Objectively measured perinatal exposure to meperidine and benzodiazepines in Finland.

We measured concentrations of meperidine and benzodiazepines in the umbilical serum of all live neonates born in Finland during a single week. Of the neonates, 31.1% were exposed to meperidine or benzodiazepines or both. One hundred twenty-one mothers of the 261 neonates exposed to meperidine were not recorded in the Finnish Medical Birth Registry as having received analgesic drugs. Infants born to primiparous mothers were more likely to be exposed. The exposures were associated with the type of delivery: vacuum extraction with a high proportion of neonates exposed to meperidine and elective caesarean section with a high proportion of neonates exposed to benzodiazepines. The exposures were influenced by the method of obstetric analgesia: epidural blockade was associated with more frequent exposure to meperidine. No significant circadian variation in exposures was detected. Validation of birth registry data is imperative before they are used for pharmacoepidemiologic studies.

The effects of quinine and 4-aminopyridine on conditioned place preference and changes in motor activity induced by morphine in rats.

1. The effects of two unselective potassium (K(+)-) channel blockers, quinine (12.5, 25 and 50 mg/kg) and 4-aminopyridine (1 and 2 mg/kg), on conditioned place preference and biphasic changes in motor activity induced by morphine (10 mg/kg) were tested in Wistar rats. Quinine is known to block voltage-, calcium- and ATP-sensitive K(+)-channels while 4-aminopyridine is known to block voltage-sensitive K(+)-channels. 2. In the counterbalanced method, quinine attenuated morphine-induced place preference, whereas 4-aminopyridine was ineffective. In the motor activity test measured with an Animex-activity meter neither of the K(+)-channel blockers affected morphine-induced hypoactivity, but both K(+)-channel blockers prevented morphine-induced secondary hyperactivity. 3. These results suggest the involvement of quinine-sensitive but not 4-aminopyridine-sensitive K(+)-channels in morphine reward. It is also suggested that the blockade of K(+)-channels sensitive to these blockers is not sufficient to prevent morphine-induced hypoactivity whereas morphine-induced hyperactivity seems to be connected to both quinine- and 4-aminopyridine-sensitive K(+)-channels.

Validation of self reported smoking by serum cotinine measurement in a community-based study.

STUDY OBJECTIVE: The validity of self reported smoking in population surveys remains an important question. An associated question is what would be the value of measuring serum cotinine concentrations in such surveys to obtain validated smoking data. DESIGN: Cross sectional analysis of data on self reported smoking and serum cotinine among a random population sample of 5846 persons aged 25 to 64 years, who participated in the FINRISK-92 survey. MAIN RESULTS: Among self reported regular smokers, 97.2% of men and 94.9% of women had a cotinine concentration of 10 ng/ml or higher in serum. Of those participants who reported to have smoked at any time during their life but not during the previous month, 6.3% of men and 5.2% of women had a serum cotinine concentration of at least 10 ng/ml. Among never smokers 2.5% of men and 2.7% of women had detectable level of cotinine in their serum. The validity of self reporting was similar among subjects from different areas, ages, and socioeconomic groups. CONCLUSIONS: In a sample of the general population in Finland the validity of self reported smoking is high, and most of the few self reported non-smokers who had cotinine in their serum had only low or moderate levels.

The acute effects of amphetamine derivatives on extracellular serotonin and dopamine levels in rat nucleus accumbens.

The acute effects of amphetamine derivatives on extracellular concentration of serotonin (5-HT) and dopamine in the nucleus accumbens were studied with in vivo microdialysis using conscious, freely moving rats. 5-HT, dopamine, and their major metabolites were measured by HPLC with electrochemical detection. Amphetamine (1.0-9.0 mg/kg) elevated dopamine levels considerably, but failed to affect the levels of 5-HT, except at the highest dose administered. 3,4-Methylenedioxyamphetamine (MDA, 1.0-9.0 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, 1.0-9.0 mg/kg) elevated both 5-HT and dopamine levels dose dependently. The failure of 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5-1.0 mg/kg) to affect the 5-HT levels suggests that extracellular levels of 5-HT play a minor role in hallucinogenic activity. The strong effects of MDA and MDMA on levels of 5-HT indicate that their actions on serotonergic mechanisms are different from those of the hallucinogens. In addition, methylenedioxyamphetamines may act via dopaminergic mechanisms similar to those of amphetamine.

