Kurt Besserer

The elimination kinetics of methanol and the influence of ethanol

SummaryFour male subjects aged between 20 and 29 years were given intravenous injections of methanol at a dosage of 10 mg per kg body weight, once without prior administration of ethanol, and once after oral ingestion of 0.3 g ethanol per kg body weight. The serum methanol concentration was monitored over the next 5 h (after methanol administration alone) and 6–7 h (after methanol administration following ethanol ingestion). The elimination of methanol administered alone was found to follow first-order kinetics with a rate constant for the elimination phase of 0.475-0.259 h−1, corresponding to an elimination half-life of 1.8-3.0h. When ethanol was also administered methanol oxidation was found to be completely blocked until the blood ethanol concentration had fallen to 0.2 g/kg. When the ethanol concentration had dropped to zero, methanol elimination followed exactly the same course as that observed in the experiment without prior administration of ethanol (k: 0.378-0.231 h−1;t/12: 1.5–2.7 h).ZusammenfassungVier männliche Probanden im Alter zwischen 20 Jahren und 29 Jahren wurden 10 mg Methanol pro Kilogramm Körpergewicht intravenös injiziert. Die Methanolapplikationen erfolgten einmal bei Ethanol-Nüchternheit, einmal nach vorangegangener oraler Zufuhr von 0,3 g Ethanol pro Kilogramm Körpergewicht. Der Verlauf der Serum-Methanolkonzentrationskurve wurde über 5 Stunden (alleinige Methanolzufuhr) bzw. 6 bis 7 Stunden (zusätzliche Ethanolzufuhr) beobachtet. Nach alleiniger Methanolapplikation folgte die Methanol-Elimination einer Funktion erster Ordnung mit terminalen Dispositionskonstanten zwischen 0,475h−1 und 0,259h−1, entsprechend Eliminations-Halbwertszeiten von 1.8 h bis 3,0 h. Nach gleichzeitiger Ethanolzufuhr wurde die Methanol-Oxydation bis herab zu Ethanolkonzentrationen von 0,2 g/kg vollständig blockiert. Nach Erreichen der Ethanol-Nüchternheit zeigte die Methanol-Elimination keine Unterschiede im Vergleich zu den Versuchen ohne gleichzeitige Ethanolbelastung (k: 0.378h−1 bis 0,231−1;t½: 1,5h bis 2,7h).

The kinetics of methanol elimination in alcoholics and the influence of ethanol

Methanol concentrations were studied during the end phase of ethanol elimination and for about five hours afterwards in 12 alcoholics admitted with alcohol intoxication for acute care. The rate of ethanol elimination (beta 60) ranged from 0.114 g/kg/h to 0.270 g/kg/h (mean 0.178 +/- 0.045 g/kg/h). The methanol concentration was found to remain almost steady as long as ethanol levels were relatively high, and changed only to an extent that could be explained by the combined opposing influences of methanol excretion and endogenous synthesis. There was no significant relationship between the rate of ethanol elimination and the methanol level. The methanol concentration began to decrease when the ethanol concentration had fallen to under 0.2 g/kg. When the ethanol concentration had fallen to base levels, methanol was eliminated at a rate characterized by an elimination constant (kel) of 0.212-0.481 h-1, and a half life of 1.44-3.27 h. There was a positive correlation between the rate of ethanol elimination and the rate of methanol elimination (r = 0.642; p < 0.05).

