Poisoning with the S-Alkyl organophosphorus insecticides profenofos and prothiofos.

BACKGROUND: Many organophosphorus (OP) insecticides have either two O-methyl or two O-ethyl groups attached to the phosphorus atom. This chemical structure affects their responsiveness to oxime-induced acetylcholinesterase (AChE) reactivation after poisoning. However, several OP insecticides are atypical and do not have these structures. AIM: We aimed to describe the clinical course and responsiveness to therapy of people poisoned with two S-alkyl OP insecticides-profenofos and prothiofos. DESIGN: We set up a prospective cohort of patients with acute profenofos or prothiofos self-poisoning admitted to acute medical wards in two Sri Lankan district hospitals. Clinical observation was carried out throughout their inpatient stay; blood samples were taken in a subgroup for assay of cholinesterases and insecticide. RESULTS: Ninety-five patients poisoned with profenofos and 12 with prothiofos were recruited over 5 years. Median time to admission was 4 (IQR 3-7) h. Eleven patients poisoned with profenofos died (11/95; 11.6%, 95% CI 5.9-20); one prothiofos patient died (1/12; 8.3%, 95% CI 0.2-38). Thirteen patients poisoned with profenofos required intubation for respiratory failure (13/95; 13.7%, 95% CI 7.5-22); two prothiofos-poisoned patients required intubation. Both intubations and death occurred late compared with other OP insecticides. Prolonged ventilation was needed in those who survived-a median of 310 (IQR 154-349) h. Unexpectedly, red cell AChE activity on admission did not correlate with clinical severity-all patients had severe AChE inhibition (about 1% of normal) but most had only mild cholinergic features, were conscious, and did not require ventilatory support. CONCLUSION: Compared with other commonly used OP insecticides, profenofos and prothiofos are of moderately severe toxicity, causing relatively delayed respiratory failure and death. There was no apparent response to oxime therapy. The lack of correlation between red cell AChE activity and clinical features suggests that this parameter may not always be a useful marker of synaptic AChE activity and severity after OP pesticide poisoning.

The effect of nicotine on perceptual, ocular motor, postural, and vegetative functions at rest and in motion.

Nicotine has wellknown, unpleasant side effects, e.g., transient dizziness, nausea, and nicotine-induced nystagmus (NIN). To investigate factors influencing these effects, we addressed three questions: (1) Is the intensity of dizziness, nausea, NIN, and unsteadiness dependent on nicotine dosage? (2) Does the intensity of perceptual, ocular motor, vegetative effects, and postural imbalance correlate? (3) Do visual or vestibular motion stimuli produce and/or aggravate distressing dizziness and nausea? Sixty healthy non-smokers or occasional smokers participated; 40 were tested once before and six times after application of a nicotine nasal spray in doses of 1 mg or 2 mg with or without motion stimulation; 20 received a placebo nasal spray. Plasma nicotine concentrations were significantly related to nicotine dosage. Dizziness, nausea, NIN, and unsteadiness also depended on the nicotine dosage (p < 0.01).Nicotine blood concentration was a better predictor for the temporal dependence of nystagmus than nicotine dosage. Dizziness correlated highly with nausea (R = 0.63, p < 0.001). The degree of nicotine-induced nausea significantly correlated with postural imbalance. The time course of postural sway differed according to nicotine dosage and gender: for women, there was no clear relationship between sway magnitude and nicotine dosage, while men showed increased sway with higher dosage. Motion stimulation increased nicotine-induced dizziness and nausea, but did not significantly influence NIN or postural imbalance. Our data support the view that all measured adverse effects reflect dose-dependent nicotine-induced vestibular dysfunction. Additional motion stimulation aggravates dizziness and nausea, i.e., nicotine increases sensitivity to motion sickness.

[Opioids and driving ability]. / Die Schmerzen sind mit Opioiden unter Kontrolle, aber ... 1st der Patient noch fahrtüchtig?

Acute ingestion of opioids is associated with various side effects, such as nausea, dizziness and light-headedness that can impair a person's fitness to drive. Over the long-term, however, tolerance to the opioids develops, and such negative effects decrease. Numerous studies have shown that, even high-dose opioid use does not necessarily abolish a person's fitness to drive. A stable dose, absence of co-consumption of other psychotropic drugs, and a good general state of health of the patient may well be associated with continuing ability to drive. Patients who are able to critically assess their own situation should be given appropriate information.

[Drugs and street traffic. Playing it safe for yourself and your patient]. / Medikamente und Strassenverkehr. So bleiben Sie und Ihr Patient auf der sicheren Seite.

