pyrimidinones and Seizures

Neurocutaneous melanosis (NCM) is a rare disorder characterised by giant or multiple melanocytic nevi and meningeal melanosis or melanoma. Onset of neurological symptoms is typically in children younger than 2 years and can be rapidly fatal. We present the case of a 13-year-old adopted girl presenting with numerous congenital melanocytic nevi and a seizure. She had no significant previous neurological history. Electroencephalogram showed epileptiform discharges over the right frontal region. MRI of the brain showed T1 hyperintensity in the bilateral amygdala and anterior temporal lobes with corresponding hyperintensity on T2 and fluid attenuated inversion recovery. There was no hydrocephalus. Along with the history of nevi, these imaging findings were concerning for NCM. The patient is being managed with levetiracetam and trametinib and shows no further neurological decline at 1-year follow-up, providing prognostic hope in this case of NCM.

Topics: Adolescent; Amygdala; Anticonvulsants; Electroencephalography; Female; Humans; Levetiracetam; Magnetic Resonance Imaging; Male; Melanosis; Mitogen-Activated Protein Kinase Kinases; Neurocutaneous Syndromes; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Seizures; Temporal Lobe

Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytochrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C19 substrate. This study quantified the pharmacokinetic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1-10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11-22). Arm B (n = 12) received PHT 300 mg QD (days 1-11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12-23). Plasma samples were collected on day 11 and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC0-12h) decreased from 70.9 +/-37.0 to 49.6 +/- 25.1 microg.h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 microg/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC0-24h decreased from 191.0+/-89.2 to 147.8+/-104.5 microg.h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0+/-4.0 to 5.3+/-4.1 microg/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.

Topics: Adult; Anticonvulsants; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pharmacogenetics; Phenytoin; Pyrimidinones; Ritonavir; Seizures

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

Topics: Animals; Anticonvulsants; Calcium Channel Agonists; Drug Discovery; Humans; Male; Microsomes, Liver; Migraine Disorders; Models, Molecular; Molecular Structure; Niacin; Pyrimidinones; Rats; Rats, Sprague-Dawley; Seizures; TRPM Cation Channels

Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu

Topics: Adult; Allosteric Regulation; Animals; Autistic Disorder; Autopsy; Disease Models, Animal; Female; Gene Expression Regulation; Hippocampus; Humans; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Knockout; Motor Cortex; Neuronal Plasticity; Pyrazoles; Pyrimidinones; Receptor, Metabotropic Glutamate 5; Rett Syndrome; Seizures; Signal Transduction; Young Adult

Herein, we described the syntheses and anticonvulsant activities of 7-(substituted-phenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1a-1o) and their derivatives. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock test (MES). The most promising compound 1i showed significant anticonvulsant activity in MES test with ED(50) value of 19.7 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard drugs. In addition, the potence of compound 1i against seizures induced by Pentylenetetrazole, Isoniazid, Thiosemicarbazide, 3-Mercaptopropionic acid, and Bicuculline in the chemical-induced seizure tests suggested that compound 1i displayed broad spectrum activity in several models, and it is likely to have several mechanisms of action including inhibiting voltage-gated ion channels and modulating GABAergic activity.

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Bicuculline; Electroshock; Isoniazid; Mice; Pentylenetetrazole; Pyrimidinones; Seizures; Semicarbazides; Structure-Activity Relationship; Triazoles

Dysfunction within the serotonin (5-HT) system plays a major role in the etiology of human depression, and treatment with antidepressant drugs downregulates 5-HT(2) receptors in rodents and humans. The consequences of another effective antidepressant treatment, electroconvulsive therapy (ECT), on 5-HT(2) receptors are less established.. We studied the effects of a course of electroconvulsive shock (ECS) on 5-HT(2) receptor binding in nonhuman primates in vivo using positron emission tomography (PET) and the radiotracer [(18)F]setoperone. Seven adult male rhesus monkeys received two bilateral ECS treatments per week for 3 weeks; PET scans were performed before treatment, and 24 hours, 1 week, and 4-6 weeks after completion of the course of ECS. Regions of interest were placed throughout the cortex, and the data analyzed as the ratio of specific:nonspecific radioactivity accumulation, with the cerebellum used as a measure of nonspecific binding.. Serotonin 5-HT(2) binding was significantly decreased at 24 hours and 1 week post-ECS, but returned to baseline 4-6 weeks posttreatment.. These results show for the first time in a primate species that chronic ECS decreases binding to 5-HT(2) receptors and indicate that 5-HT(2) receptor downregulation may be a common effect of both pharmacologic and nonpharmacologic antidepressant treatments.

