Search

The clinical benefit of implementing Bayesian approach for lithium drug monitoring was evaluated. Intervention group (N = 42) and historical control group (N = 55) patients were each divided into two groups: Dosage with immediate-release lithium carbonate or a sustained-release formulation, lithium citrate. Bayesian approach was performed in the intervention groups, and estimation of lithium steady-state trough concentration was obtained from non-steady-state blood sample, collected about 12 hr after the first lithium study dose. The estimate was compared with the actually measured steady-state concentration. In the control group, lithium monitoring was traditionally performed as steady-state blood sampling. Predicted and measured lithium concentrations were comparable. The desired lithium dose was reached significantly faster in the intervention group compared to control; 2.47 ± 2.22 days versus 9.96 ± 11.24 days (mean ± S.D.) (p = 0.0003). Bayesian approach was an advantage for the clinicians as a fast and safe aid to obtain the optimal lithium treatment dose.

Objectives. High-gram drug doses seen in multiple-drug poisonings might be close to the adsorption capacity of activated charcoal (AC). The aim was to determine the maximum adsorption capacities (Q(m)) of amitriptyline and paracetamol, separately and in combination, to AC. Methods. ACs (Carbomix® and Norit Ready-To-Use) were tested in vitro. At pH 1.2 and pH 7.2, 0.250 g AC and paracetamol and/or amitriptyline were mixed and incubated. The AC: drug ratios were 10:1, 5:1, 3:1, 2:1, and 1:1. The mixed-drug adsorption vials contained the same AC: paracetamol ratios, but amitriptyline was added as fixed dose (0.080 g) to all samples. Drug concentrations in the liquid phase were analyzed using high-performance liquid chromatography (HPLC)/UV-detection. Results. Q(m), amitriptyline, were 0.49 g/g Carbomix® and 0.70 g/g Norit Ready-To-Use, and Q(m), paracetamol, were 0.63 g/g Carbomix® and 0.72 g/g Norit Ready-To-Use. The tested pH differences had minor effect on the adsorption. The mixed-drug adsorption showed about 40% Q(m) reduction of each drug with increasing amounts of drug/g AC, but the total gram of drug adsorbed to AC was increased compared to one-drug conditions. Conclusion. The adsorption of the two compounds to AC seems to compete resulting in lower maximum adsorption capacity for both drugs when mixed. However, a great adsorptive capacity was noted and might be explained by adsorption of the drugs to different AC surface sites. Furthermore, the Norit Ready-To-Use preparation, with less volume and total weight for the same AC dose as Carbomix®, showed a higher Q(m). This might be clinically significant in terms of preventing nausea, vomiting, and subsequent aspiration.

The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal-drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross-over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol was administered, followed 1 hr later by an activated charcoal-Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration-time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25-g dose was found to be of similar size compared to the control, although statistics were weak. The AUC of the 5-g dose was 59% larger than the AUC of the 50-g dose (p = 0.0003). The terminal elimination half-life (t(1/2)) of paracetamol was 1.6 (CI 1.4-2.0) and 1.9 (CI 1.5-2.4) hr for 50 and 25 g, respectively (NS), and 2.5 (CI 1.8-3.0) hr for the 5-g dose (p = 0.003). The decrease in t(1/2) of paracetamol for the two larger activated charcoal doses indicates a possible effect of activated charcoal on paracetamol clearance and warrants further investigation. The large adsorptive reserve capacity of activated charcoal in vitro could not be reproduced for the smallest dose of activated charcoal. An activated charcoal-drug ratio of 10:1 is therefore still recommendable.

Total body clearance, half-life and volume of distribution of disopyramide (Norpace, Searle G.D.) was measured during a six to eight hour infusion to steady state in twenty four patients with either congestive heart failure or acute myocardial infarction and compared to eleven patients without these diseases. All patients were given a bolus injection of 150 mg disopyramide followed by a continuous infusion of 18-24 mg per hour. Serum concentration of disopyramide and its main dealkylated metabolite were determined by HPLC. The clearance in patients without myocardial infarction or congestive heart failure was 1.71 +/- 0.60 ml/min./kg (mean +/- S.D.), not significantly different from those who had either myocardial infarction, congestive heart failure or both. Half-life was 798 min. in patients without heart failure, not significantly different from the values in the other groups. The ratio between disopyramide and its metabolite varied between 3 to 10. Twenty-six % of the steady state serum concentrations of disopyramide were outside the recommended therapeutic range (2-5 micrograms/ml), but no adverse haemodynamic effects were observed in any of the patients. The suggested dosage regimen of disopyramide seems to result in a satisfactory response.