Participation in road traffic/driving a motorized vehicle involves numerous skills capable of being influenced by medications. Common examples of the latter are psychoactive drugs, hypnotics and sedatives, antihistaminics, analgesics and psychostimulants. Both the therapeutic effect itself and potential side effects can pose a danger, for example, via the loss of psychomotoric coordination, or equilibrium or sensory disturbances. Every fourth accident can be traced back to the influence of some medication or other. In addition, the patient himself may be harboring a variety of major risks including age, physiological and mental status and previous illnesses.

Determination of lysergic acid diethylamide in body fluids by high-performance liquid chromatography and fluorescence detection--a more sensitive method suitable for routine use.

A new method for determination of lysergic acid diethylamide (LSD) in body fluids by high-performance liquid chromatography and fluorescence detection was developed based on previously published methods. The new method is suitable for confirmation of samples tested positive by immunoassay, avoiding loss of LSD by absorption to surfaces. The reduced loss of LSD results in improved sensitivity. This is achieved by adding ethylene glycol to the samples, which cover glass surfaces. This principle can similarly be used to improve analysis of other drugs. Body fluids for analysis included urine and whole blood. An internal standard was applied for quantification of LSD. The new method offers satisfying precision data and has a detection limit of less than 0.05 ng/nL.

Determination of flunitrazepam and its main metabolites in serum and urine by HPLC after mixed-mode solid-phase extraction.

A rapid and sensitive method is presented for the simultaneous determination of flunitrazepam, norflunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam in serum, plasma, and urine. The compounds were extracted by a mixed-mode solid-phase procedure following analysis by high-performance liquid chromatography and ultraviolet detection and using methylclonazepam as the internal standard. The method revealed high recoveries and showed good precision and linearity for all compounds. The limit of detection was at least 1 ng/ml serum (plasma) for all compounds.

European multicentre evaluation of the analytical performance of the Abbott AxSYM Abused Drugs Assays.

In accordance with the guidelines of the European Committee for Clinical Laboratory Standards (ECCLS), the performance of the Abbott AxSYM Abused Drugs assays were evaluated and compared with the results provided by the following systems: Syva Emit d.a.u./Roche Cobas Mira S Plus, Abbott TDx and ADx, Syva Emit d.a.u./Syva ETS Plus, Syva Emit II/Hitachi 717 and Roche Abuscreen OnLine/Roche Cobas Mira S Plus. The test analytes, cannabinoids, cocaine metabolites, opiates, benzodiazepines and barbiturates, were each investigated in three laboratories on different systems. The imprecision of all systems in the series and from day to day was good, with CVs less than 5% or 10%, respectively. The AxSYM calibration curves were stable for 3-4 months and none of the systems displayed any shift in the results of the analyses within one day or any faults caused by sample contamination. Within the framework of this study, a total of 1860 urine samples were investigated; 741 results were positive. All results which remained discrepant between AxSYM and the comparison systems after repeated analysis (n = 17) were subjected to further investigation using a reference method, with the exception of one barbiturate and two benzodiazepine samples. An additional test criterion was the practicability of the systems investigated and the versatility of the software. During this evaluation, the results provided by the Abbott AxSYM were excellent and were fully in line with the manufacturer's claims. The reliability of the FPIA technology that has been the subject of frequent investigation was also convincing during this evaluation. The possibility of semi-quantitative determination, the stability of the calibration curves, the ability to process an emergency sample without delay and its high suitability to routine operations are the convincing benefits offered by this system.

Nonoxidative ethanol and methanol changes in the heart and brain tissue of alcohol abusers.

Fatty acid ethylesters (FAEE) are synthesized from ethanol and fatty acids in the heart and brain. Similarly fatty acid methylesters (FAME) are synthesized from methanol and fatty acids. Whereas methanol reportedly indicates recent or chronic consumption of alcoholic beverages, an elevated serum methanol concentration (SMC) indicates mainly chronic alcohol intake. We compared levels of FAEE and FAME in cardiac and brain tissues with the blood ethanol concentration(BEC) and SMC in 18 alcohol abusers and 29 control subjects without history of alcohol abuse(control) to clarify the relationships between BEC and FAEE levels and that between SMC and FAME levels. We also assessed the possibilities of discriminating the alcohol abusers from the control group and of detecting FAEE and FAME accumulations in cardiac and brain tissues. Levels of FAEE and FAME were determined by gas chromatography (GC) in autopsied cardiac and brain tissues. Heart FAEE (HFAEE) levels correlated with BEC (r = 0.61) and it was possible to distinguish between alcohol abusers and controls using discriminant analysis. HFAEE levels in the alcohol abusing group were elevated even with low BEC. Therefore, HFAEE levels indicate ethanol accumulation in cardiac tissues of alcohol abusers. Brain FAEE (BFAEE) and heart and brain FAME (HFAME and BFAME) levels did not correlated closely with BEC and SMC, respectively. However, there are some possible means of discriminating between the two groups in terms of BEC and BFAEE, and SMC and FAME respectively, using discriminant analysis. Employing this analysis, the rate of misclassification was 17-25.5%. The mean levels of HFAEE, BFAEE, HFAME and BFAME were higher in the alcohol abusing group than in the control group, even when their BEC and SMC were quite low.