Topics: Analysis of Variance; Animals; Brain; Dose-Response Relationship, Radiation; Electroshock; Fluorine Radioisotopes; Macaca mulatta; Male; Positron-Emission Tomography; Protein Binding; Pyrimidinones; Receptors, Serotonin, 5-HT2; Seizures; Serotonin Antagonists; Time Factors; Tomography, Emission-Computed

A series of 2-substituted-3-arylpyrido[2,3-d]pyrimidinones was prepared for evaluation as potential anticonvulsants. In murine screening, compounds 4a-c having a 2-oxo-2-(4-pyridyl)ethyl group in the 2-position and a 2-substituted phenyl moiety at the 3-position of the pyridopyrimidinone system displayed the most potent anti-seizure activity in both the maximal electroshock (MES) and pentylenetetrazol (scPTZ) tests at doses in the 3-10mg/kg range. Compound 4c showed no agonist activity at the GABA(A) receptor and was unable to block presynaptic sodium and calcium channels in vitro.

Topics: Animals; Anticonvulsants; Drug Evaluation, Preclinical; Male; Mice; Mice, Inbred ICR; Pyrimidinones; Rats; Seizures

In this study, some new 3-alkyl-6-arylhexahydropyrimidine-2,4-dione derivatives were synthesized as anticonvulsant agents. 6-Arylhexahydropyrimidine-2,4-diones which were used as starting materials in the synthesis of the compounds were prepared in acidic media by the cyclization of potassium cyanate and the appropriate ureido acids that were gained by the reaction of beta-aminoacids, malonic acid and ammonium acetate. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 3-arylalkyl-6-(p-chlorophenyl) derivatives were found to be protective against scMet, whereas 6-phenyl derivatives were not. 6-Phenyl-3-(2-morpholinoethyl)hexahydropyrimidine-2,4-dione was the only compound determined to be active against MES at 300 mg/kg dose at half an hour.

Topics: Alkanes; Animals; Anticonvulsants; Electroshock; Magnetic Resonance Spectroscopy; Male; Mice; Pentylenetetrazole; Postural Balance; Pyrimidinones; Seizures; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

A series of pyrrolo[2,3-d]pyrimidine-2,4-diones and intermediates was tested for anticonvulsant activity in mice. Eleven of the 15 compounds possessed anticonvulsant activity against pentylenetetrazol-induced convulsions. One compound afforded more anticonvulsant protection against pentylenetetrazol than did trimethadione (67 and 50%, respectively). A suspension of this compound was found to be as effective as a solution in producing anticonvulsant activity. The results suggest that the nitrile analogs were more potent compared to the carbamyl analog due to higher lipid solubility.

Topics: Animals; Anticonvulsants; Electroshock; Male; Mice; Pentylenetetrazole; Phenytoin; Pyrimidinones; Pyrroles; Seizures; Solubility; Structure-Activity Relationship; Trimethadione

The central action and LD50 of 11 new 2,5-substituted derivates of tetrahydropirimidinedione-4,6 with an aryl group at C2 were investigated. The most favorable action was exerted by 2-furfurylamine derivatives with an alkil or benzyl group at C5. These compounds acted in doses of 0.0025--0.01 of their LD50 synergistically with chloral hydrate and strongly with hexobarbital, delayed convulsions induced with pentetrazole and potentiated the central action of DOPA in mice pargyline-inhibited MAO activity. They did not antagonize electrogenic convulsions, amphetamine potentiated motility and the action of reserpine, and had no analgetic action. Their LD50s were 670-- 1660 mg/kg.

Topics: Amphetamine; Analgesics; Animals; Brain; Chloral Hydrate; Drug Synergism; Female; Furans; Hexobarbital; Levodopa; Male; Mice; Movement; Pentylenetetrazole; Pyrimidinones; Reserpine; Seizures; Sleep

The influence on the central nervous system of five 2-amino- and 2 amino-5-aryltetrahydropyrimidinedione-4,6 derivatives was studied. The most favorable action was exerted by benzylamine-tetrahydropyrimidinedione, which inhibited spontaneous and amphetamine-induced motility most strongly, acted synergistically with hexobarbital, was the only one of the studied group of compound which delayed convulsions induced with pentamethylenetetrazole and amphetamine, and potentiated most strongly the central action of DOPA in mice with inhibited MAO activity. The weakest effects were produced by methylpiperazinephenyl-tetrahydropyrimidinedione.

Topics: Amphetamine; Analgesia; Animals; Central Nervous System; Dihydroxyphenylalanine; Drug Synergism; Female; Hexobarbital; Lethal Dose 50; Male; Mice; Motor Activity; Movement Disorders; Pyrimidinones; Seizures; Sleep; Tetrazoles

Topics: Alkylation; Amphetamine; Animals; Central Nervous System; Drug Antagonism; Drug Synergism; Hexobarbital; Methods; Mice; Pyrimidinones; Reserpine; Seizures; Strychnine