Treatment of alcoholics with phenytoin and disulfiram (DI) simultaneously is complicated and inexpedient because of the marked drug interaction. The aim of this study was to investigate whether an interaction exists between DI and carbamazepine (CBZ). The serum levels of CBZ and the metabolite CBZ-10, 11-epoxide were measured by high-pressure liquid chromatography in seven out-patients with epilepsy, on monotherapy with CBZ, before and during two weeks administration of DI. Five patients completed the investigation. None were alcoholics. The changes in the serum levels were insignificant, i.e. without clinical important. Moreover, uncontrolled clinical experience has not indicated any interaction between DI and CBZ. Thus the influence of DI on the metabolism of CBZ is probably negligible. CBZ is suggested, therefore, when anticonvulsive therapy is needed by alcoholics in treatment with DI.

Interactions between analgesics and anti-epileptic drugs may sometimes present a serious clinical problem. The aim of the study was to investigate the influence of usually applied doses of dextropropoxyphene (DPX) on the steady state levels of carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB). Sixteen patients in monotherapy completed the trial, while four patients dropped out. In patients on CBZ serum levels increased (mean appr. 66 %) after 6 days on DPX. In three of the patients a further increase was seen after an additional week on DPX. One patient discontinued the DPX intake because of clinical signs of toxicity, but the remainder were clinically unaffected. CBZ-epoxide levels declined simultaneously. For DPH only a doubtful increase was observed after 1–2 weeks on DPX. For PB an average increase of 20 % in serum level was noted after 1 week. The protein binding of CBZ and DPH was not affected. It is concluded that patients on CBZ should be treated only with DPX if monitored properly. Patients on DPH or PB should be followed carefully until further evidence has been produced.

Background. An activated charcoal–yogurt mixture was evaluated in vivo to determine the effect on the gastrointestinal absorption of paracetamol, as compared to activated-charcoal–water slurry. The...

Aims Activated charcoal is now being recommended for patients who have ingested potentially toxic amounts of a poison, where the ingested substance adsorbs to charcoal. Combination therapy with gastric lavage and activated charcoal is widely used, although clinical studies to date have not provided evidence of additional efficacy compared with the use of activated charcoal alone. There are also doubts regarding the efficacy of activated charcoal, when administered more than 1 h after the overdose. The aim of this study was to examine if there was a difference in the effect of the two interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion.

In Denmark, haloperidol, perphenazine, and zuclopenthixol are among the most frequently requested antipsychotics for therapeutic drug monitoring. With the number of requests made at the authors' laboratory, the only rational analysis is one that can measure all three drugs simultaneously. The authors therefore decided to develop an automated high-performance liquid chromatography (HPLC) method. Two milliliters serum, 2.0 mL 10 mmol/L sodium phosphate buffer (pH 5.5), and 150 microL internal standard (trifluoperazine) solution were pipetted into HPLC vials and extracted on an ASPEC XL equipped with 1 mL (50 mg) Isolute C2 (EC) extraction columns and acetonitrile-methanol-ammonium acetate buffer (60:34:6) as extracting solution. Three hundred fifty microliters was analyzed by HPLC; a 150 x 4.6-mm S5CN Spherisorb column with a mobile phase of 10 mmol/L ammonium acetate buffer-methanol (1:9), a flow rate of 0.6-1.7 mL/min, and ultraviolet detection at 256 and 245 nm were used. Reproducibility was 5-12% and the lower limit of quantitation was 10, 1, and 5 nmol/L (4, 0.4, and 2 ng/mL) for haloperidol, perphenazine, and zuclopenthixol, respectively. The method was found to be sufficiently selective and robust for routine analysis.

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.

