Invasion and distribution of methanol.

After the enzyme systems responsible for methanol oxidation were blocked by ethanol, five test persons were given methanol at a dose of approximately 10 mg/kg weight, once orally and once parenterally. Taking into account the endogenous blood methanol levels detectable before the administration of methanol, C0 concentrations of 11.1-15.9 mg/kg were reached. This corresponds to a distribution volume of approximately 0.77 +/- 0.07 l/kg, which is comparable to the 0.78 +/- 0.09 l/kg obtained for ethanol. After parenterally administering methanol as a bolus, the distribution half-life was on average 8 min (range: 3.8-13.8 min). After oral administration of methanol diluted in 100 ml water on an empty stomach, invasion took place with a half-life of approximately 5 min (3.8-6.9 min). In one case, however, due to vegetative disturbances the invasion half-life was 23.1 min.

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

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.

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.

Endogenous methanol: variability in concentration and rate of production. Evidence of a deep compartment?

The endogenous methanol concentration was determined in 72 men aged between 18 and 35 years in the morning after a 12-h period of fasting and abstinence from alcohol. The distribution curve was found to be skewed to the right, the concentrations ranging from '0' (below the detection threshold) to 3.4 mg/kg. The median was 0.1 mg/kg and the mean 0.35 mg/kg. Significant differences were found between three groups defined according to the duration of prior abstinence from alcohol (8 h, 30 h, and 5 days). The highest values were seen after the shortest period of abstinence and the lowest values after the longest period of abstinence. The course followed by the methanol concentration in the presence of blocking of methanol oxidation by orally or parenterally administered ethanol was observed over at least 10 h on two separate occasions in a further 8 subjects aged between 24 and 35 years. At blood ethanol concentrations of more than 0.20 g/kg, the rate of production of methanol, calculated by regression, ranged from 0.09-0.37 mg/kg/h (r = 0.970-0.554, S(y.x) = 0.227-0.565 mg/kg). The rise in methanol concentration at the start of ethanol administration was significantly more rapid than the subsequent rise. It is hypothesised that there may be a so-called deep compartment for methanol that would explain the dependence of the endogenous methanol level on the duration of the preceding period of abstinence from ethanol, and the occurrence of an initial phase of faster rise in methanol concentration associated with the administration of ethanol.

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.

[Methanol level and methanol elimination in alcoholic patients]. / Methanolspiegel und Methanolelimination bei Alkoholikern.

A total of 54 male alcoholics aged between 26 and 57 years who had been admitted in an intoxicated state to a psychiatric hospital for acute care and subsequent detoxification were included in the study. The blood ethanol concentration (BEC) and serum methanol concentration (SMC) at the time of admission (n = 49) and the methanol elimination curve during ethanol elimination (n = 19) and after the ethanol concentration had fallen to zero (n = 4) were investigated. On admission, the BEC ranged from 0.21 g/kg to 3.26 g/kg and the SMC ranged from 5 mg/kg to 44 mg/kg. The gamma-alcoholics (n = 28) exhibited higher ethanol concentrations than the delta-alcoholics (n = 11) but no difference was found in the methanol concentrations. The methanol level was found to be related to the ethanol level in gamma-alcoholics (r = 0.671; p < 0.001), but not in d-alcoholics (r = 0.215; p > 0.05). The methanol content of the most recently consumed and generally preferred type of alcoholic beverage was found to influence the SMC in all the alcoholics. The SMC did not fall during ethanol oxidation (BEC > 0.2g/kg). After the ethanol concentration had fallen to zero, methanol elimination was found to follow first order kinetics; the elimination constants ranged from 0.592 h-1 to 0.209 h-1, corresponding to elimination half-life values of 1.2 h to 3.3 h. No differences were found between these values and those of non-alcoholic subjects.

The elimination kinetics of methanol and the influence of ethanol.

Four 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 1.8-3.0 h. 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; t1/2: 1.5-2.7 h).

[Alcoholic fermentation in "Schwabischen Most": ethanol and alcoholic congener alcohols]. / Alkoholische Gärung beim "Schwäbischen Most": Ethanol und Begleitalkhole Alcoholic fermentation in "Schwäbischem Most": Ethanol and congener alcohols.

The concentrations of ethanol and congener alcohols in "Schwäbischer Most" were determined (1) at various stages throughout the fermentation process in two different types of "Most", and (2) after completed fermentation in eleven different types. The fermentation process was finished after about five weeks with a final ethanol concentration of 35-54 g/l. According to the congener alcohols the different specimens of "Most" could be classified as beverages like wine. However, the concentrations were found to vary so widely that the analysis of the beverage in question is to be recommended whenever an expert opinion is given. Our studies suggest that the alcohol concentrations do not change significantly, when the fermentation process has been finished.

[Rate of ethanol elimination in alcoholics with special reference to variants of maximal values for legal calculation of blood alcohol concentration]. / Die Athanol-Eliminationsgeschwindigkeit bei Alkoholikern unter besonderer Berücksichtigung der Maximalwertvariante der forensischen BAK-Rückrechnung.

The ethanol elimination rate was measured in 15 male alcoholics who had come to the Psychiatric Clinic of the University of Tübingen as in-patients. