Catecholamine release in heat-stressed Antarctic fish causes proton extrusion by the red cells

Two species of Antarctic fish were stressed by moving them from seawater at -1 degrees C to seawater at 10 degrees C and holding them for a period of 10 min. The active cryopelagic species Pagothenia borchgrevinki maintained heart rate while in the benthic species Trematomus bernacchii there was an increase in heart rate. Blood pressure did not change in either species. Both species released catecholamines into the circulation as a consequence of the stress. P. borchgrevinki released the greater amounts, having mean plasma concentrations of 177 +/- 54 nmol.l(-1) noradrenaline and 263 +/- 131 nmol.l(-1) adrenaline at 10 min. Pla.sma noradrenaline concentrations rose to 47 +/- 14 nmol.l(-1) and adrenaline to 73 +/- 28 nmol.l(-1) in T. bernacchii. Blood from P. borchgrevinki was tonometered in the presence of isoprenaline. A fall in extracellular pH suggests the presence of a Na+/H+ antiporter on the red cell membrane, the first demonstration of this in an Antarctic fish. Treatment with the beta-adrenergic antagonist drug sotalol inhibited swelling of red blood cells taken from temperature-stressed P. borchgrevinki, suggesting that the antiporter responds to endogenous catecholamines.

Methadone maintenance and drug-related crime

Using data from an evaluation of methadone maintenance treatment, this study investigated factors associated with continued involvement irt crime during treatment, and in particular whether there appeared to be differences in effectiveness of treatment between different methadone clinics. The methodology was an observational study, in which 304 patients attending three low-intervention, private methadone clinics in Sydney were interviewed on three occasions over a twelve month period. Outcome measures were self-reported criminal activity and police department records of convictions. By self-report, crime dropped, promptly and substantially on entry to treatment, to a level of acquisitive crime about one-eighth that reported during the last addiction period. Analysis of official records indicated that rates of acquisitive convictions were significantly lower in the in-treatment period compared to prior to entry to treatment, corroborating the changes suggested by self-report. Persisting involvement in crime in treatment was predicted by two factors: the cost of persisting use of illicit drugs, particularly cannabis, and ASPD symptom count. Treatment factors also were independently predictive of continued involvement in crime. By both self-report and official records, and adjusting for subject factors, treatment at one clinic teas associated with greater involvement in crime. This clinic operated in a chaotic and poorly organized way. it is concluded that crime during methadone treatment is substantially lower than during street addiction, although the extent of reduction depends on the quality of treatment being delivered.

Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(tough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

Evaluation of an immunoassay (EMIT) for mycophenolic acid in plasma from renal transplant recipients compared with a high-performance liquid chromatography assay

Mycophenolic acid is an immunosuppressant administered as a bioavailable ester, mycophenolate mofetil. The pharmacokinetics of mycophenolic acid have been reported to be variable. Accurate measurement of concentrations of this drug could be important to adjust doses. The aim of this study was to compare the enzyme-multiplied immunoassay technique (EMIT [Dade Behring; San Jose, CA, U.S.A.]) for mycophenolic acid with a high-performance liquid chromatographic (HPLC) assay using samples collected from renal transplant recipients. The HPLC assay used solid phase extraction and a C18 stationary phase with ultraviolet (UV) detection (254 nm). The immunoassay required no manual sample preparation. Plasma samples (n = 102) from seven patients, collected at various times after a dose, were analyzed using both methods. Both assays fulfilled quality-control criteria. Higher concentrations were consistently measured in patient samples when using EMIT. The mean (+/- standard deviation [SD]) bias (EMIT-HPLC) was 1.88 +/- 0.86 mg/L. The differences in concentrations were higher in the middle of a dosage interval, suggesting that a metabolite might have been responsible for overestimation. Measurement of glucuronide concentrations by HPLC demonstrated only a weak correlation between assay differences and glucuronide concentrations. If the crossreacting substance is active, EMIT could provide a superior measure of immunosuppression; if inactive, further work is needed to improve antibody specificity. In conclusion, it was found that EMIT overestimates the concentration of mycophenolic acid in plasma samples from renal transplant recipients compared with HPLC analysis.

Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management

Twenty-three patients treated with intracerebroventricular (ICV) morphine in this study not only obtained excellent pain relief without rapid increases in dose, but also experienced a reduction in morphine-related side effects. By 24 h after initiation of ICV morphine, the mean trough cerebrospinal fluid (CSF) morphine concentration (approximately 20 mu M) was 50-fold higher than the baseline concentration (approximately 0.4 mu M), and the CSF concentration of morphine-6-glucuronide (M6G) was undetectable (

Targeting local tissues by transdermal application: Understanding drug physicochemical properties that best exploit protein binding and blood flow effects

The targeting of topically applied drug molecules into tissues below a site of application requires an understanding of the complex interrelationships between the drug, its formulation, the barrier properties of the skin, and the physiological processes occurring below the skin that are responsible for drug clearance from the site, tissue, and/or systemic distribution and eventual elimination. There is still a certain amount of controversy over the ability of topically applied drugs to penetrate into deeper tissues by diffusion or whether this occurs by redistribution in the systemic circulation. The major focus of our work in this area has been in determining how changes in drug structure and physicochemical properties, such as protein binding and lipophilicity, affect drug clearance into the local dermal microcirculation and lymphatics, as well as subsequent distribution into deeper tissues below an application site. The present study outlines our recent thinking on the drug molecule optimal physical attributes, in terms of plasma and tissue partitioning behaviour, that offer the greatest potential for deep tissue targeting. Drug Dev. Res. 46:309-315, 1999. (C) 1999 Wiley-Liss, Inc.

