Biomedical subjects
Publications and source records attributed to M Chetty.
The case is reported of a mother and baby with dehydrated hereditary stomatocytosis and perinatal ascites, an autosomal dominant condition not previously reported in Britain. Recognition is important for the management of pregnancy and for avoidance of splenectomy which, if performed, can predispose the patient to fatal thromboembolic events.
A 21-year-old female inpatient who was enrolled in a population pharmacokinetic study of chlorpromazine was given an oral chlorpromazine dose of 100 mg three times daily, and plasma concentrations of chlorpromazine were measured weekly. This dose was well tolerated during the first week of therapy. In the second week the patient took a combined oral contraceptive; this was followed by severe dyskinesias and tremor. Plasma chlorpromazine levels were found to be about sixfold higher than those in the first week, although the dose of chlorpromazine had not changed. This observation suggests that the oral contraceptive increased the plasma concentration of chlorpromazine.
The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.
Chlorpromazine (CPZ) is widely used in South African hospitals. The purpose of this study was to determine whether any physiological parameter (side-effect) could be correlated with plasma concentrations of CPZ or its metabolites. In the absence of a blood level, such a correlation could serve as a qualitative indicator of the amount of chlorpromazine in the body. Such a marker can assist the psychiatrist with therapeutic decisions regarding poor compliance and the lack of response with the drug. Fifteen schizophrenic patients were included in this study and regression analysis was used to determine any correlation between CPZ, 7-hydroxychlorpromazine, Chlorpromazine-N-oxide, Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine sulfoxide, Nor2 chlorpromazine sulfoxide and blood pressure, pulse rate, sedation and finger tremor. No correlation was seen between blood pressure or pulse rate and plasma concentrations of CPZ or the metabolites. A good correlation was seen between sedation, 7- hydroxychlorpromazine (P=0.035) and chlorpromazine sulfoxide (P=0.016). The results suggest that as the levels of chlorpromazine sulfoxide increase, the probability of sedation increases, while increasing levels of 7-hydroxychlorpromazine have the opposite effect. A good correlation was also seen between finger tremor and chlorpromazine levels (P=0.035). These results suggest that there is a 50% probability that the patient would experience finger tremor when the plasma concentration of chlorpromazine is 46 ng/ml. This study demonstrated the potential for the use of sedation and finger tremor as qualitative indicators of the plasma concentration of CPZ and two metabolites. Further studies with larger patient numbers are warranted.
The accuracy and the precision with which a drug concentration is quantified in the blood has a significant impact on the therapeutic drug monitoring (TDM) of the drug. In the absence of a system of accreditation of laboratories in South Africa, this study was designed to compare the accuracy and the precision of the measurement of antiepileptic drugs by 24 South African laboratories with those of non-South African laboratories that participate in the United Kingdom National External Quality Assessment Scheme (UKNEQAS). Three test samples, containing a range of concentrations of phenytoin, valproate, carbamazepine, and phenobarbitone spiked into newborn calf serum were distributed to participating laboratories, which were asked to measure the serum concentrations using their routine assay method. Coefficients of variation were used to assess precision of measurements, and the percentage difference of the consensus mean from the spike value was used as an assessment of accuracy. There was comparable precision in the measurements for both the South African and the non-South African groups. However, there appeared to be a difference in the accuracy of measurement between the two groups. It was noted that the majority (77%) of the South African laboratories used the Abbott fluorescence polarization immunoassay (FPIA) with TDx analyzers (Abbott Laboratories, Abbott Park, IL, USA). Further analysis of the results of the South African and UKNEQAS subgroups using the FPIA technique showed a reduction in statistic bias, suggesting that part of the explanation for the statistic difference in the accuracy may be an intertechnique bias related to the use of a nonhuman matrix for sample preparation. Additional studies are required to determine other causes for the statistic differences in accuracy. However, the differences in accuracy are unlikely to be of clinical significance.
