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Drug and Alcohol Dependence Oct 1995This double-blind placebo-controlled treatment study tested the efficacy of mazindol in currently cocaine-dependent out-patients. Forty-three patients were randomized to... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
This double-blind placebo-controlled treatment study tested the efficacy of mazindol in currently cocaine-dependent out-patients. Forty-three patients were randomized to mazindol (2 mg QD) vs. placebo treatment for 6 weeks. All patients received weekly group counseling. Patients improved with respect to objective (urine toxicology) and subjective (self-report of times used, dollars spent, craving, etc.) measures. There was no response difference between patients treated with mazindol and those who received placebo.
Topics: Adult; Central Nervous System Stimulants; Cocaine; Double-Blind Method; Female; Humans; Male; Mazindol; Neurologic Examination; Substance Abuse Detection; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 8556974
DOI: 10.1016/0376-8716(95)01174-4 -
Neuropsychopharmacology : Official... Mar 2017Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal...
Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [H]mazindol), D1 receptor ([H]SCH23390), and D2 receptor ([H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R=0.31, p<0.05) that was not present in suicides (R=0.00, p=0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R=0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R=0.32, p<0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R=0.12, p<0.05; DAT: R=0.36, p<0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoradiography; Benzazepines; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Mazindol; Mental Disorders; Middle Aged; Neostriatum; Protein Binding; Receptors, Dopamine D1; Receptors, Dopamine D2; Suicide; Sulpiride; Young Adult
PubMed: 27402414
DOI: 10.1038/npp.2016.124 -
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 -
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 -
Brain Research. Molecular Brain Research Jan 1991Xenopus oocytes can express biologically relevant transport activity after injection of mRNAs encoding several carrier molecules. mRNA from PC12 cells, as well as... (Comparative Study)
Comparative Study
Xenopus oocytes can express biologically relevant transport activity after injection of mRNAs encoding several carrier molecules. mRNA from PC12 cells, as well as transcripts from a rat ventral midbrain library, can be expressed in these oocytes and allow them to display pharmacologically specific dopamine uptake. mRNA-injected oocytes incubated with tritiated dopamine contain tritiated dopamine and metabolites; lower amounts of radiolabeled dopamine and more radiolabeled metabolites are found in oocytes co-incubated with cocaine or in water-injected oocytes. Tritiated dopamine uptake into mRNA-injected oocytes is time, sodium, and temperature dependent. It is blocked by cocaine and mazindol, but not by haloperidol. It is not found after injection of mRNA from other brain regions. A size-selected rat midbrain library constructed in the plasma vector pCDM8 yields mRNA transcripts whose injection into oocytes causes cocaine-blockable [3H]dopamine uptake. These findings provide an assay for purification of the dopamine transporter cDNA by sib selection techniques.
Topics: Adrenal Gland Neoplasms; Animals; Carrier Proteins; DNA; Dopamine; Dopamine Plasma Membrane Transport Proteins; Gene Expression; Membrane Glycoproteins; Membrane Proteins; Membrane Transport Proteins; Microinjections; Nerve Tissue Proteins; Oocytes; Pheochromocytoma; RNA, Messenger; RNA, Neoplasm; Rats; Rats, Inbred Strains; Tumor Cells, Cultured; Xenopus laevis
PubMed: 1850075
DOI: 10.1016/0169-328x(91)90126-i -
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 -
Nature Nov 2013The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective...
The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.
Topics: Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Bacterial Proteins; Binding, Competitive; Biogenic Amines; Chlorides; Crystallography, X-Ray; Humans; Mazindol; Models, Molecular; Mutation; Norepinephrine; Plasma Membrane Neurotransmitter Transport Proteins; Protein Conformation; Recombinant Fusion Proteins; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors; Sertraline; Sodium; Structure-Activity Relationship
PubMed: 24121440
DOI: 10.1038/nature12648 -
Neuroscience Aug 1995Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's...
Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding and in the number of Nissl-stained neurons in the substantia nigra pars compacta and the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-specifically damages intrinsic striatal neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis centered around the needle track, which increased in size with the dose of neurotoxin. Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0 micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2 receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose, suggesting preservation of the striatal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Apomorphine; Autoradiography; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mazindol; Neural Pathways; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Substantia Nigra; Time Factors
PubMed: 7675192
DOI: 10.1016/0306-4522(95)00066-r -
The Journal of Neuroscience : the... Jun 1985Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using...
Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using [3H]mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits [3H]mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific [3H] mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific [3H]mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific [3H]mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific [3H]mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases [3H]mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce [3H]mazindol binding to either the ipsilateral or contralateral caudate-putamen. Thus, the DA uptake sites in the caudate-putamen are located on the presynaptic terminals of dopaminergic axons originating from the SN.
Topics: Animals; Autoradiography; Brain; Corpus Striatum; Desipramine; Dopamine; Indoles; Male; Mazindol; Norepinephrine; Rats; Rats, Inbred Strains; Tritium
PubMed: 4009243
DOI: 10.1523/JNEUROSCI.05-06-01513.1985 -
The Journal of Biological Chemistry Jul 1998Human and Drosophila melanogaster serotonin (5-HT) transporters (SERTs) exhibit similar 5-HT transport kinetics and can be distinguished pharmacologically by many, but...
High affinity recognition of serotonin transporter antagonists defined by species-scanning mutagenesis. An aromatic residue in transmembrane domain I dictates species-selective recognition of citalopram and mazindol.
Human and Drosophila melanogaster serotonin (5-HT) transporters (SERTs) exhibit similar 5-HT transport kinetics and can be distinguished pharmacologically by many, but not all, biogenic amine transporter antagonists. By using human and Drosophila SERT chimeras, major determinants of potencies of two transporter antagonists, mazindol and citalopram, were tracked to the amino-terminal domains encompassing transmembrane domains I and II. Species-scanning mutagenesis, whereby amino acid substitutions are made switching residues from one species to another, was employed on the eight amino acids that differ between human and Drosophila SERTs in this region, and antagonist potencies were reassessed in 5-HT uptake assays. A single mutation in transmembrane domain I of human SERT, Y95F, shifted both citalopram and mazindol to Drosophila SERT-like potencies. Strikingly, these potency changes were in opposite directions suggesting Tyr95 contributes both positive and negative determinants of antagonist potency. To gain insight into how the Y95F mutant might influence mazindol potency, we determined how structural variants of mazindol responded to the mutation. Our studies demonstrate the importance of the hydroxyl group on the heterocyclic nucleus of mazindol for maintaining species-selective recognition of mazindol and suggest that transmembrane domain I participates in the formation of antagonist-binding sites for amine transporters.
Topics: Animals; Binding Sites; Binding, Competitive; Biological Transport; Carrier Proteins; Citalopram; Drosophila; Drosophila Proteins; HeLa Cells; Humans; Mazindol; Membrane Glycoproteins; Membrane Proteins; Membrane Transport Proteins; Models, Molecular; Molecular Structure; Mutagenesis, Site-Directed; Nerve Tissue Proteins; Recombinant Fusion Proteins; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Transfection
PubMed: 9677366
DOI: 10.1074/jbc.273.31.19459