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Expert Review of Neurotherapeutics Jul 2019: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of...
: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of attention-deficit/hyperactivity disorder (ADHD). : The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past 5 years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturer websites to find recent RCTs on novel non-stimulant ADHD medications. : The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), , and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a 'one size fits all' to a 'precision medicine' approach.
Topics: Attention Deficit Disorder with Hyperactivity; Cannabinoid Receptor Modulators; Central Nervous System Stimulants; Humans; Neurotransmitter Agents; Piperidines; Randomized Controlled Trials as Topic; Vitamin B Complex
PubMed: 31167583
DOI: 10.1080/14737175.2019.1628640 -
NPJ Schizophrenia Dec 2019The dopamine hypothesis proposes that there is a hypodopaminergic state in the prefrontal cortex and a hyperdopaminergic state in the striatum of patients with...
The dopamine hypothesis proposes that there is a hypodopaminergic state in the prefrontal cortex and a hyperdopaminergic state in the striatum of patients with schizophrenia. Evidence suggests the hyperdopaminergic state in the striatum is due to synaptic dopamine elevation, particularly in the dorsal striatum. However, the molecular mechanisms causing disrupted dopaminergic function in schizophrenia remains unclear. We postulated that the dopamine transporter (DAT), which regulates intra-synaptic dopamine concentrations by transporting dopamine from the synaptic cleft into the pre-synaptic neuron, could be involved in dopaminergic dysfunction in schizophrenia. Therefore, we measured levels of DAT in the cortex and striatum from patients with schizophrenia and controls using postmortem human brain tissue. Levels of desmethylimipramine-insensitive mazindol-sensitive [H]mazindol binding to DAT were measured using in situ radioligand binding and autoradiography in gray matter from Brodmann's area (BA) 10, BA 17, the dorsal striatum, and nucleus accumbens from 15 patients with schizophrenia and 15 controls. Levels of desmethylimipramine-insensitive mazindol-sensitive [H]mazindol binding were significantly higher in BA 10 from patients with schizophrenia (p = 0.004) and significantly lower in the dorsal striatum (dorsal putamen p = 0.005; dorsal caudate p = 0.007) from those with the disorder. There were no differences in levels of desmethylimipramine-insensitive [H]mazindol binding in BA 17 or nucleus accumbens. These data raise the possibility that high levels of DAT in BA 10 could be contributing to lower synaptic cortical dopamine, whereas lower levels of DAT could be contributing to a hyperdopaminergic state in the dorsal striatum.
PubMed: 31792225
DOI: 10.1038/s41537-019-0087-7 -
Biochemical Pharmacology Oct 2017Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake...
Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2-24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2-24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2-24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (-)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure-function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors.
Topics: Animals; Azides; Binding Sites; Cocaine; Cross-Linking Reagents; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; LLC-PK1 Cells; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Mutant Proteins; Peptide Mapping; Photoaffinity Labels; Protein Binding; Structure-Activity Relationship; Substance-Related Disorders; Swine; Tropanes
PubMed: 28734777
DOI: 10.1016/j.bcp.2017.07.015 -
Journal of Clinical Medicine Mar 2024(1) : The number of severely obese patients worldwide is rapidly increasing. Recently, novel therapeutic approaches, such as bariatric surgery or GLP-1 receptor...
(1) : The number of severely obese patients worldwide is rapidly increasing. Recently, novel therapeutic approaches, such as bariatric surgery or GLP-1 receptor agonists, have emerged, bringing about a paradigm shift in this field. However, these therapies sometimes face challenges, such as peri-surgical complications or supply shortages. Mazindol, which is an appetite suppressant approved decades ago in Japan, remains a valuable option. In this study, we investigated the effectiveness of mazindol in reducing body weight in 147 patients, and we examined the factors influencing said effectiveness. (2) : The patients were divided into four groups based on the treatment cycles they underwent: 1 cycle, 2 cycles, 3-5 cycles, and over 6 cycles. We compared the changes in body weight before and after the treatment among these four groups. Additionally, we sought to identify the factors correlated to the effectiveness of mazindol. (3) : The change in body weight was more pronounced in the group which underwent 3-5 cycles compared to the groups which underwent 1 cycle and 2 cycles; this change was also more pronounced in the group which underwent over 6 cycles compared to those which underwent 1 cycle. Furthermore, we observed a significant correlation between the initial body weight and the extent of body weight change. (4) : Mazindol demonstrated effectiveness in reducing the body weight of patients in a cycle-dependent manner.