Carboxyhemoglobin blood concentrations in suicides by fire.

A total of 21 suicides by fire (16 males and 5 females) were investigated. In at least 18 of the 21 cases, flammable liquids were used as accelerants leading to severe and extensive burns. The determination of carboxyhemoglobin concentrations revealed comparatively low levels of between 3 and 30 per cent in suicides committed in the open whereas four out of five deceased found dead in gutted cars showed carbon monoxide saturations ranging from 34 to 87 per cent. In 18 cases (86%) soot was detectable in the airways even in cases with slightly elevated carboxyhemoglobin concentrations, indicating the importance of a careful examination of the airways at autopsy for the detection of vital signs.

Evaluation of a solid-phase extraction procedure for the simultaneous determination of morphine, 6-monoacetylmorphine, codeine and dihydrocodeine in plasma and whole blood by GC/MS.

Different procedures of solid-phase extraction were re-examined and a new solid-phase extraction procedure was developed using gas chromatography-mass spectrometry for the simultaneous detection and quantitation of morphine, 6-monoacetylmorphine, codeine and dihydrocodeine in plasma and whole blood. The effects of different types of sorbent and buffer solutions on the recoveries and purity of the extracts were also studied. Some preparation techniques on whole blood samples were also investigated. The method developed using Chromabond C18 (100) with spiked plasma samples had good recoveries for all opiates of interest: morphine 93.1% +/- 7.4%, 6-monoacetylmorphine 68.0% +/- 6.7%, codeine 77.0% +/- 8.3% and dihydrocodeine 67.9% +/- 8.4%. The detection limit of all compounds was less than 5 micrograms/L. The blank plasma showed no interfering peaks in the GC/MS-analysis.

Modification and evaluation of Abuscreen OnLine assays for drug metabolites in urine performed on a COBAS FARA II in comparison with EMIT d.a.u. Cannabinoid 20.

OnLine assays for cannabinoids, barbiturates, opiates, and cocaine from Roche Diagnostics were run on the automatic analyzer COBAS FARA II. The assay programs and the cutoff definition were modified to obtain maximum sensitivity and reagent economy. The limits of detection and curve stability data of the modified assays were compared with the original, as well as with EMIT d.a.u. Cannabinoid 20 assay, and the modified assays were found to be more favorable. Modified OnLine assays appear to be a convenient and cost-effective method for drug screening in urine.

Influence of halothane on the effect of cAMP-dependent and cAMP-independent positive inotropic agents in human myocardium.

Volatile anaesthetics have a variety of effects on the myocardium, namely a negative inotropic effect and a catecholamine sensitizing effect. The present study was designed to see if the hydrocarbon anaesthetics interact specifically with subcellular targets of the myocardial cell, by examining the effects of halothane in the presence of positive inotropic agents with different mechanisms of action. Experiments were performed in isolated electrically driven left ventricular preparations (1 Hz, 37 degrees C, Ca2+ 1.8 mmol litre-1) from human hearts obtained at cardiac surgery. The concentration-response curves of noradrenaline, milrinone, BayK 8644 and Ca2+ were investigated in the absence and in the presence of halothane. Halothane enhanced the efficacy of noradrenaline and milrinone but not of Ca2+ or BayK 8644. The potency of milrinone was also increased by halothane, whereas the potency of BayK 8644 was decreased and those of noradrenaline and Ca2+ were unchanged. Halothane differentially influences the effects of agents with different positive inotropic mechanisms. This experimental approach can be taken as a functional method to localize the mechanisms of action of the inhalation anaesthetics in human myocardium, namely sensitization of cAMP formation and interaction with L-type Ca2+ channels.

[Unusual injection site in a drug fatality in prison]. / Bemerkenswerte Lokalisation von Einstichstellen bei einem Drogentodesfall in der Haftanstalt.

A lethal heroin-intoxication of a prisoner with localization of hardly detectable injection marks on the frenulum praeputii is reported. An extensive external examination in particular in cases of death in jail or of drug addicts is necessary to detect unusual signs of intravenous drug addiction.

