Exploring the relationship of drug-induced neutrophil immaturity & haematological toxicity to drug chemistry using quantitative structure-activity models.

An investigation of the relationships between physicochemical features of ten antipsychotic drugs and previously reported influence of these drugs on neutrophil maturity was made. A quantitative structure-activity relations (QSAR) approach was adopted, in which several numerical parameters describing physicochemical characteristics of the antipsychotics were estimated. Possible connections between these parameters and neutrophil maturity were explored. Influence of drug physicochemistry on the incidence of agranulocytosis and neutropenia reported in the literature was documented. Overall it was found that drugs with the greatest tendency to induce neutrophil immaturity (chlorpromazine, clozapine and olanzapine) also showed the greatest tendency to cause agranulocytosis and neutropenia. Moreover marked induction of neutrophil immaturity occurred with compounds of moderately amphipathic character, whose amphipathic indices (AI) fell in the range 3-5; higher or lower AI values correlated with less immaturity. Consideration of the QSAR findings suggest that toxicity could be associated with selective uptake into the most fluid intracellular membranes, those of the endoplasmic reticulum and the outer mitochondrial membrane. The AI hazard zone (AI = 3-5) does constitute a predictive tool to assess risk of agranulocytosis and neutropenia arising from antipsychotic and other psychoactive drugs - and not only risk arising from medication but also from experimental or even proposed compounds.

Formation of immature neutrophil leucocytes in schizophrenic patients treated with various antipsychotic drugs: comparisons and predictions.

The neutrophils of schizophrenic patients taking antipsychotic drugs were evaluated. Neutrophil immaturity was assessed by determining mean nuclear lobe number in peripheral blood smears of patients and controls. Subjects were patients medicated with typical (upenthixol (n 6), uphenazine (n 7), haloperidol (n 23), thioridazine (n 15), and triuoperazine (n 6)) or atypical (olanzapine (n 15), risperidone (n 10), and sulpiride (n 7)) antipsychotic drugs. Controls (n 58) were healthy, non-medicated clinical and academic staff. Mean lobe number was determined using light microscopy and examining 300 neutrophils per individual. For subject and control groups, means and medians of mean lobe numbers, and also mean white cell and neutrophil counts, were determined. Means for each group were compared using the Mann-Whitney U test; variances using F ratios. Mean lobe numbers of all patients were decreased compared to controls. The left shift occurring in patients medicated with haloperidol, olanzapine, risperidone, thioridazine, and triuoperazine was signícantat P 0.0001; for upenthixol P 0.001, and for sulpiride P 0.05. The left shift for uphenazine was not statistically signíant. For one patient, mean lobe numbers were obtained before and after medication with olanzapine commenced, and a lowering of mean lobe number was seen. Although the coefficient of variation in the patient groups was large compared to the controls, nevertheless more than half of the patients had mean lobe numbers outside the observed range of values seen in the control population. White blood cell and neutrophil counts in patients and controls were not signiécantly different. This study demonstrated that patients taking antipsychotic drugs have immature neutrophils, but normal total white cell and neutrophil numbers. The effect was seen with both typical and atypical antipsychotic drugs, and is probably drug-induced. It is possible that mean lobe number may predict patients at risk from neutropenia or agranulocytosis, as is also suggested by an analysis of the relative numbers of literature reports of neutrophil pathology for these drugs. It is of interest that olanzapine, which has been considered a haematologically non-hazardous drug, was shown to be associated with a significant decrease in mean lobe number.

Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients.

Subclinical abnormality of neutrophil populations of patients suffering from schizophrenia and medicated with antipsychotic drugs was evaluated using cellular immaturity as a criterion. Neutrophil maturity of patients and controls was compared by determining mean nuclear lobularity in peripheral blood smears. White blood cell and neutrophil counts were made. Subjects were patients medicated with chlorpromazine (n = 17) or clozapine (n = 48). Controls (n = 58) were healthy, non-medicated clinical and academic staff. Determination of mean lobe number involved assessment of 300 neutrophils per individual. For subject and control groups, means and medians of mean lobe numbers and mean white cell and neutrophil counts were determined. Means for each group were compared using the Mann-Whitney U-test; variances using F ratios. Means of lobe numbers of both patient populations were significantly different (p < 0.0001) compared to controls. Two-thirds of patients had mean lobe numbers outside the control range. Dose-response (mean lobe number) plots were significant for patients medicated with both chlorpromazine and clozapine. White cell and neutrophil counts in patients and controls did not differ significantly. For six patients, mean lobe numbers were obtained before and after medication commenced and all showed lowering of mean lobe number. The mean lobe number of the one patient who subsequently suffered from agranulocytosis was at the low end of the patient range. Thus, patients medicated with antipsychotic drugs typically have immature neutrophils, but normal white cell and neutrophil numbers. This effect is probably drug-induced. Mean lobe number may predict patients at risk from agranulocytosis.

The biology of dementia due to Parkinson's disease.

This article is one of a series focusing on dementias due to an underlying biological factor. The reader should refer to the previous articles in the series (Delieu and Keady, 1996a,b). This article focuses on the normal structures within the brain which are involved in motor control and describes what occurs when this system is disrupted by an inappropriate reduction in the neurotransmitter dopamine. In time, this reduction in dopamine may have deleterious effects on other neuronal systems within the central nervous system, namely the diminished acetylcholine neurones which may lead to a dementional state. Possible causes of Parkinson's disease are discussed and some treatments briefly outlined.

The biology of Alzheimer's disease: 2.

In this article, the second of two parts, the authors continue their review of the biological processes of Alzheimer's disease and the implications for nursing practice. A glossary of terms can be found in the first article (Vol 5(3): 162-7). This article considers the function of the subcortical area of the brain and explores its effects on the world of the person with Alzheimer's disease. Nursing responses are also discussed.

The biology of Alzheimer's disease: 1.

This article, the first of two parts, attempts to take dementia care back to its foundations by informing nursing practice of the biology and degenerative effects on the brain of Alzheimer's disease, the most prevalent form of dementia. This biological understanding will then be used to illustrate the effect on the emotional, perceptual, behavioural and social world of the individual sufferer and will be selectively applied to inform nursing practice. Studying the biological process of AD is not easy, but an understanding is essential if a comprehensive and holistic stance is to be adopted by clinical nurse practitioners. These articles will also address the medical definitions of dementia, the onset and spread of neuritic plaques and neurofibrillary tangles, and the genetic and aluminium components, and will compare the impact of AD on brain structure and function with that of the normal ageing brain. At the conclusion of the second article, future prospects and the nursing response will be considered.