The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference.

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives.

An improved derivatization method for analysing 12 ring- and N-substituted amphetamine-derivatives in body fluids or seized materials by gas chromatograph combined either with mass spectrometer, electron capture or nitrogen phosphorus detector is presented. Heptafluorobutyric anhydride is used as derivatization reagent. No heating or standing period is needed in this procedure. Most of the drugs considered were distinguishable from each other according to their retention times and all of them according to their EI mass spectra. The base peak or one of the most intense peaks in the mass spectra contained benzyl radical and the m/e values were different according to the substituent.

A comparison between on-site immunoassay drug-testing devices and laboratory results.

The aim with this study was to evaluate the accuracy of several on-site testing devices on the market. A part of this study is included in the European Union's (EU's) roadside testing assessment project (ROSITA). An other request for this kind of study came from the Finnish prison department in the Ministry of Justice. The evaluation was performed on both urine assays and oral fluid assays. The on-site test results were compared with laboratory results (gas chromatography-mass spectrometry (GC/MS)). The samples were tested on amphetamines (AMP), cannabinoids (THC), opiates (OPI) and cocaine metabolites (COC). Some of the tests also included a metamphetamine (MET) and a benzodiazepine (BZO) test. Both positive and negative samples were tested. A total of 800 persons and eight on-site devices for urine and two for oral fluid testing were included in this study. Good results were obtained for the urine on-site devices, with accuracies of 93-99% for amphetamines, 97-99% for cannabinoids, 94-98% for opiates and 90-98% for benzodiazepines. However, differences in the ease of performance and interpretation of test result were observed. It was possible to detect amphetamines and opiates in oral fluid by the used on-site devices, but the benzodiazepines and cannabinoids did not fulfil the needs of sensitivity.

Drugged driving in the Nordic countries--a comparative study between five countries.

The purpose of this study was to compare whether the high incidence of drugged driving in Norway was different to that in the other Nordic countries. All blood samples received by Nordic forensic institutes during one week in 1996, from drivers suspected by the police of driving under the influence (Denmark: n = 255, Finland: n = 270, Iceland: n = 40, Sweden: n = 86, Norway: n = 149), were analysed for alcohol and drugs (benzodiazepines, cannabinoids, amphetamines, cocaine, opiates and a number of antidepressant drugs) independent of the primary suspicion, and using the same analytical cut-off levels at the different institutes. The primary suspicion was directed towards drugs in more than 40% of the Norwegian cases, drugs were detected in more than 70% of these samples. In only 0-3% of the cases from Denmark, Finland and Iceland, were drugs suspected, while the corresponding frequency for Sweden was 17%. However, evidential breath analyses were used for about three-quarters of the Swedish drivers suspected to be influenced by alcohol. Blood alcohol concentrations (BAC's) below the legal limits were found in 32, 18 and 2% of the Norwegian, Icelandic and Finnish cases, respectively (BAC < 0.05%), in 10% of the Danish cases (BAC < 0.08%) and in 20% of the Swedish cases (BAC < 0.02%). Drugs were most frequently found in the Norwegian and Swedish cases with no alcohol (80-83%). Similar frequencies of drugs in samples with BAC's above the legal limits (19-22%), were obtained for all countries. Benzodiazepines, tetrahydrocannabinol and amphetamine represented the most commonly detected drugs. Our results show that differences between Norway and other Nordic countries with regard to drugs and driving, are connected to the selection criteria made by the police and with more focus on drugged driving in Norway.

Drugs usage of drivers suspected of driving under the influence of alcohol and/or drugs. A study of one week's samples in 1979 and 1993 in Finland.