Applications of NMR in drug design: Sructure-activity relationships in disulfide-rich peptides

NMR is a powerful technique for determining structures of biologically active molecules in solution. In recent years. our laboratory has focussed on the structure determination of small disulfide-rich proteins from both plants and animals which are valuable targets in drug design applications. This article will review these structural studies and their implications in drug design.

Alcohol- and drug-use disorders in Australia: implications of the National Survey of Mental Health and Wellbeing

Objective: This study reports the prevalence and correlates of ICD-10 alcohol- and drug-use disorders in the National Survey of Mental Health and Wellbeing (NSMHWB) and discusses their implications for treatment. Method: The NSMHWB was a nationally representative household survey of 10 641 Australian adults that assessed participants for symptoms of the most prevalent ICD-10 and DSM-IV mental disorders, including alcohol- and drug-use disorders. Results: In the past 12 months 6.5% of Australian adults met criteria for an ICD-10 alcohol-use disorder and 2.2% had another ICD-10 drug-use disorder. Men were at higher risk than women of developing alcohol- and drug-use disorders and the prevalence of both disorders decreased with increasing age. There were high rates of comorbidity between alcohol- and other drug-use disorders and mental disorders and low rates of treatment seeking. Conclusions: Alcohol-use disorders are a major mental health and public health issue in Australia. Drug-use disorders are less common than alcohol-use disorders, but still affect a substantial minority of Australian adults. Treatment seeking among persons with alcohol- and other drug-use disorders is low. A range of public health strategies (including improved specialist treatment services) are needed to reduce the prevalence of these disorders.

Conformational selection of inhibitors and substrates by proteolytic enzymes: Implications for drug design and polypeptide processing

Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/ substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.

Challenge of reducing drug-related deaths

The public-health attention given to deaths caused by illicit drug use in general, and by drug overdose in particular, should be commensurate with their contribution to premature death. For too long these deaths have been regarded as an unavoidable hazard of illicit drug use, their neglect abetted by the implicit view that the lives of illicit drug users are less deserving of being saved than those of others. In its report published this week,1 the UK Advisory Council on the Misuse of Drugs (ACMD) has rejected these implicit assumptions. Its view is that “drug-related deaths can, will and must in the near future be radically reduced in number”. It points out that the effort that society expends on preventing premature deaths “should apply no less to drug misusers than it does to other classes of people”.1

The effects of the Cannabis Expiation Notice System on the prevalence of cannabis use in South Australia: evidence from the National Drug Strategy Household Surveys 1985-95

This study sought to examine the impact of the Cannabis Expiation Notice (CEN) scheme on the prevalence of lifetime and weekly cannabis use in South Australia. Data from five National Drug Strategy Household Surveys between 1985 and 1995 were examined to test for differences in trends in self-reported: (1) lifetime cannabis use; and (2) current weekly cannabis use, after controlling for age and gender, between South Australia and the other states and territories. Between 1985 and 1995, rates of lifetime cannabis use increased in SA from 26% to 36%. There were also significant increases in Victoria (from 26% to 32%), Tasmania (from 21% to 33%) and New South Wales (from 26% to 33%). The increase in South Australia was significantly greater than the average increase throughout the rest of Australia, but the other Australian states differed in their rates of change. Victoria and Tasmania had similar rates of increase to South Australia; New South Wales, Queensland and Western Australia showed lower rates of increase; and the Northern Territory and the Australian Capital Territory had high rates that did not change during the period. There was no statistically significant difference between SA and the rest of Australia in the rate of increase in weekly cannabis use. While there was a greater increase in self- reported lifetime cannabis use in South Australia between 1985 and 1995 than in the average of the other Australian jurisdictions it is unlikely that this increase is due to the CEN system, because similar increases occurred in Tasmania and Victoria (where there was no change in the legal status of cannabis use), and there was no increase in the rate of weekly cannabis use in South Australia over the same period.

Effects of replacing meat with soyabean in the diet on sex hormone concentrations in healthy adult males

A randomised crossover dietary intervention study was performed to evaluate the effects of replacing meat protein in the diet with a soyabean product, tofu, on blood concentrations of testosterone, dihydrotestosterone, androstanediol glucuronide, oestradiol, sex hormone-binding globulin (SHBG), and the free androgen index (total testosterone concentration/SHBG concentration x 100; FAI). Forty-two healthy adult males aged 35-62 years were studied. Diets were isoenergetic, with either 150 g lean meat or 290 g tofu daily providing an equivalent amount of macronutrients, with only the source of protein differing between the two diets. Each diet lasted for 4 weeks, with a 2-week interval between interventions. Fasting blood samples were taken between 07.00 and 09.30 hours. Urinary excretion of genistein and daidzein was significantly higher after the tofu diet (P