PubMed: 38610625
DOI: 10.3390/jcm13071860 -
Psychopharmacology Feb 2017The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by...
RATIONALE
The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated.
OBJECTIVES
The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol.
METHODS
Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [C]raclopride binding.
RESULTS
Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24-25 %, and the binding potential of [C]raclopride was reduced by 2.8-4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [C]raclopride binding in the limbic striatum.
CONCLUSIONS
A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. TRIAL REGISTRATION HTTPS://UPLOAD.UMIN.AC.JP/CGI-OPEN-BIN/CTR_E/CTR_VIEW.CGI?RECPTNO=R000009703 : UMIN000008232.
Topics: Brain; Carbon Radioisotopes; Consciousness; Corpus Striatum; Depersonalization; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Humans; Male; Mazindol; Positron-Emission Tomography; Raclopride; Young Adult
PubMed: 27766370
DOI: 10.1007/s00213-016-4464-x -
Forensic Science International Oct 2020The use of psychoactive substances has been associated with increased risk for traffic accidents. Hair testing has become a routine practice in clinical and forensic...
The use of psychoactive substances has been associated with increased risk for traffic accidents. Hair testing has become a routine practice in clinical and forensic toxicological laboratories, with a unique perspective in the investigation of drug consumption. The study aimed to develop and validate a UHPLC-MS/MS method for the determination of multiple drugs in hair, to be used for toxicological examination in driving license granting. Sample preparation was a one-step liquid extraction of milled hair with methanol, which was incubated for 15h at 50°C. The chromatographic separation was performed in a reversed phase column, with a run time of 2.2min. Measured compounds were cocaine, benzoylecgonine, norcocaine, anhydroecgonine methyl ester, cocaethylene, amphetamine, methamphetamine, methylenedioxyamphetamine, methylenedioxymethamphetamine, fenproporex, amfepramone, mazindol, codeine, morphine, 6-monoacetylmorphine, and tetrahydrocannabinol. The assay was linear for all substances (r>0.99), accurate (86.63-105.87 %), and precise, with a cv ranging from 1.9-13.5 % for intra-assay and 3.3-14.3 % for inter-assay. There was no significant carry over effect and the internal standard corrected matrix effect was minimal. The relative uncertainty percentages were below 9% for all the substances at cut-off values. The method was successfully applied to 50 hair samples from injured drivers, with 12% of positivity, including cocaine, MDMA and THC.
Topics: Automobile Driving; Chromatography, High Pressure Liquid; Hair; Humans; Illicit Drugs; Licensure; Limit of Detection; Mass Spectrometry; Psychotropic Drugs; Substance Abuse Detection; Substance-Related Disorders
PubMed: 32771886
DOI: 10.1016/j.forsciint.2020.110428 -
The Journal of Pharmacology and... Apr 2016Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760%...
Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.
Topics: Adenine; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; HEK293 Cells; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Nucleosides; Protein Binding; Serotonin Plasma Membrane Transport Proteins; Sodium; Structure-Activity Relationship; Symporters; Vesicular Monoamine Transport Proteins
PubMed: 26813929
DOI: 10.1124/jpet.115.229666 -
Nihon Rinsho. Japanese Journal of... Dec 2015Obesity has been increasing not only in Japan but also in both developed and developing countries. Mean body mass index of Japanese patients with type 2 diabetes has...
Obesity has been increasing not only in Japan but also in both developed and developing countries. Mean body mass index of Japanese patients with type 2 diabetes has been increasing, and it reached 25.0 in 2013. If body weight decreases more than 3% of initial body weight in patients with metabolic syndrome, not only glucose metabolism but also dyslipidemia and hypertension improve. To reduce the excess body weight, behavior therapy, calorie restriction, and exercise are necessary. The next strategies are drugs including mazindol, glucose-like peptide-1 receptor agonist and sodium-dependent glucose cotransporter 2 inhibitor, and bariatric surgery. Because it is often difficult to reduce body weight using only present non-invasive therapies, clarification of appetite mechanisms and development of novel anti-obesity drugs with few side effects are needed.
Topics: Bariatric Surgery; Diabetes Mellitus; Exercise Therapy; Humans; Life Style; Obesity; Weight Loss
PubMed: 26666154
DOI: No ID Found