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Biochemical markers of alcohol consumption are useful for the detection and monitoring of problem drinking. Blood samples from 37 patients attending an alcohol treatment clinic were analysed for GGT and %CDT, and results were compared with self-reported periods of abstinence and alcohol consumption. Poor correlation was obtained between GGT and %CDT, and between these assays and self-reported alcohol use. The apparent sensitivity and specificity of GGT (57%, 63%) and %CDT (43%, 88%), were considerably lower than those reported by other workers.

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Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

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BACKGROUND: The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis. AIM: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease. SUBJECTS AND METHODS: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy-proven cirrhosis (Child's grade; 1 A, 4 B, 4 C: aetiology: 7 alcohol-related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg. RESULTS: The area under the serum concentration-time curve was increased (152.34 mg/L.h +/- 50.38 s.d.) in cirrhotics compared with normal controls (93.86 mg/L.h +/- 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h +/- 1.87 s.d.) compared with controls (6.47 L/h +/- 0.78: P < 0.01). CONCLUSIONS: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.

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Bionike one-step tests were used to screen urine samples for amphetamines, methamphetamines, benzodiazepines, cannabinoids, methadone and opiates, and results were compared with those obtained using enzyme multiplied immunoassay technique d.a.u. assays. Taking into consideration different threshold levels and possible differences in cross-reactivities, there was good agreement between the methods. Results of Bionike tests correlated well with amphetamines, methadone and opiates detected in urine using gas chromatography-mass spectrometry. Bionike methods are rapid, simple to use, and relatively inexpensive for on-site testing of individual drugs or groups of drugs in urine.

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OBJECTIVE: To determine whether the antidote for acetaminophen poisoning, N-acetylcysteine, administered to pregnant women with acetaminophen toxicity, crosses the placenta and can be measured in the newborn circulation following delivery. DESIGN: Over a 15-month period, four pregnant women with acetaminophen toxicity, who delivered their infants while receiving the antidote N-acetylcysteine, were studied. Maternal and cord blood from three viable infants, and cardiac blood sampled during an autopsy on the fourth, were analyzed for the presence of N-acetylcysteine using high-performance liquid chromatography. Maternal and cord blood aminotransferase activities, and autopsy findings on the nonviable infant were used to assess hepatic injury. RESULTS: N-Acetylcysteine was detected in the cord blood of three viable infants and in cardiac blood of a fourth, sampled at the time of autopsy. The mean N-acetylcysteine concentration in cord blood was 9.4 micrograms/mL (+/-1.3). This is well within the range associated with therapeutic doses of N-acetylcysteine typically administered to adults with acetaminophen poisoning. No adverse sequelae developed in the three viable infants. The fourth infant, delivered at 22 weeks gestational age died 3 h after birth. All mothers recovered and none of the four infants had evidence of acetaminophen-related toxicity. CONCLUSIONS: This is the first study documenting placental transfer of N-acetylcysteine in humans and provides impetus for research establishing a direct antidotal effect of N-acetylcysteine in the fetus.

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OBJECTIVE: To assess the role of caffeine restriction in the management of patients with symptomatic idiopathic ventricular premature beats. DESIGN: A randomised, double blind, 6 week intervention trial incorporating dietary caffeine restriction, caffeinated coffee, and decaffeinated coffee. SETTING: Cardiac outpatient clinic. PATIENTS: 13 patients with symptomatic frequent idiopathic ventricular premature beats. MAIN OUTCOME MEASURES: Weekly measures of serum caffeine concentration, coffee consumption, visual analogue score of palpitations, and 24 hour ventricular premature beat frequency. RESULTS: The interventions achieved significant alterations in serum caffeine concentrations (P < 0.001) which correlated with coffee consumption (r = 0.70; P < 0.001). Visual analogue palpitation scores showed a small, but significant correlation with ventricular premature beat frequencies (r = 0.34; P = 0.003). However, there were no significant changes in palpitation scores or ventricular premature beat frequencies during the intervention weeks and no significant correlations were found between these variables and serum caffeine concentrations. CONCLUSIONS: Caffeine restriction has no role in the management of patients referred with symptomatic idiopathic ventricular premature beats.

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Widespread use of drugs at the currently popular 'raves' has caused concern principally because of an increasing number of cases of serious toxicity and even death. The availability and use of drugs at raves, mainly in the Edinburgh area, have been investigated and self-reported use of drugs compared with results of urine screening. Use of Ecstasy and LSD have been confirmed and there is evidence to support the use of Khat. A new preparation, Herbal Ecstasy, is readily available at Edinburgh raves and appears to be widely used. All urines tested positive for one or more drugs or drug metabolites and in general analytical results correlated well with self-reported use of drugs.

