ABSTRACT
Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.
Subject(s)
Antipsychotic Agents/therapeutic use , Body Weight/drug effects , Depression/drug therapy , Receptors, G-Protein-Coupled/agonists , Schizophrenia/complications , Schizophrenia/drug therapy , Analysis of Variance , Animals , Antipsychotic Agents/pharmacology , Attention/drug effects , Attention/physiology , Benzodiazepines/therapeutic use , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Depression/etiology , Disease Models, Animal , Dopamine Uptake Inhibitors/administration & dosage , Electroencephalography , Hallucinogens/toxicity , Haloperidol/adverse effects , Humans , Macaca fascicularis , Magnetic Resonance Imaging , Male , Mental Recall/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microinjections , Motor Activity/drug effects , Motor Activity/genetics , Mutation , Olanzapine , Oocytes , Oxazoles/pharmacokinetics , Phencyclidine/toxicity , Phenethylamines/pharmacokinetics , Protein Binding/drug effects , Protein Binding/genetics , Pyrrolidinones/administration & dosage , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Reinforcement, Psychology , Schizophrenia/etiology , Schizophrenia/genetics , Swimming/psychology , Telemetry , Tritium/pharmacokinetics , XenopusABSTRACT
OBJECTIVE: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. MATERIALS AND METHODS: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. RESULTS: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively. CONCLUSIONS: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).
Subject(s)
Central Nervous System Stimulants/pharmacokinetics , Dexmethylphenidate Hydrochloride , Methylphenidate/pharmacokinetics , Adult , Area Under Curve , Biological Availability , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/blood , Delayed-Action Preparations , Female , Humans , Isomerism , Male , Methylphenidate/adverse effects , Methylphenidate/analogs & derivatives , Methylphenidate/blood , Therapeutic EquivalencyABSTRACT
The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.
Subject(s)
Acetates/pharmacokinetics , Amines , Cyclohexanecarboxylic Acids , Renal Insufficiency/metabolism , gamma-Aminobutyric Acid , Acetates/administration & dosage , Acetates/blood , Acetates/urine , Administration, Oral , Adolescent , Adult , Aged , Creatinine/blood , Creatinine/urine , Female , Gabapentin , Humans , Kidney Diseases/metabolism , Male , Middle Aged , Renal Insufficiency/blood , Renal Insufficiency/urineABSTRACT
PIP: The attempt was made to determine whether there has been a statistically significant change in the incidence of strokes among women of childbearing age in Bakersfield, California since oral contraceptives (OCs) came into general use in 1960 and whether the change in this incidence is similar to that determined by the staff of the Mayo Clinic in its study of Rochester, Minnesota. Results obtained for each city reveal that both the number and the incidence of strokes were greater during the 1st study period than they were during the 2nd. The incidence of strokes was markedly greater in Rochester than it was in Bakersfield during the 1st study period, but the incidence in each city during the 2nd period was about the same. It is concluded that in neither Rochester nor Bakersfield did the number or incidence of strokes among women of childbearing age increase after OC came into general use. In actuality, strokes decreased.^ieng
Subject(s)
Cerebrovascular Disorders/epidemiology , Contraceptives, Oral/adverse effects , California , Cerebrovascular Disorders/chemically induced , Epidemiologic Methods , Female , Humans , Minnesota , Pregnancy , Sex Factors , Statistics as Topic/methodsABSTRACT
PIP: This criticizes published data in a recent article on oral contraception and increased risk of cerebral ischemia or thrombosis. Data appear to establish a statistically significant increased risk of thrombotic and hemorrhagic stroke among young women using oral contraceptives. This risk is believed exaggerated. In the 98 case-controlled pairs there were 10 patients with a thrombotic times greater among users as among nonusers. The authors mathematically analyze why they feel the risk was improperly computed. Also the relative risk of stroke by age and race are considered to be improperly stated.^ieng