A simple and sensitive method for the enantioselective high-performance liquid chromatographic determination of methadone and its main metabolite, EDDP, in human urine is described. (-)-(R)-Methadone, (+)-(S)-methadone, (+)-(R)-EDDP, (-)-(S)-EDDP and imipramine as an internal standard are detected by ultraviolet detection at 200 nm. The enantiomers of methadone and EDDP were extracted from human urine by a simple liquid-liquid extraction procedure. The extracted sample was reconstructed in mobile phase and the enantiomers of methadone and EDDP were quantitatively separated by HPLC on a short analytical LiChrospher RP8 column coupled in series with a chiral AGP column. Determination of all four enantiomers was possible in the range of 0.03 to 2.5 microM. The recoveries of methadone enantiomers and EDDP enantiomers added to human urine were about 90% and 80%, respectively. The method was applicable for determination of methadone enantiomers and the enantiomers of its main metabolite in urine samples from methadone maintenance patients and patients suffering from severe chronic pain.

rac-Isradipine is a dihydropyridine type calcium antagonist. Its calcium entry blocking effect is due primarily to the (+)-(S)-enantiomer. This study describes a sensitive enantioselective method for the determination of isradipine in human serum. Following alkaline extraction into hexane, the enantiomers of isradipine are separated quantitatively by high-performance liquid chromatography on a Chiralcel OJ column at 39 degrees C. The collected fractions were evaporated and assayed using capillary gas chromatography on a HP 50+ column with nitrogen selective detection. Using 2.0 ml of serum, 0.7 nmol/1 (0.26 ng/ml) of each enantiomer could be determined with acceptable precision. The method has successfully been used to measure (+)-(S)- and (-)-(R)-isradipine concentrations in samples from volunteers after intravenous and oral administration of isradipine.

Ten patients with chronic pain were randomized to an open, balanced, crossover study. Each patients received two different preparations of racemic methadone, i.e., tablets and intravenous infusion. The pharmacokinetic parameters of the R- and S-enantiomers of the racemate are reported. The analgesically active R-methadone has a significantly longer mean elimination half-life than the optical antipode S-methadone (t1/2 = 37.5 and 28.6 h, respectively). The mean total volume of distribution is 496.6 L for R-methadone and 289.1 L for S-methadone. Significant differences in the mean clearance between R- and S-methadone are seen (0.158 and 0.129 L/min, respectively). However, the lagtime after oral administration and the bioavailability did not show differences between the isomers. The data suggest that both enantiomers of methadone should be measured if correlations between pharmacodynamics and kinetics are made due to the stereoselective differences in half-life, total volume of distribution, and clearance.

A high-performance liquid chromatography method for the simultaneous analysis of dapsone (DDS), the major metabolite of DDS, monoacetyldapsone (MADDS), and pyrimethamine (PYR) was modified for capillary blood samples obtained by finger prick and dried on filter paper. Limit of quantitation using 150 microliters whole blood dried on filter paper was found to be 20 ng/ml for DDS and PYR and 15 ng/ml for MADDS (precision < 15%). The clinically relevant concentrations of DDS are 50-2,000 ng/ml and for PYR 25-150 ng/ml. No interference from several drugs were observed. The accuracy of the filter paper method and the original whole-blood method was almost comparable. Standardization could therefore be obtained by the more simple whole-blood method. Dried filter paper samples stored at 19-22 degrees C were stable for months and for 2 weeks stored at 35 degrees C. The concentrations of simultaneously collected capillary blood and conventional venous blood samples correlated well. The present method using capillary blood dried on filter paper is reliable, simple, sensitive, and applicable in the field with limited technical facilities.

The clinical benefit of implementing Bayesian approach for lithium drug monitoring was evaluated. Intervention group (N = 42) and historical control group (N = 55) patients were each divided into two groups: Dosage with immediate-release lithium carbonate or a sustained-release formulation, lithium citrate. Bayesian approach was performed in the intervention groups, and estimation of lithium steady-state trough concentration was obtained from non-steady-state blood sample, collected about 12 hr after the first lithium study dose. The estimate was compared with the actually measured steady-state concentration. In the control group, lithium monitoring was traditionally performed as steady-state blood sampling. Predicted and measured lithium concentrations were comparable. The desired lithium dose was reached significantly faster in the intervention group compared to control; 2.47 ± 2.22 days versus 9.96 ± 11.24 days (mean ± S.D.) (p = 0.0003). Bayesian approach was an advantage for the clinicians as a fast and safe aid to obtain the optimal lithium treatment dose.