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(1) In order to provide an efficient and reliable service for drugs of abuse screening in urine, the laboratory should analyse 20-30 samples per week, and the staff should include a scientist with special expertise in the subject. (2) Turnaround times should be between 2-3 days of sample collection. To achieve this aim it may be necessary to make special arrangements for the delivery of samples to the laboratory. Results should preferably be transmitted by electronic mail or facsimile with the necessary precautions for security and confidentiality: hardcopy reports may also be required. (3) Good communications between the requesting clinician and the laboratory are essential. An advisory service should be provided by the laboratory and clinicians should be encouraged to discuss requests and results with laboratory staff. It is important that the laboratory inform doctors of the range of substances detected and the sensitivity and specificity of laboratory assays. (4) Assays should be performed according to the manufacturer's protocols, or by modified methods that have been rigorously validated. Quality control samples should be included in each analytical run and participation in an external quality assessment scheme, e.g. UKNEQAS, is essential to provide independent confirmation and confidence that results compare with those from other laboratories. Other requirements include adequate training and supervision of staff, and careful recording of samples and results. (5) Drugs to be tested will depend on the drug 'scene' in the area but should include those drugs regularly prescribed for maintenance therapy (e.g. methadone, dihydrocodeine, benzodiazepines), and drugs frequently misused (e.g. heroin, buprenorphine, amphetamines, cocaine). (6) Positive results obtained by preliminary screening methods e.g. EMIT, should be confirmed by another analytical technique, e.g. TLC, GC or GC-MS. If there are potentially serious or legal implications, and in employment and preemployment testing, confirmation of positive results is mandatory. In some cases, e.g. checking for methadone or benzodiazepine compliance, it may be considered unnecessary to confirm positive results although possible spiking of samples cannot be excluded without checking for the presence of metabolites by a chromatographic procedure.

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The use of a drug screening service has been investigated over a nine month period during which 1500 urine samples from 765 patients were analysed. Preliminary drug screening of urine samples was performed by EMIT immunoassays adapted for use on the Cobas Bio analyser; further identification and confirmation were carried out by Toxi-Lab thin-layer chromatography and capillary gas chromatography. A large number of positive results were obtained for benzodiazepines, cannabinoids, methadone and opiates (mainly dihydrocodeine). Only a limited number of urines gave positive results for amphetamine and related stimulants; cocaine metabolite was rarely detected in samples. The service proved to be of considerable value in the management of drug misusers, and for the identification of new substances taken by the local population.

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Cost-effective immunoassays for the detection of amphetamines, benzodiazepines, and methadone in urine have been developed using Syva EMIT reagents and a Cobas Bio centrifugal analyser. With this method up to 2470 samples can be assayed with a single 100 test EMIT kit while maintaining acceptable precision. Mean CVs of 3.8-6.6% were obtained for concentrations around the manufacturer's recommended threshold level (300 micrograms/l). Comparison of the methods with the Abbott TDx system showed good correlation for methadone. The methods compared less well for amphetamines, and it was not possible to obtain a useful correlation for benzodiazepines. Heat treatment prior to analysis did not affect the detection of benzodiazepines and methadone; there was a mean decrease of 14% for amphetamines.

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We have developed simple and rapid screening tests for methanol and ethylene glycol in plasma of poisoned patients, based on the Toxi-Lab alcohol screening test. The compounds are first converted to formaldehyde, which diffuses from the patient's sample into a glass-fiber test sheet impregnated with Schiff's formaldehyde detection reagent. Subsequent exposure of the test sheet to acid and heat distinguishes formaldehyde from acetaldehyde. We recommend that samples giving positive results be analyzed by another technique to confirm the identity and concentration of the poison for use in prognosis and treatment.

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The detection of drugs of abuse in urine by four commercial immunoassay systems (TDx, BCL and PFI-20 opiates, and PFI-20 morphine) and one commercial TLC system (Toxi-Lab) was investigated and results compared with those obtained by a dual-column capillary GC system. The TDx system was the most reliable method for preliminary screening of urines for opiates; all the commercial immunoassay systems gave some results which were at variance with those of the GC. The GC method proved to be more reliable than the commercial TLC system in discriminating between the different opiates and is recommended for identification of drugs of abuse in urine specimens in which positive results have been obtained with preliminary screening procedures.

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Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT greater than 500 mu/l) and severe on 5 (ALT less than 1000 mu/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg.h.l-1, 2.91 h and 3.18 ml.min-1.kg-1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.

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A method has been developed for the simultaneous determination of the sympathomimetic drugs salbutamol and terbutaline in the plasma of poisoned patients, using ion-pair high-performance liquid chromatography with amperometric detection. Plasma concentrations of the drugs, measured in 8 poisoned patients, were well above the therapeutic range. The clinical and metabolic effects of overdose with these drugs were considerably less severe than those seen in patients with plasma theophylline concentrations elevated to the same degree.

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The toxicological screening of 200 urine samples from 55 known heroin users claiming to be abstinent revealed that in 18% of samples (24% of users tested) opiates were unexpectedly detected. Other substances, many of which were psychoactive drugs, were identified in 35% of samples. Cocaine was not detected in any samples. In addition, nicotine was found in 91% of users and caffeine in 44%. The data showed the presence of polydrug abuse in 29% of subjects and suggested there is an illegal supply of drugs originating from doctors' prescriptions. The requirement for more general use of toxicological screening and the implications of the results for management of drug takers in general practices are discussed.

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Three colorimetric techniques and one enzymatic technique have been compared with an HPLC method for the analysis of salicylate in the plasma of patients after self-poisoning with aspirin. The enzymatic technique was specific but expensive to perform. The colorimetric techniques were simple, cheap and precise. The Keller method, however, was susceptible to interference from endogenous substances. We report a modification of the Keller method that eliminates most of this interference and improves the accuracy of the analysis. The new method is easier and safer to perform under emergency conditions than the Trinder technique.

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