The use and abuse of population viability analysis

A recent study by Brook ef al. empirically tested the performance of population viability analysis (PVA) using data from 21 populations across a wide range of species. The study concluded that PVAs are good at predicting the future dynamics of populations. We suggest that this conclusion is a result of a bias in the studies that Brook et al, included in their analyses, We present arguments that PVAs can only be accurate at predicting extinction probabilities if data are extensive and reliable, and if the distribution of vital rates between individuals and years can be assumed stationary in the future, or if any changes can be accurately predicted. In particular, we note th at although catastrophes are likely to have precipitated many extinctions, estimates of the probability of catastrophes are unreliable.

Matching prescription claims with medication data for nursing home residents: Implications for prescriber feedback, drug utilisation studies and selection of prescription claims database

Medication data retrieved from Australian Repatriation Pharmaceutical Benefits Scheme (RPBS) claims for 44 veterans residing in nursing homes and Pharmaceutical Benefits Scheme (PBS) claims for 898 nursing home residents were compared with medication data from nursing home records to determine the optimal time interval for retrieving claims data and its validity. Optimal matching was achieved using 12 weeks of RPBS claims data, with 60% of medications in the RPBS claims located in nursing home administration records, and 78% of medications administered to nursing home residents identified in RPBS claims. In comparison, 48% of medications administered to nursing home residents could be found in 12 weeks of PBS data, and 56% of medications present in PBS claims could be matched with nursing home administration records. RPBS claims data was superior to PBS, due to the larger number of scheduled items available to veterans and the veteran's file number, which acts as a unique identifier. These findings should be taken into account when using prescription claims data for medication histories, prescriber feedback, drug utilisation, intervention or epidemiological studies. (C) 2001 Elsevier Science Inc. All rights reserved.

Increasing relevance of pharmacogenetics of drug metabolism in clinical practice

Much of the individual variation in drug response is due to genetic drug metabolic polymorphisms. Clinically relevant examples include acetylator status; cytochrome P450 2D6, 2C9 and 2C19 polymorphisms; and thiopurine methyltransferase deficiency. It is important to be aware of which drugs are subject to pharmacogenetic variability. In the future, population-based pharmacogenetic testing will allow more individualized drug treatment and will avoid the current empiricism.

Application of DNA microarrays to study human alcoholism

An emerging idea is that long-term alcohol abuse results in changes in gene expression in the brain and that these changes are responsible at least partly for alcohol tolerance, dependence and neurotoxicity, The overall goal of our research is to identify genes which are differentia[ly expressed in the brains of well-characterized human alcoholics as compared with non-alcoholics. This should identify as-yet-unknown alcohol-responsive genes, and may well confirm changes in the expression of genes which have been delineated in animal models of alcohol abuse. Cases were carefully selected and samples pooled on the basis of relevant criteria; differential expression was monitored by microarray hybridization. The inherent diversity of human alcoholics can be exploited to identify genes associated with specific pathological processes, as well as to assess the effects of concomitant disease, severity of brain damage, drinking behavior, and factors such as gender and smoking history. initial results show selective changes in gene expression in alcoholics; of particular importance is a coordinated reduction in genes coding for myelin components, Copyright (C) 2001 National Science Council, ROC and S. Karger AG, Basel.

Drug use evaluation of ipratropium bromide at two tertiary referral hospitals in Brisbane.

Objective: To assess the appropriateness of ipratropium bromide prescribing in two tertiary referral hospitals. Method: Criteria for optimal use were developed based on current literature and modified after consultation with respiratory physicians and clinical pharmacists. A prospective review of prescribing was performed over a 2-month period to assess conformity to these criteria. Results: Information was collected from 84 patients; 5% were receiving inhalers and 96% nebuliser therapy (one patient used both). 77% of patients (n = 65) had a principal diagnosis of chronic obstructive pulmonary disease, 14% (n = 12) asthma and 8% (n = 7) had neither diagnosis. 75% of patients were using ipratropium outside the guidelines. The major areas where the guidelines were not met were a lack of therapeutic justification, use of inappropriate doses, and use of an inappropriate delivery device. Feedback and educational interventions were designed and delivered based on the data obtained. Conclusions: There was widespread use of ipratropium outside the developed guidelines. Interventions in specific areas could lead to significant improvements in the use of this high cost drug

Dipeptidyl peptidase IV is a target for covalent adduct formation with the acyl glucuronide metabolite of the anti-inflammatory drug zomepirac

The nonsteroidal anti-inflammatory drug zomepirac (ZP) is metabolised to a chemically reactive acyl glucuronide conjugate (ZAG) which can form covalent adducts with proteins. In vivo, such adducts could initiate immune or toxic responses. In rats given ZP, the major band detected in liver homogenates by immunoblotting with a polyclonal ZP antiserum was at 110 kDa. This adduct was identified as ZP-modified dipeptidyl peptidase IV (DPP IV) by immunoblotting using the polyclonal ZP antiserum and monoclonal DPP IV antibodies OX-61 and 236.3. In vitro, ZAG, but not ZP itself, covalently modified recombinant human and rat DPP IV. Both monoclonal antibodies recognized DPP IV in livers from ZP- and vehicle-dosed rats. Confirmation that the 110 kDa bands which were immunoreactive with the ZP and DPP IV antibodies represented the same molecule was obtained from a rat liver extract reciprocally immunodepleted of antigens reactive with these two antibodies. Furthermore, immunoprecipitations with OX-61 antibody followed by immunolotting with ZP antiserum, and the reciprocal experiment, showed that both these antibodies recognised the same 110 kDa molecule in extracts of ZP-dosed rat liver. The results verify that DPP IV is one of the protein targets for covalent modification during hepatic transport and biliary excretion of ZAG in rats. (C) 2001 Elsevier Science Inc. All rights reserved.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol

Aims Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect charges in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers. to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. Methods Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (Mean +/- s.d.) was calculated as the ratio of the amount excreted in urine and thearea-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. Results The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/-3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). Conclusions This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes call be used to simultaneously investigate pathways of renal drug elimination.