Biomedical subjects
Publications and source records attributed to G M Simpson.
The development of phenothiazines used to treat psychotic states, and later of long-acting injectable forms, is discussed. Considerations affecting the clinical use of these drugs, including patient compliance and relapse, are reviewed briefly. The depot neuroleptics appear particularly useful for noncompliant, forgetful, and treatment-resistant patients.
A major source of concern in using MAOIs is the risk of hypertensive crises, often called the "cheese effect" and thought to represent a drug-induced enhancement of the tyramine pressor effect. Several approaches to reduction of this risk are being explored, including use of inhibitors specific for the B vs. the A type of the enzyme, coadministration of tricyclic with MAOI, and development of reversible inhibitors which might be competitively displaced by tyramine. Such approaches require assessment of sensitivity to tyramine, usually given by the intravenous route. The oral tyramine pressor test, while cumbersome and in need of technical refinement, represents a significantly closer laboratory analogue to the clinical situation.
Depressed patients (N = 31), who met Research Diagnostic Criteria for major affective disorder-depressed, were severely ill and maintained drug-free for a 1-week period on inpatient status. They received a fixed dose (150 mg/day) of desipramine for a 4-week period with drug plasma level determination and clinical ratings performed at fixed time intervals throughout the study. Despite these rigid criteria for entrance and clinical outcome measures, no obvious relationship between plasma desipramine level and clinical outcome was found. The clinical implications of this finding are discussed.
Explore the source record for details and available documents.
Antidepressants are a key treatment in depression. The wide interindividual differences in plasma levels of these agents were initially seen as an explanation for nonresponse and a potential major advance in treating depressive disorders. However, efforts to relate plasma levels to therapeutic outcome have, in general, been disappointing. In the few instances where such relationships have been claimed, they have been weak and useful only for specific and problematic clinical conditions.
Urinary acidification is widely used to increase the excretion rate of PCP in abusers. Various acidifying techniques were used and compared with regard to efficacy in lowering pH, side effects, and patient acceptability. On the basis of our findings and data from routine monitoring with test tapes, we would recommend the following acidifications procedures as efficacious and reasonably well tolerated: Ammonium chloride, 4 gm. per day, 1 gm. q.i.d., with sufficient water or cranberry juice. Lysine dihydrochloride, 6 gm. per day, 2 gm. t.i.d., with sufficient water or cranberry juice. Lysine hydrochloride, 8 gm. per day, 2 gm. q.i.d., with water or cranberry juice. Cranberry juice, 18 or more oz. per day alone, or plus lysine, ammonium chloride, or ascorbic acid.
Explore the source record for details and available documents.
Leukocytosis is a common finding in patients given lithium salts, but few studies have addressed the possibility of persistent leukocyte elevation during long-term lithium therapy. We followed leukocyte counts in 32 manic-depressive patients over a 1-year period and in 25 over a 2-year period of lithium therapy, after establishing prelithium leukocyte baselines. During the first few weeks, most patients showed significant increases, which persisted throughout the course of treatment. These findings indicate that lithium might play a role in the treatment of certain leukopenic conditions.