The extent of drug use among drivers suspected of driving under the influence of alcohol and/or drugs in Finland was studied. All blood samples submitted to the laboratory during 1 week in two study periods, in 1979 (n = 298) and 1993 (n = 332), were analyzed for alcohol and psychotropic drugs. Drugs classified as hazardous to traffic safety were detected in 7.0% of the samples in 1979 and 26.8% in 1993. Benzodiazepines were the most frequently found drugs in both years: 6.0% of the cases in 1979 and 22.9% in 1993. Illegal drugs were found in 4% of the cases in 1993. Of the samples tested, 296 in 1979 and 317 in 1993 were from drivers suspected of driving under the influence of alcohol only. In 1979 every fourteenth and in 1993 every fourth of these suspected drunken drivers had drugs in their blood. Drugs, other than alcohol, were found six times more often than expected by the police. The results indicate that the trend of drug use, multidrug use and drug abuse is increasing among cases suspected of driving under the influence of alcohol/drugs.

Comprehensive drug screening in blood for detecting abused drugs or drugs potentially hazardous for traffic safety.

A comprehensive drug screening procedure for detecting drugs in the blood samples of car drivers suspected of driving under the influence of drugs, is presented. Amphetamines, cannabinoids, opioids, cocaine and benzodiazepines were screened by an immunological EMIT ETS system after acetone precipitation. Gas chromatographic methods were used to screen and quantitate basic, neutral and acidic drugs. The free amino groups of basic drugs were derivatized with heptafluorobutyric anhydride. Analysis was performed by a dual channel gas chromatograph combined with a nitrogen phosphorus and an electron capture detector. Phenyltrimethylammonium hydroxide was used as a methylathing agent for acidic substances before analysis with a gas chromatograph connected to a nitrogen phosphorus detector. A gas chromatograph/mass spectrometry was used as a common confirmation method. Tetrahydrocannabinol was quantitated after bis(trimethylsilyl)trifluoroacetamide derivatization, opiates after pentafluoropropionic anhydride derivatization and benzoylecgonine after pentafluoropropionic anhydride and pentafluoropropanol derivatization. Excluding benzodiazepines, which were confirmed with a gas chromatograph connected to a nitrogen phosphorus and an electron capture detector, the other basic drugs as well as the acidic drugs were confirmed after the same derivatization procedures as in the screening methods. Alcohols were quantitated in triplicate by gas chromatography using three different kinds of columns. Although urine is the most important specimen for screening abused drugs, it has only limited use in forensic toxicology. The described system is most useful for analyzing a wide range of substances, including illicit drugs, benzodiazepines, barbiturates, antidepressants and phenothiazenes in forensic samples when urine is not available.

Comprehensive drug screening in urine using solid-phase extraction and combined TLC and GC/MS identification.

A simple and sensitive identification system for the detection of a broad spectrum of drugs is described. ChemElut extraction tubes were used for isolation of drugs from urine. Specimens were screened by thin-layer chromatography (TLC) and confirmed by gas chromatography/mass spectrometry (GC/MS). Special procedures for buprenorphine, cannabinoids, cocaine, LSD, morphine, phencyclidine, halogenated hydrocarbons, paracetamol, and alcohols were used. This system is useful for screening samples in misuse, impaired driving, poisoning, and other forensic cases. It covers about 300 substances including all potentially abused drugs and their metabolites.

Comparison of RapiTest with Emit d.a.u. and GC-MS for the analysis of drugs in urine.

Results obtained with RapiTest THC (One Step delta 9-Tetrahydrocannabinol Test), RapiTest MOP (One Step Morphine Test), RapiTest MET (One Step Methamphetamine Test), and RapiTest COC (One Step Cocaine Test) were compared with the results obtained with Emit d.a.u. and with gas chromatographic-mass spectrometric (GC-MS) methods. In all, 81 urine samples taken from specimens submitted for routine analysis in the Laboratory of Pharmacology and Toxicology were analyzed. Samples were screened with Emit, reanalyzed by RapiTests, and quantitated using GC-MS methods. Both positive and negative urine samples were tested. The results obtained with RapiTests correlated well with the Emit d.a.u. and GC-MS data when operating above the cutoff concentrations specified for these methods. RapiTest MOP was found to have crossreactivity with codeine and ethylmorphine, and RapiTest MET crossreacted with amphetamine.

GCD quantitation of opiates as propionyl derivatives in blood.