Information regarding phenytoin auto-induction is sparse and conflicting. However, confirmation of the presence or absence of auto-induction by phenytoin could have important implications in phenytoin therapy and research. This was an open, randomized, three-way crossover study in which each of the eighteen volunteers received three different formulations of phenytoin, which was allocated in a random order. The period effect between each crossover was determined to assess the effect of the previous exposure to phenytoin on the area under the concentration-time curve (AUC). The point estimate ratio of AUC(o-t) for the third dose relative to the first dose was 81.19% with 90% t-confidence limits of 74.37% to 88.00% and p = 0.3847. The point estimate ratio of AUC(o-infinity) for the third dose relative to the first dose was 76.25% with 90% t-confidence limits of 65.3% to 87.2% and p = 0.7169. These results suggest that the AUC (o-infinity) and AUC(o-t) measured after the third dose of phenytoin was statistically significantly smaller than those measured after the first dose. This decrease in AUC after the third dose of phenytoin is probably caused by enhanced elimination of the drug as a result of enzyme induction.
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The relationship between chlorpromazine, six of its metabolites and therapeutic response in chronic schizophrenic patients was investigated in this study. Logistic regression revealed no correlation between therapeutic response and four metabolites viz. Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine-N-oxide and Nor2 chlorpromazine sulfoxide. A good correlation was seen between CPZ (P = 0.036), 7-hydroxychlorpromazine (P = 0.004), chlorpromazine sulfoxide (P = 0.002) and therapeutic response. Good therapeutic response was correlated to high levels of chlorpromazine and its 7-hydroxy metabolite while high levels of the sulfoxide metabolite appeared to have a negative effect on therapeutic response. Poor responders who had high levels of chlorpromazine also had high levels of the sulfoxide metabolite. This suggests that the difference in response may lie in the difference in the metabolism of the drug.
The NADPH oxidase of phagocytes is known to be expressed in Epstein-Barr-virus-transformed B-lymphocytes, albeit at levels only approx. 5% of those found in neutrophils. We have investigated the basis of this low level of expression and find that all four specific components of the NADPH oxidase are expressed in B-lymphocytes, but only p47-phox protein attains levels equivalent with those found in neutrophils. This component was shown to phosphorylate and translocate to the membrane normally on activation. The other cytosolic component, p67-phox, did show a deficit, and by supplementing a B-cell cytosol extract with recombinant p67-phox, this was shown to account for the somewhat reduced activity of B-cell cytosol in a cell-free oxidase system. The cell-free analysis also clearly located the major deficiency in superoxide-generating capacity of B-lymphocytes to the membrane. Western blotting of membrane proteins revealed major reductions in the amount of cytochrome b558. Analysis of the levels of mRNA for both subunits of cytochrome b558, however, showed levels greater than expected. Significantly more mRNA for gp91-phox was present in B-cells than in undifferentiated HL60 cells, although it was not quite as abundant as in differentiated HL60 cells, which are capable of producing large amounts of superoxide. We conclude that the failure of B-lymphocytes to generate amounts of superoxide equivalent to those generated by neutrophils is primarily due to a post-transcriptionally determined block to the accumulation of cytochrome b558.
The population pharmacokinetic parameters of chlorpromazine (CPZ) in chronic schizophrenic patients were evaluated using 189 plasma concentration measurements from 31 patients. A NONMEM analysis demonstrated that the clearance of CPZ depended on the patient's body weight. Cigarette smoking and cannabis smoking increased the clearance of CPZ. Chronic alcohol consumption and the concurrent use of anticholinergics did not appear to influence the clearance of CPZ significantly.
Plasma concentrations of chlorpromazine (CPZ) and six metabolites were measured in 12 chronic schizophrenic patients on a fixed dose of CPZ. All six metabolites were measured in significant concentrations, ranging from 12 to 57% of the parent drug concentration. They are listed in order of decreasing mean concentration as follows: chlorpromazine-N-oxide > chlorpromazine sulfoxide > 7-OH chlorpromazine > Nor2 chlorpromazine sulfoxide > Nor2 chlorpromazine > Nor1 chlorpromazine. CPZ concentrations showed significant correlation with the 7-OH chlorpromazine metabolite concentration. Since these metabolites have been associated with in vitro activity and occur in significant concentrations, it is recommended that all six metabolites be measured in studies correlating drug levels with pharmacodynamic effects.