When the authors investigated aggressive behavior on a phencyclidine (PCP) detoxification and rehabilitation unit and compared similar types of behavior on a heroin unit, they found no differences between the two units. The urinary PCP levels of a subgroup of 75 patients admitted to the PCP unit who had PCP-positive urine were significantly higher than those of 75 patients admitted to an acute psychiatric ward because of violent behavior who also had PCP-positive urine. The authors discuss the implications of these findings and the need for more information on the relationship between PCP levels in blood and urine and behavior.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Tardive dyskinesia is now widely recognised as a neurological side effect produced in susceptible individuals by ingestion of neuroleptics. In general, the disorder tends to be late in onset, but has also been reported in a small number of individuals who have received neuroleptics for only brief periods. Much effort has been spent searching for predisposing factors, but the only consistent findings are that subjects are usually elderly (and elderly females in particular), in addition to having been exposed to neuroleptic agents. More recently, the increased finding of the presence of buccolingual facial movements in elderly populations never exposed to neuroleptics may bring out a re-evaluation of the role of these agents in the aetiology of tardive dyskinesia. Although much information on tardive dyskinesia has accrued in recent years, the precise definition, subtypes and pathophysiology remain unclear. With the development and availability of standardised rating scales, the clinical description of tardive dyskinesia has expanded from the initial buccolingual masticatory syndrome to include various abnormal movements of the fingers, arms, legs etc. Efforts have been made to distinguish withdrawal tardive dyskinesia from persistent tardive dyskinesia, but, irrespective of the classification, the disorder is in many instances reversible. However, it is impossible at present to predict the reversibility of each patient: therefore early detection of tardive dyskinesia remains an important clinical goal. Pharmacological treatments are based on the currently accepted hypothesis of dopamine receptor hypersensitivity. Selective dopamine blockers (D2) which suppress tardive dyskinesia without causing an increase in Parkinsonian symptoms are at various stages of development. Acetylcholine and gamma-aminobutyric acid (GABA) also appear to play a reciprocal role with dopamine as seen by moderate success using cholinergics and 'GABAergics'. However, there is no completely satisfactory treatment at present, indicating that prevention must be the primary aim. Above all, clinicians should carefully evaluate the indication for neuroleptic drugs, and avoid their use in conditions which may be treated with more benign drugs. A strategy for management of tardive dyskinesia is presented, and indications for withdrawing or continuing neuroleptics, the treatment of withdrawal dyskinesias and the role of experimental therapies are discussed.
Explore the source record for details and available documents.
Data on usage patterns of 100 hospitalized chronic phencyclidine abusers was collected. Weekly urine samples were monitored using a new gas chromatographic nitrogen detector analysis for PCP. Abusers were found to be, on the average, young males who had used PCP for approximately 40 months (range 12 to 96 months) and approximately 3 to 4 d/week. Except for one subject, urines became negative for PCP within 30 d after last use with a mean of 14 d. There was rapid excretion during the first 9 d followed by a more gradual reduction in urine PCP levels.
"Loads," a combination of glutethimide and codeine, are a relatively new form of drug abuse that is increasing in popularity in the Los Angeles area as a heroin-substitute. Preliminary findings based on interviews and treatment of a group of preferential Loads abusers seen over a one-year period suggest that this combination has a potential for serious intoxications and withdrawal complications. The common withdrawal symptoms include those produced by both a sedative-hypnotic and a major narcotic and necessitate a detoxification plan based on the pharmacologic rationale of the abused combination.
In normal volunteer study (20 subjects) where each ingested 75 mg desmethylimipramine (DMI), blood and saliva samples were collected at 1, 2, 3, 4, 5, 7, 12, 24, and 32 h post dose. Each subject then was given DMI 25 mg b.i.d. for 15 days. Blood and saliva samples were collected on days 3, 4, 12, 13, 14, and 15. All samples were analyzed for total DMI content. Strong correlations were found between the blood samples collected 12, 24, and 32 h post dose (r = 0.93, 0.96, 0.95) and saliva samples collected 24 and 32 h post single dose (r = 0.91, 0.84) and the subjects' respective steady states. Although the correlation between blood and saliva levels was weaker (r = 0.7) because of considerable interindividual variation in the saliva/plasma DMI ratio (16-fold variation), this ratio in individual subjects was stable. These data suggest that, as has been shown for other psychotropic drugs, single blood measures at 24 h post ingestion of 75 mg DMI can be used to predict optimal dosage in individual patients. Acceptable predictions of steady state plasma levels were obtained when this technique was applied to patient data available in the literature. It is also suggested that if the saliva/plasma ratio is established for each individual patient, their drug level monitoring may be possible using this noninvasive approach.
The treatment of refractory schizophrenia requires careful definition. This is usually a statement based on clinical and/or intuitive experience. The definition can be extended and tightened if laboratory evidence is incorporated into this definition. Suggestions on how to accomplish this, e.g. measuring blood levels of antipsychotic agents, are made. Strategies for "trials of therapy' in nonresponsive patients and for decisions for changing to a new antipsychotic agent are presented. Clinical and laboratory difficulties in tackling this problem are also discussed.