
PubMed: 28794657
DOI: 10.2147/JPR.S136581 -
Journal of Affective Disorders Jan 2023Dopamine dysregulation is known to play a major role in the pathophysiology of major depressive disorders (MDD) and bipolar disorders (BD). The dopamine transporter...
Dopamine dysregulation is known to play a major role in the pathophysiology of major depressive disorders (MDD) and bipolar disorders (BD). The dopamine transporter (DAT) plays a critical role in regulating dopamine concentration at the synaptic cleft and therefore could have an important role in the molecular pathology of MDD and BD. To test this hypothesis, we measured levels of [H]mazindol binding to DAT in Brodmann's area (BA) 10, BA 17 as well as in the dorsal and ventral striatum from 15 controls, 15 patients with MDD and 15 patients with BD, obtained postmortem, using in situ radioligand binding with autoradiography. Compared to controls, levels of [H]mazindol binding to DAT was significantly higher in BA10 from patients with MDD but not BD. There was no significant difference in [H]mazindol binding to DAT in BA 17 or the dorsal and ventral striatum from patients with MDD or BD. In addition, levels of [H]mazindol binding show no correlation with donor age, postmortem interval, tissue pH, sex or duration of illness. In conclusion, our data suggest that changes in levels of DAT may be selectively affecting dopamine homeostasis in BA 10 in patients with MDD.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Depressive Disorder, Major; Mazindol; Dopamine; Mood Disorders
PubMed: 36162690
DOI: 10.1016/j.jad.2022.09.065 -
Biomedical Chromatography : BMC Aug 2014Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though...
Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though their sale is banned, they can be found in illegal markets, such as those located on the country's borders. The use of oral fluid to monitor drug levels has many advantages over plasma and urine because it is noninvasive, easier to collect and more difficult to adulterate. The aim of this study was to develop and validate a sensitive and specific method to quantify mazindol in human oral fluid by liquid chromatography-mass spectrometry (LC-MS). The LC system consisted of an LC-MS system operated in selected ion monitoring mode. The mobile phase was composed of water at pH 4.0, acetonitrile and methanol (60:15:25 v/v/v) at a flow rate of 1.0 mL/min and propranolol was used as internal standard. Total running time was 10 min. The lower limit of quantification was 0.2 ng/mL and the method exhibited good linearity within the 0.2-20 ng/mL range (r = 0.9987). A rapid, specific, sensitive, linear, precise and accurate method was developed for determination of mazindol in human oral fluid according to European Medicines Agency guidelines, and is suitable for monitoring mazindol levels in oral fluid of professional drivers.
Topics: Automobile Driving; Brazil; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Drug Stability; Humans; Linear Models; Male; Mazindol; Reproducibility of Results; Saliva; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization
PubMed: 24458547
DOI: 10.1002/bmc.3120 -
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