Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons

1 The effects of intravenous (i.v.) anaesthetics on nicotinic acetylcholine receptor (nAChR)-induced transients in intracellular free Ca2+ concentration ([Ca2+](i)) and membrane currents were investigated in neonatal rat intracardiac neurons. 2 In fura-2-loaded neurons, nAChR activation evoked a transient increase in [Ca2+](i), which was inhibited reversibly and selectively by clinically relevant concentrations of thiopental. The half-maximal concentration for thiopental inhibition of nAChR-induced [Ca2+](i) transients was 28 muM, close to the estimated clinical EC50 (clinically relevant (half-maximal) effective concentration) of thiopental. 3 In fura-2-loaded neurons, voltage clamped at -60mV to eliminate any contribution of voltage-gated Ca2+ channels, thiopental (25 muM) simultaneously inhibited nAChR-induced increases in [Ca2+](i) and peak current amplitudes. Thiopental inhibited nAChR-induced peak current amplitudes in dialysed whole-cell recordings by - 40% at - 120, -80 and -40 mV holding potential, indicating that the inhibition is voltage independent. 4 The barbiturate, pentobarbital and the dissociative anaesthetic, ketamine, used at clinical EC50 were also shown to inhibit nAChR-induced increases in [Ca2+](i) by similar to40%. 5 Thiopental (25 muM) did not inhibit caffeine-, muscarine- or ATP-evoked increases in [Ca2+](i), indicating that inhibition of Ca2+ release from internal stores via either ryanodine receptor or inositol-1,4,5-trisphosphate receptor channels is unlikely. 6 Depolarization-activated Ca2+ channel currents were unaffected in the presence of thiopental (25 muM), pentobarbital (50 muM) and ketamine (10 muM). 7 In conclusion, i.v. anaesthetics inhibit nAChR-induced currents and [Ca2+](i) transients in intracardiac neurons by binding to nAChRs and thereby may contribute to changes in heart rate and cardiac output under clinical conditions.

Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

Aim To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (C-ss) outside the therapeutic range of 0.5-1.2 IU ml(-1). Methods A nonlinear mixed effects model was developed with NONMEM (R) for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h(-1). Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on C-ss and (ii) compare the impact of different infusion rates on predicted C-ss. The best dose was selected based on the highest probability that the C-ss achieved would lie within the therapeutic range. Results A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg(-1) per 12 h (4.2 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). The best doses for patients in the general medical unit were 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 100 IU kg(-1) per 12 h (8.3 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the C-ss achieved would lie within the therapeutic range. Conclusion The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

Application of Monte Carlo simulations to identify an appropriate dosage strategy for patients receiving a continuous intravenous infusion of enoxaparin

Aim: To identify an appropriate dosage strategy for patients receiving enoxaparin by continuous intravenous infusion (CII). Methods: Monte Carlo simulations were performed in NONMEM, (200 replicates of 1000 patients) to predict steady state anti-Xa concentrations (Css) for patients receiving a CII of enoxaparin. The covariate distribution model was simulated based on covariate demographics in the CII study population. The impact of patient weight, renal function (creatinine clearance (CrCL)) and patient location (intensive care unit (ICU)) were evaluated. A population pharmacokinetic model was used as the input-output model (1-compartment first order output model with mixed residual error structure). Success of a dosing regimen was based on the percent of Css that is between the therapeutic range of 0.5 IU/ml to 1.2 IU/ml. Results: The best dose for patients in the ICU was 4.2IU/kg/h (success mean 64.8% and 90% prediction interval (PI): 60.1–69.8%) if CrCL60ml/min, the best dose was 8.3IU/kg/h (success mean 65.4%, 90% PI: 58.5–73.2%). Simulations suggest that there was a 50% improvement in the success of the CII if the dose rate for ICU patients with CrCL

The Swiss heroin trials: testing alternative approaches

Over half a million heroin misusers receive oral methadone maintenance treatment world-wide1 but the maintenance prescription of injectable opioid drugs, like heroin, remains controversial. In 1992 Switzerland began a large scale evaluation of heroin and other injectable opiate prescribing that eventually involved 1035 misusers. 2 3 The results of the evaluation have recently been reported.4 These show that it was feasible to provide heroin by intravenous injection at a clinic, up to three times a day, for seven days a week. This was done while maintaining good drug control, good order, client safety, and staff morale. Patients were stabilised on 500 to 600 mg heroin daily without evidence of increasing tolerance. Retention in treatment was 89% at six months and 69% at 18 months.4 The self reported use of non-prescribed heroin fell signifianctly, but other drug use was minimally affected. The death rate was 1% per year, and there were no deaths from overdose among participants . . . [Full text of this article]

Investigation of the antinociceptive efficacy and relative potency of extended duration injectable 3-acylmorphine-6-sulfate prodrugs in rats