A relatively simple, sensitive and precise gas chromatographic method for the determination of isradipine, a calcium antagonist of the dihydropyridine type, and its main metabolite in serum is described. Using a one-step extraction procedure, a wide-bore column and a nitrogen—phosphorus detector, a limit of quantitation of 0.5 and 2.0 n M for isradipine and the metabolite was found. No interferences from several drugs were observed. The method was successfully used in a pharmacokinetic study in hypertensive women during pregnancy.

The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal-drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross-over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol was administered, followed 1 hr later by an activated charcoal-Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration-time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25-g dose was found to be of similar size compared to the control, although statistics were weak. The AUC of the 5-g dose was 59% larger than the AUC of the 50-g dose (p = 0.0003). The terminal elimination half-life (t(1/2)) of paracetamol was 1.6 (CI 1.4-2.0) and 1.9 (CI 1.5-2.4) hr for 50 and 25 g, respectively (NS), and 2.5 (CI 1.8-3.0) hr for the 5-g dose (p = 0.003). The decrease in t(1/2) of paracetamol for the two larger activated charcoal doses indicates a possible effect of activated charcoal on paracetamol clearance and warrants further investigation. The large adsorptive reserve capacity of activated charcoal in vitro could not be reproduced for the smallest dose of activated charcoal. An activated charcoal-drug ratio of 10:1 is therefore still recommendable.

The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.

An activated charcoal--yogurt mixture was evaluated in vivo to determine the effect on the gastrointestinal absorption of paracetamol, as compared to activated-charcoal--water slurry. The potential advantage of the activated-charcoal--yogurt mixture is a better palatability and general acceptance by the patients without loss of efficacy. In addition, paracetamol adsorption studies were carried out in vitro to calculate the maximum adsorption capacity of paracetamol to activated-charcoal--yogurt mixture.In vivo: A randomized crossover study on 15 adult volunteers, using paracetamol 50 mg/kg as a simulated overdose. Each study day volunteers were given a standard meal 1 h before paracetamol, then 50 g activated charcoal 1 h later in either of two preparations: standard water slurry or mixed with 400 mL yogurt. Paracetamol serum concentrations were measured using HPLC. The areas under the concentration-time curve (AUC) of the two preparations were compared and used to estimate the efficacy of each preparation. The palatability of both preparations was evaluated using a visual-analogue scale where the volunteers were asked to evaluate the appearance, smell, flavor, texture, ability to swallow, and overall impression of the mixtures. The time spent to consume the activated charcoal was also registered. In vitro: Activated charcoal, simulated gastric (pH 1.2) or intestinal (pH 7.2) fluid, and paracetamol were mixed with yogurt followed by 1 h incubation. The maximum adsorption capacity of paracetamol to activated charcoal was calculated using Langmuir's adsorption isotherm. Paracetamol concentration was analyzed using HPLC.In vivo there was no significant difference (p0.05) in the AUC of paracetamol between the two activated-charcoal preparations. Geometric mean values and 95% CI for the AUCs were (in mg/l x min): 6307 (4932-8065) for the activated charcoal--water slurry and 6525 (5111-8330) for the activated charcoal--yogurt mixture. The palatability study showed significant difference (p0.05) only in duration of administration, in favor of the activated charcoal--water slurry. In vitro the maximum adsorption capacity of activated charcoal with added yogurt was 544 mg paracetamol/g activated charcoal (pH 1.2), and 569 mg paracetamol/g activated charcoal (pH 7.2).The two activated-charcoal preparations showed equal (NS) absorption reduction of paracetamol in vivo. Mixing activated charcoal with yogurt rather than water prolonged the ingestion time, but did not improve the palatability in adults. The presence of yogurt reduced the adsorption capacity in vitro by 9-13% (p0.05) compared to control without yogurt (previous study with the same setup).

