Biomedical subjects
Publications and source records attributed to N G Best.
We describe Bayesian hierarchical-spatial models for disease mapping with imprecisely observed ecological covariates. We posit smoothing priors for both the disease submodel and the covariate submodel. We apply the models to an analysis of insulin Dependent Diabetes Mellitus incidence in Sardinia, with malaria prevalence as a covariate.
We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (P<0.01). High short-term variability in cyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.
We have attempted to quantify the optimal clinical use of cyclosporine during the first 3 months after heart-lung transplantation. We used multiple logistic regression to investigate the influence of blood cyclosporine concentrations and other potential risk factors on histologically confirmed acute lung rejection in 50 heart-lung transplant recipients. A 50% increase in cyclosporine concentration was associated with a 25% reduction in risk of rejection in the subsequent 5 days (P=0.008). Increasing oral corticosteroid dose also protected against rejection (P=0.006). Rejection was over 4 times more likely to occur during the first 20 postoperative days (P=0.002). After 20 days, an FEV1 < or = 70% of the age-, sex-, and height-adjusted expected score was associated with a 4-fold increase in risk of rejection (P=0.01). Patients who had multiple previous rejection episodes were also predisposed to further rejection (P=0.005). An investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that cyclosporine concentrations above 500 microg L(-1) provide optimal protection against acute lung allograft rejection. This result provides an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart-lung transplantation.
We have attempted to identify major risk factors for cytomegalovirus (CMV) infection and disease following heart transplantation, with emphasis on the degree and type of immunosuppression used. One hundred and eleven consecutive heart transplant recipients were studied for the first 4 months. Data from the 95 who survived at least 1 month were analyzed using multiple Cox regression. Blood cyclosporine concentrations (CsAbc) > 550 micrograms L-1 were associated with a 4.4-fold increase in risk of CMV infection during the next week (95% confidence interval = 1.2-16.2). Other significant risk factors for CMV infection included antirejection treatment in the past 14 days, a drop in white blood cell count, receiving a CMV antibody-positive donor organ, and primary diagnosis other than cardiomyopathy. We found that patients experiencing a CMV infection were at 3 times the risk of subsequently developing symptomatic CMV disease (95% confidence interval = 1.1-9.7). In addition, the proportion of patients developing symptomatic CMV disease was significantly higher amongst those with a median CsAbc > 550 micrograms L-1 for at least 1 week (29% vs. 10%; P = 0.02) or who had been treated for rejection more frequently than once every 6 weeks (31% vs. 12%; P = 0.04) during the first 4 months. CMV antibody-negative recipients of antibody-positive donor organs had a higher rate of symptomatic CMV disease than did other serological combinations (67% vs. 10%; P = 0.0001). We conclude that the risk of CMV infection and symptomatic disease following heart transplantation may be critically influenced by early management of immunosuppression as well as by donor serology.
Quantification of the average and interindividual variation in pharmacokinetic behavior within the patient population is an important aspect of drug development. Population pharmacokinetic models typically involve large numbers of parameters related nonlinearly to sparse, observational data, which creates difficulties for conventional methods of analysis. The nonlinear mixed-effects method implemented in the computer program NONMEM is a widely used approach to the estimation of population parameters. However, the method relies on somewhat restrictive modeling assumptions to enable efficient parameter estimation. In this paper we describe a Bayesian approach to population pharmacokinetic analysis which used a technique known as Gibbs sampling to simulate values for each model parameter. We provide details of how to implement the method in the context of population pharmacokinetic analysis, and illustrate this via an application to gentamicin population pharmacokinetics in neonates.
Explore the source record for details and available documents.
OBJECTIVE: To compare the pharmacokinetics of cyclosporine in patients with either cystic fibrosis or Eisenmenger's syndrome. METHODS: Patients in the study were heart and lung transplant candidates with either cystic fibrosis (n = 6) or Eisenmenger's syndrome (n = 5), as well as patients who received heart and lung transplantation for either cystic fibrosis (n = 13) or Eisenmenger's syndrome (n = 7). This was no experimental pharmacokinetic study in transplant candidates and an exploratory population pharmacokinetic study in transplant recipients. RESULTS: Patients with cystic fibrosis showed higher blood cyclosporine clearance, higher apparent oral clearance, shorter mean residence time, and more erratic absorption. The coefficient of variation of pharmacokinetic parameters was higher in patients with cystic fibrosis. There were no significant differences in metabolite indexes between the two groups of patients after either oral or intravenous administration. A significant negative correlation was found between cyclosporine clearance and hematocrit (r = 0.81 [95% confidence interval, -0.95 to -0.4.1]). Dose-normalized predose blood concentration measurements were lower in patients with cystic fibrosis after transplantation. There was a significant correlation between hematocrit and log dose-normalized cyclosporine concentration (r = 0.40 [95% confidence interval, 0.30 to 0.49]). The total daily dose per 100 ng/ml trough blood concentration required was estimated to be 2.36 times (95% confidence interval, 1.96 to 2.84) higher in patients with cystic fibrosis. CONCLUSIONS: Cyclosporine pharmacokinetics is more variable in patients with cystic fibrosis. The difference in cyclosporine clearance between the two groups is accounted for by differences in binding in blood rather than metabolism. The findings suggest that patients with cystic fibrosis could be conservatively given initial oral doses that are 1.5 times higher than those for patients who receive transplants because of Eisenmenger's syndrome.
The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.
1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)