The stability of four commonly used anticonvulsant drugs, viz., valproic acid, carbamazepine, phenytoin, and phenobarbital in whole blood was investigated after storage at conditions simulating storage and transport from outlying rural clinics. Storage conditions included 24 h at 23-25 degrees C, 24 h at 37 degrees C, 48 h at 37 degrees C, and 48 h at 23-25 degrees C. Valproic acid, carbamazepine, and phenobarbital were stable for 48 h at both storage temperatures. Phenytoin was stable at 23-25 degrees C for 48 h. However, small but statistically significant decreases in phenytoin concentrations were observed in samples that were stored for 24 h or longer at 37 degrees C. These changes may not be clinically significant.
Failure of a superoxide generating system, the NADPH oxidase, present in neutrophils and other phagocytes gives rise to chronic granulomatous disease (CGD), a group of single-gene inherited disorders all characterized by an extreme susceptibility to pyogenic infection, with potentially fatal consequences. About 30% of CGD cases are caused by an autosomally inherited deficiency of a 47-Kd cytoplasmic component of the oxidase (p47-phox). Epstein-Barr virus (EBV) immortalized B-lymphocyte lines established from these CGD patients also express this NADPH oxidase defect and consequently are rendered incapable of generating superoxide on stimulation. We have used a p47-phox-deficient EBV-transformed B-cell line as a recipient for retroviral transfer of a functional p47-phox cDNA. The presence and activity of the retrovirally encoded p47-phox in the transduced cells is demonstrated and we show that this restores their capacity to generate superoxide.
Chronic Granulomatous Disease (CGD) manifests as a predisposition to infection as a result of defective function of the NADPH oxidase of phagocytic cells. Proteins identified as part of this system include two subunits of a cytochrome b (cytochrome b-245) and two cytosolic factors. The affected oxidase component was determined in 63 CGD patients from 57 families, by Western blotting of extracts of their neutrophils with antibodies to those proteins. 38 (67%) of the families were X-linked with a defect of the beta subunit of the cytochrome. 13 (23%) lacked p47-phox, 3 (5%) p67-phox, and 3 (5%) the alpha subunit of the cytochrome.
The concentrations of chlorpromazine (CPZ) and six of its metabolites in patient plasma samples that had been stored for 24 h at -20 degrees C, for 1 week at -20 degrees C, and for 4 weeks at -70 degrees C were compared. The concentrations of CPZ and six of its metabolites in human plasma spiked with known concentrations and stored at -70 degrees C for either 3 or 12 months were also compared. No significant difference was seen in the concentrations after storage under nitrogen and analysis by a high-performance liquid chromatography technique.
The peripheral blood WBC size distribution was assessed by morphological and volume measurements in 73 patients with B-cell chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL). Patients with typical CLL, with less than or equal to 10% prolymphocytes, had a homogeneous major population of small cells which could be recognized both by morphology and volume (median volume 211.5 +/- 32.5 fl). In PLL, the volume of the main cell component was significantly larger than in CLL: in two-thirds of cases the major cell population was distributed in a first lognormal fitted curve of the volume histogram, with median volume 281.8 +/- 38.0 fl; in the remaining cases the main cell component showed a larger median volume (353.5 +/- 71.9 fl) contained within the second lognormal curve which was preceded by a minor peak. CLL patients with 11-55% prolymphocytes (CLL/PL) had characteristic cell volume histograms in which two lognormal curves could always be fitted: in 80% of cases the main cell component was located in a first curve with median volume of 257.9 +/- 28.6 fl; in the remaining cases the major population was represented by cells with median volume of 349.0 +/- 83.9 fl distributed in a second peak. Although in both CLL and CLL/PL the majority of cells was defined morphologically as small, the median volume of these lymphocytes was significantly larger in CLL/PL. The degree of concordance in the assessment of cell size between morphology and volume measurements was high in CLL, whereas in CLL/PL and PLL morphology underestimated the cell size of the major population, compared with its actual volume, in over 50% of cases. We conclude that the identification of prolymphocytes as larger cells in blood films may be hampered by distortions and artefacts of spreading. Volume measurements may provide a more objective indicator of the cell populations in this group of disorders.