ABSTRACT
Ten in-patients with tardive dyskinesia (TD) (mean AIMS score 16.7) and 8 controls were recruited to the study, and 3 h after oral administration of promethazine a blood sample was taken for assay of levels of promethazine and its immediate metabolites by high-performance liquid chromatography (HPLC). The TD group had a variety of indicators of impaired or slow metabolism compared to the controls. There was a significant difference in the ratio of promethazine to promethazine sulphoxide (P < 0.05) between patients with TD and the control group. The TD group but not the controls showed increasing metabolic impairment with age. This small study confirms the previous reports of impaired neuroleptic metabolism in TD, particularly in the elderly.
Subject(s)
Aging/metabolism , Dyskinesia, Drug-Induced/metabolism , Promethazine/metabolism , Adult , Female , Humans , Male , Middle Aged , Phenothiazines/metabolism , Prospective StudiesSubject(s)
Cytochrome P-450 CYP2D6/genetics , Psychotropic Drugs/adverse effects , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Antipsychotic Agents/pharmacokinetics , Cytochrome P-450 CYP2D6/physiology , Dose-Response Relationship, Drug , Drug Interactions , Genotype , Humans , Metabolic Clearance Rate/genetics , Psychotropic Drugs/administration & dosage , Psychotropic Drugs/pharmacokineticsABSTRACT
There appears to be a remarkably consistent structural and functional relationship between the phenylethylamine hallucinogens and the microtubule inhibitor colchicine. Such a relationship is not sustained in simple form through to the indoleamine hallucinogens and the indole based Vinca alkaloids. However, LSD and the more potent hallucinogens retain the full potential to disrupt the structure of the brain's cytoskeleton indirectly via serotonin and the raphe system. Serotonin appears to have a direct role in regulating and maintaining microtubules and microfilaments. It appears that a second receptor mediated action is required for full hallucinogenic activity. It is deduced that cytoskeletal restraints may have a role in governing central information processing. A theory for the cellular mechanisms of thought disorder and drug induced hallucinations is proposed. Schizophrenia may reflect a subtle disorder of central cytoskeletal function.
Subject(s)
Cytoskeleton/drug effects , Hallucinogens/toxicity , Schizophrenia/etiology , Animals , Brain/drug effects , Brain/physiopathology , Cytoskeleton/physiology , Dopamine/physiology , Humans , Kindling, Neurologic/physiology , Lisuride/toxicity , Models, Biological , Phenethylamines/toxicity , Schizophrenia/physiopathology , Serotonin/physiology , Structure-Activity RelationshipABSTRACT
Activation of the inositol cycle by a factor capable of by-passing the normal controls on exocrine secretion by an interaction with a coupling protein could produce effects similar to a calcium ionophore or the ciliary dyskinesia factor. The chloride permeability defect may represent a secondary adaptive change, able to limit the consequences of this via an acid shift in intracellular pH. The model predicts that lithium treatment would limit the effects of the disease.
