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Biomedical subjects

M D Watanabe

Publications and source records attributed to M D Watanabe.

9 recordsLinked to original sources
PubMed1997

Acute dietary tryptophan depletion: effects on schizophrenic positive and negative symptoms.

Because brain serotonin levels depend directly on the amounts of exogenous tryptophan (TRP) available for its synthesis, amounts of TRP in the diet may be manipulated to alter the corresponding levels of serotonin. This technique has been used for probing the role of serotonin in mediating various forms of pyschopathology. In this study, 16 patients meeting DSM III-R criteria for schizophrenia (n = 14) or schizoaffective disorder (n = 2) were assessed for the effects of acute dietary TRP depletion under controlled conditions. The hypothesis was that lowering of serotonin would result in a diminution of 'positive' and/or 'negative' symptoms of psychotic disorders. No clinically or statistically significant improvement compared to baseline occurred when TRP depletion was imposed. Indeed, there was a statistically significant deterioration on measures of negative symptoms. The results are discussed in the context of the methodological issues.

Adult↗
PubMed1995

Successful methylphenidate treatment of apathy after subcortical infarcts.

A patient with prominent apathy secondary to multiple subcortical infarcts was treated successfully with methylphenidate. SPECT and reaction time testing showed selective improvement of frontal system function, consistent with a recent model of frontal-subcortical circuits and behavior.

Activities of Daily Living↗
PubMed1994

Depot antipsychotic drugs. Place in therapy.

The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals of from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. Unfortunately, patients who do not reliably take their oral medications are unlikely to volunteer for controlled studies. This is because the same factors that influence a patient to not cooperate with the physician in taking the medication as prescribed will also interfere with their willingness to volunteer for research protocols. Thus, evidence from blinded controlled trials may not necessarily reflect the actual patient population at risk. We feel that particularly important evidence of efficacy of depot vs oral medication comes from mirror-image studies. In these trials, the number of hospitalisations after initiation of depot medication is compared with that observed when the patient was solely taking oral medication. Studies of this type show that depot medication substantially reduces the rate of relapse. There is considerable evidence about how long depot medications should be used. For many patients, depot medication to prevent relapse in schizophrenia should be used for the life of the patient. As the conventional antipsychotic agents are replaced by a new generation of agents, the need for depot formulations will continue, and the knowledge gained about the current formulations should transfer to future generations of drugs.

Antipsychotic Agents↗
PubMed1991

Atypical antipsychotics.

This chapter discusses the clinical application of the currently studied atypical antipsychotics in the United States and abroad. A description of the proposed mode of action of these medications and the most relevant studies is included.

Animals↗
PubMed1991

Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables.

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.

Administration, Oral↗
PubMed1990

Pathophysiologic basis for schizophrenia and the efficacy of antipsychotics.

Current concepts of schizophrenia and its treatment are discussed. Schizophrenia entails negative symptoms, such as behavioral and cognitive deficits, attributed to loss of normal functions, and positive, or florid, symptoms that originate from the disturbed function of the remainder of the brain. Schizophrenia type I has positive symptoms predominating, and schizophrenia type II has negative symptoms predominating. Many atypical antipsychotics are now in Phase II and Phase III development; the prototype, clozapine, is now available. These agents challenge traditional views about drug treatment in schizophrenia. Schizophrenia may be explained by a persistent impairment in one or more neurotransmitter or neuromodulatory regulatory mechanisms, resulting in unstable or erratic neurotransmission. A more complex conceptualization of the role of the dopaminergic system makes it possible to understand the lack of biochemical tolerance to the therapeutic effects of antipsychotics, the varied time to onset of effects and prevalence of extrapyramidal symptoms, and the differences in efficacy within and among patients. Drug selection on the basis of patient-specific biological markers and neuropsychological function might expedite treatment responses. Drug therapy should augment homeostatic mechanisms and restore appropriate dopaminergic responses to physiological stimuli. Atypical antipsychotics may act by stabilizing presynaptic activity at a new set point, activating prefrontal dopaminergic systems and inhibiting mesolimbic systems, or exerting pharmacologic or functional effects on other neurotransmitter and neuropeptidergic systems. The traditional view that schizophrenia is simply a manifestation of dopaminergic overactivity is inadequate. New investigative techniques and the study of atypical antipsychotics suggest that a dysregulation hypothesis may be more consistent with the complexities of schizophrenia.

Antipsychotic Agents↗
PubMed1989

Clozapine: an atypical antipsychotic agent.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.

Antipsychotic Agents↗
PubMed1987

Free radical pathways in the in vitro hepatic metabolism of phenelzine.

The in vitro metabolism of phenelzine (2-phenylethylhydrazine) by phenobarbital-pretreated rat liver microsomes yields ethylbenzene, 2-phenylethanol, 2-phenylacetaldehyde, benzaldehyde, benzylalcohol, and toluene as metabolites. Isotopic studies demonstrate that the oxygen atom of 2-phenylethanol derives from molecular oxygen and that this alcohol is not produced by reduction of 2-phenylacetaldehyde. The rates of destruction of cytochrome P-450, accumulation of spin-trapped 2-phenylethyl radicals, and formation of ethylbenzene and 2-phenylethanol are the same for [1,1-2H]-2-phenylethylhydrazine as for the undeuterated substrate. Small primary isotope effects are observed, however, for the formation of 2-phenylacetaldehyde (kH/kD greater than 1) and benzaldehyde (kH/kD less than 1). Synthetic 2-phenylethylhydroperoxide is converted by liver microsomes to the same alcohol and aldehyde metabolites. The results indicate that the metabolism of phenelzine by rat liver microsomes proceeds primarily via the 2-phenylethyl radical.

Animals↗