Methanol elimination in non-alcoholics: inter- and intraindividual variation

Five male subjects aged between 25 and 40 years were given methanol at a dose of 10 mg/kg, once orally and once intravenously, while the enzyme systems responsible for methanol oxidation were blocked by ethanol. The study assessed the duration of inhibition of methanol oxidation in relation to the blood ethanol concentration, and the elimination of methanol not influenced by ethanol. Methanol elimination was found to begin at a blood ethanol concentration of 0.04-0.13 g/kg. Elimination constants of 0.406-0.267 h-1 with corresponding half-lives of 1.71-2.60 h were established for methanol not influenced by ethanol. When data from a previous study using an identical protocol for parenteral administration were included, making the total number of subjects nine, the mean elimination constant was found to be 0.298 +/- 0.470 h-1 and the mean half-life 2.37 +/- 0.357 h, distribution being normal. No evidence of any differences in methanol elimination kinetics between alcoholics and non-alcoholics or of a significant influence of the route of administration was found. The extent of intraindividual variation in methanol elimination as indicated by the difference in each subject between the values established, expressed as a percentage of the corresponding mean values, was found to be 3-25%, which is comparable to the magnitude of intraindividual variation in the rate of ethanol elimination.

Forensic significance of acetylcholine esterase histochemistry in organophosphate intoxication

SummaryThe reduction of acetylcholine esterase (AChE) activity or the complete blocking of AChE to be observed by histochemical demonstration of AChE in tissue after experimental and spontaneous (human) organophosphate intoxication (especially paraoxone = E 600 and parathion = E 605) should be interpreted as an indication of an in vivo inhibition of the cholinergic system. In animal experiments, a relationship was demonstrated between AChE activity and the applied dose of organophosphorous compounds. In addition, enzyme inhibition was observed in in vitro systems using AChE-containing mouse tissue sections pretreated with organophosphate solutions or with body fluids containing organophosphates. Examination of the concentration dependency indicated that the inhibiting solution must contain at least 0.15 μg/ml paraoxone or 5 mg/ml parathion to block AChE in the section. Using the same in vitro system, a half-life of 6–7 min was established for the paraoxone inactivating enzyme in blood. The in vivo and in vitro inhibited AChE was reactivated by consecutive treatment of blocked sections with toxogonin. This possibility of reactivation therefore allows qualitative classifications of the AChE-inhibiting toxin to the alkylphosphates. The postmortem persistence of the AChE inhibitory effect was demonstrable for about a 2-month interval. Since the histochemically demonstrable activity of the enzyme AChE is more or less constant during a postmortem interval of at least 70h, the model of histochemical demonstration is a method which provides a morphological equivalent for acute organophosphate intoxication.ZusammenfassungDie Reduktion oder vollständige Hemmung der histochemisch nachweisbaren Acetylcholinesterase (AChE)-Aktivität nach experimentellen und spontanen (menschlichen) Organophosphatvergiftungen (besonders mittels Paraoxon = E 600 und Parathion = E 605) muß als Zeichen einer in vivo-Hemmung des cholinergen Systems interpretiert werden. Im Tierversuch wurde eine Beziehung zwischen der AChE-Aktivität und applizierten Dosis der Organophosphate nachgewiesen. In einem in vitro-System konnte die Enzymhemmung nach Exposition von AChE-enthaltenden histologischen Schnitten mit Organophosphat-enthaltenden Körperflüssigkeiten bzw. angesetzten Lösungen festgestellt werden. Bei Untersuchung der Dosisabhängigkeit wurde ferner festgestellt, daß mindestens 0.15 μg/ml Paraoxon oder 5 mg/ml Parathion notwendig sind, um in vitro die AChE zu blockieren. Bei Anwendung desselben in vitro-Systems konnte eine Halbwertzeit für das Paraoxoninaktivierende Enzym im Blut von 6–7 min nachgewiesen werden. Die in vivo und in vitro gehemmte AChE war bei anschließender Behandlung der Schnitte mit Toxogonin reaktivierbar; die Möglichkeit der Reaktivation erlaubt eine qualitative Zuordnung des AChE-hemmenden Toxins zu den Alkylphosphaten. Eine postmortale Persistenz der Enzymhemmung war am menschlichen Material für ca. 2 Monate nachweisbar. Da auch die Acetylcholinesterase in weitgehend unveränderter Aktivität nach einem postmortalen Intervall von wenigstens 70 h nachweisbar ist, muß der histochemische Nachweis als morphologisches Äquivalent einer akuten Organophosphatintoxikation angesehen werden.