The effect of added food mixture (as if food was present in the stomach of an intoxicated patient) or 4 different types of ice cream (added as a flavouring and lubricating agent) on the adsorption of paracetamol (acetaminophen) to 2 formulations of activated charcoal was determined in vitro and compared with results from previous investigations showing a maximum adsorption capacity to the two activated charcoal-water slurries at about 0.62-0.72 g paracetamol/g activated charcoal. Activated charcoal (Carbomix or Norit Ready-To-Use), simulated gastric (pH 1.2) or intestinal (pH 7.2) fluid, and paracetamol were mixed with either food mixture or ice cream followed by one hr incubation. The maximum adsorption capacity of paracetamol to activated charcoal was calculated using Langmuirs adsorption isotherm. Paracetamol concentration was analyzed using high pressure liquid chromatography. In the presence of food, the paracetamol adsorption capacity of the 2 activated charcoals was reduced by max. 19% (P

Paracetamol (acetaminophen) intoxication often in combination with ethanol, is seen commonly in overdose cases. Doses of several grams might be close to the maximum adsorption capacity of the standard treatment dose (50g) of activated charcoal. The aim of this study was to determine the maximum adsorption capacity for paracetamol for two types of high surface-activated charcoal [Carbomix and Norit Ready-To-Use (not yet registered trademark in Denmark) both from Norit Cosmara, Amersfoort, The Netherlands] in simulated in vivo environments: At pH 1.2 (gastric environment), at pH 7.2 (intestinal environment), and with and without 10% ethanol.Activated charcoal, at both gastric or intestinal pHs, and paracetamol were mixed, resulting in activated charcoal-paracetamol ratios from 10:] to 1:1. In trials with ethanol, some of the gastric or intestinal fluid was replaced with an equivalent volume of ethanol, resulting in an ethanol concentration of 10% v/v. After incubation, the concentration of unabsorbed paracetamol was analyzed by high-performance liquid chromatography. The maximum adsorption capacity of paracetamol to activated charcoal was calculated as mg paracetamol adsorbed/g activated charcoal, using Langmuir's isotherm.Carbomix [95% confidence limits are shown in square brackets]: 623.7 [612.8;634.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 626.2 [611.6;640.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2); Norit Ready-To-Use: 693.6 [676.8;710.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 722.6 [687.4;757.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2). For experiments with ethanol (10% v/v) the results with Carbomix were 465.7 [449.2;482.2] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 498.6 [481.8;515.6] mg paracetamol adsorbed/g activated charcoal (pH 7.2); with Norit Ready-To-Use: 617.2 [606.6;627.7] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 640.6 [624.9;656.4] mg paracetamol adsorbed/g activated charcoal (pH 7.2).Under conditions simulating immediate treatment with charcoal, a standard dose of 50 g of either of the two tested activated charcoals adsorbed a sufficient amount of paracetamol to be beneficial in the treatment of the majority of overdoses of this drug. For both types of activated charcoal, with or without ethanol, there was no significant difference in the adsorption of paracetamol at pH 1.2 and 7.2. Norit Ready-To-Use had a larger maximum adsorption capacity than Carbomix, and was not as sensitive as Carbomix to environmental changes (pH and ethanol). The presence of 10% ethanol lowered the adsorption capacity of the two tested activated charcoal preparations by an amount that might be clinically relevant in cases of intoxications by high-gram doses.

This study examines the feasibility of a steady-state bolus-integration method with the dopamine D2/D3 receptor single photon emission computer tomography (SPECT) tracer, [123I]IBZM, for determination of in vivo affinity of haloperidol. The nonspecific binding of [123I]IBZM was examined in the rat brain by infusion of haloperidol to plasma levels approximately 100 times the Kd level in man. In humans, Kd for haloperidol binding was measured in four healthy volunteers that were examined twice: once with partial dopamine D2/D3 receptor blockade obtained by a scheduled infusion of unlabeled haloperidol (0.7 mg total dosage), and once in an unblocked state. Blood sampling and SPECT were performed intermittently during 6 hours after intravenous [123I]IBZM bolus injection. Plasma [123I]IBZM was determined by octane extraction. Plasma haloperidol was determined by a radioimmunoassay, and plasma protein binding was determined by equilibrium dialysis. In humans, the striatal D2/D3 receptor occupancy was 0.27 ± 0.085 and the in vivo Kd for haloperidol was 0.25 ± 0.1 nmol/L, which is comparable to Kd values as obtained from in vitro studies. The authors conclude that steady-state [123I]IBZM SPECT studies allow for determination of dopamine D2/D3 receptor occupancy in striatum and in vivo measurement of drug affinity to striatal dopamine D2 and D3 receptors.