We describe a method using a gas chromatograph with electron ionization detection (GCD) for the simultaneous determination of morphine, codeine, 6-monoacetylmorphine, ethylmorphine, and dihydrocodeine in blood. The method employs propionic anhydride in the presence of triethylamine to propionylate free hydroxyl groups of the opiates in blood. The quantitation is achieved by using GCD with selected ion monitoring of the two most characteristic ions for each analyte. The quantitation limit was 0.01 mg/L and the linearity was 0.01-10 mg/L for dihydrocodeine, ethylmorphine, and 6-monoacetylmorphine. For the other investigated opiates, the quantitation limit was 0.025 mg/L and linearity was 0.025-10 mg/L. The intraday relative standard deviation (RSD) varied from 7.2 to 10% at the 0.5 mg/L level, and the day-to-day RSDs varied from 7.5 to 11% at the 0.85 mg/L level.

Drugs and driving: the Finnish perspective.

Drugs can cause behavioural impairment of the driver's ability to operate safely That impairment of driving ability can be documented, and biological fluids can be tested for drugs. Most countries have legislation that covers driving under the influence of alcohol and/or drugs. Some countries have introduced zero-tolerance laws (per se laws), which prohibit the operation of a motor vehicle while an illicit drug or its metabolite is present in the body, whether or not impairment is manifested. There is growing interest in using saliva (oral fluid) in preliminary roadside testing. Legislation in the state of Victoria, Australia, already allows the use of oral fluid for evidentiary testing in the case of cannabis and methamphetamine. Nevertheless, blood testing will probably remain the most common form of evidentiary testing. It has been estimated that the prevalence of illicit drug use among the general driving population in Europe is in the range of 1-5 per cent, while the prevalence of licit drugs, such as benzodiazepines, affecting driving performance is higher: 5-10 per cent. Epidemiological research is often carried out on offenders and drivers involved in collisions. Among drivers suspected of driving under the influence of drugs, there is a high percentage of licit and/or illicit drug use, as the statistics for Finland in the present article show. The drugs of most concern are amphetamine and amphetamine-type substances, cocaine, cannabis, opiates and benzodiazepines and other sedative-hypnotics. The handling of drugs and driving cases are presented, and a summary of areas for further study are provided.

Simultaneous screening and quantitative analysis of benzodiazepines by dual-channel gas chromatography using electron-capture and nitrogen-phosphorus detection.

A rapid twin-column gas chromatographic method for the simultaneous screening and determination of commonly prescribed benzodiazepines from plasma and whole blood is presented. Identical fused-silica SE-54 columns were inserted in a common split-splitless injector and connected to nitrogen-phosphorus and electron-capture detectors. By combining these specific and sensitive detectors considerable and accurate chromatographic information was obtained in a single run. The drugs were extracted from 1 ml of buffered plasma or blood with n-hexane-dichloromethane (70:30) and analysed without derivatization. Flurazepam was used as internal standard. The method was reproducible enough to permit reliable quantitation of plasma diazepam, nordiazepam, oxazepam, lorazepam, chlordiazepoxide, temazepam, midazolam, alprazolam, clobazam, norclobazam, adinazolam, flunitrazepam, bromazepam, triazolam, nitrazepam and clonazepam within 12 min.

Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients.

The combination of carbamazepine and an antidepressant (doxepin, amitriptyline, mianserin) was given to 22 psychiatric inpatients with 29 measurements of their serum antidepressant concentrations. For comparison, sex-, age-, and dose-matched inpatients, treated with the antidepressant but not with carbamazepine, were selected as controls (N = 29). All the patients were treated with their routine daily dose for at least 7 days before the gas-chromatographic measurement of serum predose concentrations of the antidepressants. In patients with carbamazepine, serum doxepin and doxepin + nordoxepin concentrations (N = 17) were decreased significantly (p less than 0.05), on average to 46% and 45%, respectively, as compared to that in subjects without carbamazepine. Also in carbamazepine + amitriptyline patients, serum nortriptyline and amitriptyline + nortriptyline concentrations (N = 8) were significantly lower than in those not receiving carbamazepine (p less than 0.05). The mean serum antidepressant levels were decreased to 42% and 40%, respectively. The serum mianserin concentration of carbamazepine patients (N = 4) was reduced to 30% of that in patients not treated with carbamazepine (p less than 0.01). The percentage fractions of demethylated metabolites (nordoxepin, nortriptyline) from the total antidepressant levels were not influenced by carbamazepine. In patients treated with carbamazepine, serum total antidepressant concentrations remained more often below the suggested therapeutic ranges than in those patients without carbamazepine. The results suggest that serum antidepressant concentrations are reduced by concurrent carbamazepine therapy, and that the concentrations should be carefully monitored when carbamazepine is added to the antidepressant regimen.