This investigation was designed to examine the antinociceptive activity in rats of 3-O-acyl prodrugs of M6S relative to the parent drug, after intravenous and intramuscular injection, using the tail flick latency test of antinociception. M6S, 3-acetylmorphine-6-sulfate (3AcM6S), 3-propionylmorphine-6-sulfate (3PrM6S), 3-butanoylmorphine-6-sulfate (3BuM6S) and 3-heptanoylmorphine-6-sulfate (3HpM6S) were administered by the IV route in a dose of 4.10 mu mol/kg. Relatively high levels of antinociception (>40% Maximum Possible Effect) were achieved following administration of M6S, 3AcM6S and 3PrM6S, whereas insignificant antinociception (<20%MPE) was achieved following administration of 3BuM6S or 3HpM6S. Although the mean duration of action for 3AcM6S (6 h) was longer than for M6S or 3PrM6S (4 h), the mean area (+/- S.E.M.) under the degree of antinociception versus time curve (AUG) for 3AcM6S (151.6 +/- 6.9%MPE h) was not significantly different (p <0.05) from that for M6S (120.8 +/- 32.7%MPE h) or for 3PrM6S (106.0 +/- 21.3%MPE h). The mean ED50 (range) doses for M6S, 3AcM6S and 3PrM6S were calculated to be 4.16 (3.61-4.48), 4.32 (3.55-5.09) and 4.54 (4.21-4.79) mu mol/kg, respectively. Preliminary studies were conducted on potential long-acting formulations containing 8 x ED50 doses of M6S and the 3-acetyl and 3-propionyl esters suspended in soybean oil. These showed that 3PrM6S gave a greater AUC (mean + S.E.M.) (1087.4 +/- 97.4%MPE h) and longer duration of action (20 h) than did M6S (613.1 +/- 155.9%MPE h; 10 h duration) or 3AcM6S (379.3 + 114.2%MPE h: 8 h duration). Further studies are needed to more fully investigate these findings. (C) 1998 Elsevier Science B.V. All rights reserved.

Methadone maintenance treatment reduces heroin injection in New South Wales prisons

The purpose of this study was to examine whether methadone maintenance treatment reduces injecting risk behaviour land therefore transmission of blood-borne viral infections) among prisoners in New South Wales (NSW), using comparison of retrospective reports of drug use in prisons for people who received standard drug treatment, time-limited methadone treatment and methadone maintenance treatment, The setting for the study was the NSW prison system. One hundred and eighty-five injecting drug users who had been recently released from NSW prisons were recruited in 1993, Self-reported drug use and injecting risk behaviour were compared in inmates who received standard drug treatment (counselling), time-limited methadone treatment and methadone maintenance treatment. HIV status was determined by serology, Intervention comprised high and low dose methadone treatment and counselling. The groups were similar in terms of most basic demographic characteristics but subjects who had been maintained on methadone reported a significantly lower prevalence of heroin injection, syringe sharing and scored lower on an HIV Risk-taking Behavioural Scale than subjects who received standard drug treatment and time-limited methadone treatment, This study suggests that methadone treatment is associated with reduced injecting risk behaviour in prison with adequate (greater than 60 mg) dose and duration in treatment. These treatment conditions are known to increase effectiveness in community-based methadone programmes. Prospective studies are required to evaluate the effectiveness of methadone programmes in the prevention of HIV and other blood-borne viral infections among IDU prisoners.

H-ras activation is an early event in the ptaquiloside-induced carcinogenesis: Comparison of acute and chronic toxicity in rats

Bracken fern (Pteridium spp.) produces cancer of the urinary bladder and oesophagus in grazing animals and is a suspected human carcinogen, The carcinogenic principle ptaquiloside (PT), when activated to a dienone (APT), forms DNA adducts which eventually leads to tumor. Two groups of female Sprague-Dawley rats were given a chronic dose of 3 mg APT weekly for 10 weeks either by intravenous (iv) tail vein or by intragastric (ig) route, A third group was given a weekly dose of 6 mg of APT for 3 weeks by the ig route corresponding to acute dosing. Both chronic iv and ig dosed animals showed ischemic tubular necrosis in the kidney but only iv dosed animals developed adenocarcinomas of the mammary glands. Acutely dosed ig animals produced apoptotic bodies in the liver, necrosis of blood cell precursors in the bone marrow and ischemic tubular necrosis in the kidney but they did not develop tumors, No mutations were found in the H-ras and p53 genes in the mammary glands of either the ig rats or the tumor-bearing iv rats. However, the mammary glands of a fourth group of rats, which received APT by iv and killed before tumor development, carried Pu to Pu and Pu to Py double mutations in codons 58 and 59 of H-ras. This study indicates that the route of administration plays a role in the nature of the disease expression from ptaquiloside exposure. In addition to confirming the role of APT in the PT-induced carcinogenesis our finding suggests that activation of H-ras is an early event in the PT-carcinogenesis model. (C) 1998 Academic Press.

Role of maintenance treatment in opioid dependence

Methadone maintenance treatment (MMT) involves the daily administration of the oral opioid agonist methadone as a treatment for opioid dependence-a persistent disorder with a substantial risk of premature death. MMT improves health and reduces illicit heroin use, infectious-disease transmission, and overdose death. However, its effectiveness is compromised if low maintenance doses of methadone (