The aim of this study was to investigate the relation between Antabus® dosage and the disulfiram-alcohol reaction (DAR) after ethanol challenge. Fifty-two healthy volunteers, 29 men and 23 women, aged 20-61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.

A high-performance liquid chromatography (HPLC) method was developed for the simultaneous analysis of trimethoprim (TMP), sulphamethoxazole (SMX), and acetylsulphamethoxazole (AcSMX) in small amounts of blood. The method involved precipitation with 50 microL trichloracetic acid (1M) to 125 microL plasma or serum sample. 60 microL supernatant was added to 60 microL mobile phase, modified with 50microL 1 M sodium hydroxide/mL. The mobile phase consisted of 20% acetonitrile and 80% phosphate buffer adjusted to pH 6.15. Using 125 microL of the sample, limits of quantitation were 0.1 microg/mL for TMP, 1.0 microg/mL for SMX, and 1.0 microg/mL for AcSMX. The precision of the method was 2% to 11% over the range of concentrations tested, 0.5-30 microg/mL for TMP, 5-300 microg/mL for SMX, and 2.5-150 microg/mL for AcSMX, respectively. No interference with other commonly used drugs was observed. The method is rapid, simple, specific, and sensitive enough for pharmacokinetic studies. The small amount of blood required makes it suitable for pediatric patients. The method was used to analyze samples from Tanzanian children aged 6-59 months participating in a cotrimoxazole (TMP/SMX)/chloroquine randomized trial for the treatment of uncomplicated malaria. Venous blood samples from 68 children were collected 2 hours after the first dose of TMP/SMX (4 mg/kg TMP/20 mg/kg SMX at two divided doses for 5 days) and again at treatment day 4. Individual variations in plasma concentrations of TMP, SMX, and AcSMX were considerable. The mean and SEM plasma concentrations (g/mL) of TMP, SMX, and AcSMX 2 hours after the first treatment dose were 2.0 +/- 1.0 (range 0.5-6), 53 +/- 22 (range 24-146), and 13.5 +/- 12 (range 0-65), respectively. On the fourth day the attained plasma concentrations were not significantly different from samples collected after the first dose.

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

A simple and sensitive HPLC method with ultraviolet absorption detection at 200 nm is described for the determination of methadone enantiomers in human serum, using dextropropoxyphene as an internal standard and organic solvent extraction. Separation was performed on two serially coupled columns, CN and Chiral AGP, with a mobile phase consisting of acetonitrile, dimethyloctylamine and phosphate buffer. Using 1.0 ml of serum, 5 nmol/1 of each enantiomer could be determined with an acceptable precision. No interactions from several drugs were observed. The method has been successfully used in a pharmacokinetic study. More than 2500 serum samples have been separated on the same AGP colunm with acceptable selectivity and resolution.

rac-Methadone is used clinically for the chronic maintenance treatment of heroin addiction and for the relief of pain. As the pharmacological activity of methadone is due primarily to the (−)-(R)-enantiomer, stereospecific measurements of methadone serum concentrations in methadone-treated patients are expected to be more relevant for clinical studies than earlier described total drug measurements. This study describes a stereospecific gas chromatographic (GC) method for the determination of methadone in serum. The extracted methadone was derivatizised with (−)-menthyl chloroformate. The diastereometric derivatives were analysed by GC on a capillary column and detected with a nitrogen-phosphorus detector. The resolution factor obtained for the methadone enantiomers was 1.1 with a relatively short time of analysis (30 min). By analysing the pure (−)-(R)-enantiomer, no racemization was seen during the analysis. The lower limit of quantitation was 75 nmol/1 for each enantiomer. Measurements of the ratio between (−)-(R)- and (+)-(S)-methadone concentrations in serum from five methadone-treated patients showed interindividual differences (range 0.5–1.1). The patient results correlated well with those from another GC method measuring total methadone.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.