Fatal nitrosamine poisoning.

A case is reported in which progressive liver symptoms with rise in bilirubin concentration, hemorrhagic diathesis, and signs of portal hypertension developed three years before death in liver coma. The pathologic and neuropathologic findings are described. The case was clarified after dimethylnitrosamine was demonstrated in food intended for the patient and after it was established that small amounts of nitrosamine could have been repeatedly ingested by the patient over a period of years.Comparable cases of human dimethylnitrosamine poisonings published in the literature are presented. The relatively typical morphologic alterations in the liver are described. Problems involved in the histological interpretation of such liver changes as well as the forensic conclusions to be drawn are discussed.

Curvilinear increase in methanol concentration after inhibition of oxidation by ethanol: significance for the investigation of endogenous methanol concentration and formation.

Abstract Endogenous methanol production was assessed over a period of 5 h in subjects given an infusion of ethanol to inhibit methanol oxidation in the liver after a period of fasting and abstinence from alcohol. Ethanol was administered to each of five subjects at rates of 0.35 g/kg per hour and 0.70 g/kg per hour. The rise in methanol concentration was biphasic regardless of the rate of ethanol administration, with a steeper gradient in the first 10–30 min. This may be due to the existence of a deep compartment from which methanol can be displaced by ethanol. This could take the form of loose binding of methanol to the hepatic oxidation enzymes as an enzyme-substrate complex, or a shift of the oxidation-reduction equilibrium between methanol and formaldehyde. The biphasic nature of the increase, with an initial steeper rise, means that the values obtained in the first 30 min should be excluded from the calculations when the rate of endogenous methanol production is determined by linear regression analysis. Endogenous methanol concentrations to be taken into account after ethanol administration are on average 0.4–0.6 mg/kg higher than those detectable in the absence of ethanol due to the additional method displaced from the deep compartment.

Identification and quantitation of intact diastereoisomeric benzodiazepine glucuronides in biological samples by high-performance liquid chromatography

A rapid and simple high-performance liquid chromatographic method for the simultaneous detection of intact glucuronides of different benzodiazepines is described. Separation of the diastereomers of the following benzodiazepine glucuronides can be achieved on a reversed-phase column (octadecyl or select B): oxazepam, nordiazepam, temazepam, lorazepam and 3-hydroxyprazepam. If the sample contains both S-lorazepam and R-temazepam glucuronides, or both S-temazepam and nordiazepam glucuronides, further separation on a beta-cyclodextrin column is required. The detection limit ranges between 5 and 10 ng of glucuronides per ml of plasma or urine, respectively.

Über die Auswertung chemisch-toxikologischer Befunde mit Hilfe der maschinellen Datenverarbeitung

A system for documentation and data processing of forensic-toxicological results in the time between May 1. 1964 and December 31. 1972 is reported. The objective of this system is to have fast access to the stored information. The first part deals with the development of a code system. The second part presents results we have found. The main problem was finding code numbers for substances and their metabolites. This was done successfully.SummaryA system for documentation and data processing of forensic-toxicological results in the time between May 1. 1964 and December 31. 1972 is reported. The objectiv of this system is to have fast access to the stored information. The first part deals with the development of a code-system. The second part presents results we have found. The main problem was finding code numbers for substances and their metabolites. This was done successfully.ZusammenfassungEs wird über Dokumentation und maschinelle Verarbeitung chemisch-toxikologischer Befunde aus der Zeit vom 1.5.1964 bis 31.12.1972 berichtet. Sinn und Zweck dieses Verfahrens soll sein, archivierte Untersuchungsbefunde jederzeit abrufbar zu halten.Im ersten Teil wird über die Entwicklung eines Code-Systems berichtet, im zweiten Teil werden damit gewonnene Ergebnisse vorgestellt. Das Hauptproblem — die Aufstellung eines Stoff- und Metabolitenschlüssels — konnte, wie die Prüfung im Ergebnisteil zeigte, ohne Schwierigkeiten gelöst werden.