Drug death autopsies at the Munich Institute of Forensic Medicine (1981-1992).

A total of 638 drug death autopsy cases in southern Bavaria from 1981 to 1992 were analysed, including epidemiological and toxicological investigations. The rate of HIV infections decreased during the last few years. Cocaine does not (yet) play a major role. Suicide rates are high. Heroin intoxications are the most frequent cause of death, mostly in combination with other drugs and alcohol. In 1992 we observed a sharp increase of the number of deaths associated with dihydrocodeine abuse. This seems to be a local phenomenon and has to be explained by uncritical and uncontrolled prescription of large amounts of this opiate by individual physicians.

Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease.

There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gallstone formation and mitigate biliary pain in gallstone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gallbladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 x 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05 +/- 0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94 +/- 0.27 versus 0.93 +/- 0.32 mg/ml) or total protein (5.8 +/- 0.9 versus 6.4 +/- 1.3 mg/ml), cholesterol saturation (1.3 +/- 0.2 versus 1.5 +/- 0.2), or nucleation time (2.0 +/- 3.0 versus 1.5 +/- 2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9 +/- 0.6 versus 5.6 +/- 1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content.(ABSTRACT TRUNCATED AT 250 WORDS)

[Isopropanol and acetone level in serum after preoperative surface disinfection with antiseptics containing isopropanol]. / Isopropanol- und Acetonspiegel im Serum nach präoperativer Flächendesinfektion mit isopropanolhaltigen Antiseptika.

After preoperative skin disinfection in pediatric surgery, serum levels of isopropanol up to 12.2 mg/l (MW 5.0 mg/l +/- 3.37, n = 26) were found. They result from a rapid and prolonged but uncharacteristic percutaneous resorption of the isopropanol-containing disinfectant. In about 50% of the cases, serum levels of acetone showed an increase up to 82 mg/l already before skin disinfection, presumably caused by preoperative starvation. After skin disinfection, raised acetone levels were found in 19 of 26 cases. As increased isopropanol and acetone levels are discussed as alcoholism markers, a falsification of congener analysis after skin disinfection, e.g. in cases of adult victims of accidents, has to be taken into consideration. Endogenous serum levels of methanol (0.87 mg/l +/- 0.49), ethanol (0.32 mg/l +/- 0.09), acetaldehyde (0.31 mg/l +/- 0.10) and others remained unaffected. Some uncharacteristic elevations of propanol-1 levels are caused by contaminated rubber caps.

[Change in congener analysis caused by percutaneous absorption of propanol-containing antiseptics]. / Veränderung von Begleitstoffanalysen durch percutane Resorption propanolhaltiger Antiseptika.

According to the forensic literature, an alteration of blood alcohol concentration through alcohol disinfection before venepuncture is unlikely, however, percutaneous resorption of alcohol containing antiseptics is well documented. There are no investigations available, elucidating to what extent this is also correct for congener alcohols, particularly propanol-1/-2, which have serum levels in range of mg/l. In experiments with surgical hand and local skin disinfection, carried out with and without oral alcohol, relevant levels of propanol-1/-2 between 0.2 and 2 mg/l were measured. We conclude, that the routine clinical use of antiseptics is able to alterate and to falsify congener levels and can lead to incorrect interpretation of congener analysis.

[Statistical approach to forensic conversion values for alcoholics]. / Statistiche Annäherung an forensische Rückrechnungswerte für Alkoholiker.

With collaboration of the study groups from Tübingen, Munich and Kiel and consideration of the results of Bonnichsen et al 1968, alcohol elimination curves of 98 alcoholics were subjected to a joint evaluation for determination of the beta 60 values. The average elimination rate was 0.21 g/kg/h (s = 0.05 g/kg/h). By analogy to average beta 60 values and back-conversion factors of nonalcoholics, the limit values for alcoholics were estimated as being between 0.12 g/kg/h (minimum value) and 0.29 g/kg/h (maximum value).

Reduced binocular depth inversion as an indicator of cannabis-induced censorship impairment.

Measurements of binocular depth inversion using a stereoscopic slide projection with polarized light were performed in healthy volunteers before and after cannabis intake. Since binocular depth inversion represents an illusion occurring in the perception of semantically meaningful objects projected in a 3-D inverted fashion, the hypothesis can be tested that cannabis-induced "psychedelic states" represent a condition in which the human CNS is unable to correct implausible perceptual hypotheses. The data demonstrate a strong cannabis-induced impairment of binocular depth inversion.