This paper describes a simple high-performance liquid chromatographic method for the determination of disopyramide and lidocaine simultaneously with their dealkylated metabolites. After basic tert-butyl methyl ether extraction and back-extraction with phosphoric acid, the drugs and their metabolites were injected into a Supelcosil CN column and the absorbance of the eluate was measured at 215 nm. The sensitivity was 0.3 mumol/l and the obtained precision, selectivity and stability during storage were adequate for the performed clinical studies in patients therapeutically treated with disopyramide and/or lidocaine. Some results from the clinical studies are briefly presented.

A method is described for determination of acetaldehyde in blood by head space gas chromatography. The method utilizes sodium nitrite-sulfosalicylic acid as an inhibitor of the ethanol oxidizing systems by means of which the interference of ethanol is reduced considerably. The detection limit was 0.4 mumol/l, the recovery 101.5 +/- 5.2% and the coefficient of variation was 7.8% (1.5 mumol/1 acetaldehyde). There was no disappearance of acetaldehyde if the head space vials were kept at -20 degree C for 24 h. In the comparison study with the semicarbazide method our results were 0.7-4.1 mumol/l lower. The values for acetaldehyde in blood after ethanol ingestion (0.5 g/kg) by volunteers were 0.5-1.3 mumol/l.

A relatively simple gas chromatographic method has been developed for the quantitative determination of hydralazine simultaneously with its acetylated metabolite, 3-methyl- s -triazolo[3,4-α]phthalazine (MTP). The proteins were removed by means of sulfosalicylic acid and Sure-Sep®. On treatment with formic acid, hydralazine and its internal standard were converted into their formylated derivatives. These derivatives, MTP and its internal standard were extracted with toluene and determined by gas chromatography with a nitrogen-selective detector. The lower limits of detection for hydralazine and MTP were 0.13 and 0.27 μmol/l, respectively.

Intravenous infusion of lidocaine has a pain-relieving effect in patients with painful diabetic neuropathy. We measured plasma beta-endorphin (beta-EP), dynorphin immunoreactivity (DYN), and met-enkephalin (MET) before and after lidocaine infusion in 8 patients with painful diabetic neuropathy and in 10 controls. The pretreatment level of beta-EP and DYN was identical in the two groups. After lidocaine, beta-EP increased in diabetic patients from 3.4 to 5.5 pmol/L (median) (p less than 0.02) and in controls from 3.4 to 5.0 pmol/L (p less than 0.02). The concentration of DYN was stable, and MET was undetectable before and after lidocaine. Lidocaine reduced symptoms and pain score in diabetic patients was uncorrelated with the changes in beta-EP. Intravenous lidocaine increased plasma beta-EP and diminished complaints in patients with painful diabetic neuropathy.

The effect of atenolol on the total elimination of disopyramide and its main dealkylated metabolite was studied in 6 patients and 3 volunteers. During administration of 50 mg atenolol b.i.d. the clearance of disopyramide decreased significantly (p less than 0.02) from 1.90 +/- 0.71 (mean +/- SD) to 1.59 +/- 0.68 ml/kg/min, while its half-life, concentration of the metabolite, and the volume of distribution remained unchanged. The reduction in the clearance of disopyramide by atenolol might contribute to the alleged pharmacodynamic interaction between disopyramide and beta-blocking drugs.

The anticonvulsive properties of pregnanolone (as an emulsion) were evaluated in mice and compared with similar properties of Althesin and thiopentone. Pregnanolone emulsion was found to antagonize convulsions induced by the GABA antagonists pentetrazole, bicuculline and picrotoxin and by the specific glycine receptor antagonist, strychnine. The drug was effective in all four convulsive tests at subanaesthetic doses with maximal activity appearing within less than 1 min. The anticonvulsive therapeutic indices of pregnanolone emulsion were superior when compared with the therapeutic indices of Althesin and thiopentone in all four tests. Pregnanolone emulsion might be a useful alternative drug in the management of convulsive states resistant to conventional therapy.