Comparison of eight commercial on-site screening devices for drugs-of-abuse testing.

Eight commercially available on-site drugs-of-abuse testing devices for detecting cannabinoids (THC-COOH), opiates (OPI), cocaine (COC), amphetamines (AMP), metamphetamines (MET) and benzodiazepines (BZO) were evaluated. The used urine specimens suspected of being drug positive were all confirmed by gas chromatographic/mass spectrometry (GC/MS). For AMP and MET, sensitivities varied between 83 and 95% and specificities between 98 and 100%. Correspondingly, sensitivities between 88 and 98% and specificities between 95 and 100% were observed for THC-COOH. For BZO, sensitivities varied between 91 and 97% and specificities between 97 and 100%. Only a few confirmed positive samples were available for OPI and COC, the sensitivities being between 83 and 100% and 100%, respectively. On-site devices did not always find extremely high drug concentrations. False-negative results were found with AMP in particular. Pholcodine, commonly used as medicine, was observed to give false-positive results with most of the devices and was not, however, included in given cross-reactivity tables. It was found that the devices differed markedly with respect to interpretation of test results and to ease of test performance, leading to the suggestion that different criteria for selecting on-site devices for either emergency laboratories in hospitals or for police stations and prisons should be used. Since the overall specificity of any of the devices was not 100% and false positives were identified, we found it important to confirm any positive screening test result.

Debrisoquine hydroxylation phenotypes of patients with high versus low to normal serum antidepressant concentrations.

Debrisoquine hydroxylation phenotype was determined in 22 psychiatric patients who had previously developed exceptionally high serum antidepressant (AD) concentrations, and in 22 sex-, age-, and dose-matched counterparts who had low to normal serum AD levels. The patients were recruited from 641 subjects in whom serum AD levels were monitored. In each AD level group, 16 patients had been treated with tricyclic antidepressants (amitriptyline, doxepin, trimipramine, imipramine, clomipramine) and 6 with mianserin. Eight poor metabolizer (PM) phenotypes (debrisoquine/hydroxydebrisoquine ratio in 6-hour urine greater than or equal to 41.5) were identified in the high AD level group, but only two in the group with low to normal AD level (p = 0.03, Fisher's test). Comedications in the two study groups did not differ markedly from ach other and could not, therefore, explain the greater frequency of PMs among the patients with high serum AD levels. Three of 6 mianserin patients, who had developed high serum AD levels, were PMs. This high proportion of PMs raises the question of a possible involvement of the same metabolic pathway (cytochrome P-450IID6 isoenzyme) also in mianserin hydroxylation. The results suggest further that during AD therapy with standard dosage, PM phenotypes are at special risk for high serum AD concentrations and, consequently, for clinical symptoms of toxicity.

5-HT3 receptor antagonist MDL 72222 dose-dependently attenuates cocaine- and amphetamine-induced elevations of extracellular dopamine in the nucleus accumbens and the dorsal striatum.

The effects of a 5-HT3 receptor antagonist MDL 72222 on cocaine- and amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and the dorsal striatum were studied with microdialysis technique using halothane anaesthesized rats. Dopamine and its metabolites were measured by HPLC with electrochemical detection. Cocaine elevated extracellular dopamine in the nucleus accumbens and to a lesser extent in the dorsal striatum, but it did not affect dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. Pretreatment with MDL 72222 (25-100 micrograms/kg) dose-dependently attenuated cocaine-induced elevation of dopamine in both of the nuclei studied. Amphetamine elevated extracellular dopamine and reduced DOPAC and homovanillic acid equally in the nucleus accumbens and in the dorsal striatum. MDL 72222 also attenuated the amphetamine-induced elevation of extracellular dopamine concentration in both brain areas studied, but first at a dose of 100 micrograms/kg. The different potencies of the interactions of the 5-HT3 receptor antagonist with cocaine and amphetamine could be related to the different mechanisms by which these drugs primarily elevate extracellular dopamine.