The haemodynamic effects of concomitant intravenous administration of disopyramide (Norpace) and atenolol (Tenormin) were studied in a cross-over trial in 7 patients with ischaemic heart disease. Following 150 mg disopyramide i.v. the cardiac index (CI) and stroke volume index (SVI) decreased by 14% and 26%, respectively and the heart rate (HR) and preejection period index (PEPI) increased by 13% and 19%, respectively. A decrease in CI of 14% and HR of 21%, respectively were noted after intravenous administration of 7.5 mg atenolol; PEPI increased by 10% whereas SVI remained unchanged. The cardiac Index (CI) fell by 33% following the administration of both drugs. The effect on CI of the two drugs was additive. The effect of disopyramide and atenolol on HR, SVI and PEPI was not significantly modified by coadministration of the other drug. No change in blood pressure was observed after disopyramide or atenolol. A correlation (rho) of 0.540 and 0.387 was observed between the change in PEPI and the log free and total serum concentrations of disopyramide, respectively. Combined intravenous use of the two drugs in patients with incipient or overt heart failure is not recommended, unless it is due to the arrhythmia to be treated.

This paper describes an HPLC method with a relatively simple extraction procedure. Using a cyano column and fluorescence detection, MPZ and AMPZ could be determined simultaneously with sufficient sensitivity, precision and selectivity

This paper describes a rapid, sensitive anodic stripping voltammetry (ASV) method for measuring quantities of cadmium in blood. An advantage of this method is the minimal sample preparation required, using a metal-exchange reagent. A sensitivity of 4 nmol/l can be obtained. The results correlate with those obtained by atomic absorption spectroscopy. Within-run, the coefficient of variation (CV) was 8.9% at a cadmium concentration of 32 nmol/l. Between run CV was 5.4% at 37 nmol/l. The reference interval for blood cadmium concentration was 5-60 nmol/1 for non-smokers and 5-85 nmol/l for cigarette-smokers. This method of cadmium analysis shows that ASV is a rapid, sensitive method for determination of blood cadmium in the normal range.

In a double blind cross-over study 10 healthy male volunteers were given either 300 mg dextropropoxyphene napsylat (DP) or placebo daily for 16 days. The serum levels of DP and the metabolite nordextropropoxyphene were measured on day 3, 6 and 16. Haemodynamic measurements were made on day 1 and day 16, both at rest and during exercise. The measurements were made non-invasively, with a pulsed ultrasound Doppler. Blood pressure, heart rate, velocity, cardiac output, left cardiac work, increased during work, but showing no significant differences between the groups. The systolic time intervals were also measured by the ultrasound Doppler. The preejection period increased significantly in the DP-group, whereas the ratio preejection period/left ventricular ejection time which reflects the contractility of the heart did not differ significantly. It is concluded that DP taken daily in a normal dose for 16 days did not affect the heart function in healthy young men.

Displacement from human plasma proteins of lidocaine by disopyramide was investigated in serum from nine patients receiving lidocaine treatment because of severe ventricular arrhythmias. From each patient disopyramide in concentrations of 5.9 and 14.7 mumol/l was added to three different serum concentrations of lidocaine and the displacement was examined. At a serum concentration of disopyramide of 14.7 mumol/l the percentage of unbound lidocaine increased from 30.4 +/- 0.2 to 36.3 +/- 0.2% (mean +/- S.E.M., P less than 0.001) at an average total serum concentration of lidocaine of 22.7 mumol/l. The study implies a stronger binding affinity of disopyramide than lidocaine to alpha-1-acid glycoprotein. We recommend caution when using disopyramide immediately after an infusion of lidocaine. With the dosage regimen used serum concentrations considerably above the suggested therapeutic level were achieved in the majority of patients.

Disposition kinetics of disopyramide was examined in an open randomised cross-over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909 +/- 0.04, P less than 0.05 (injection study); 0.787 +/- 0.11, P less than 0.05 (infusion study] were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half-life were significantly higher in the steady state experiment than in the bolus injection study.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.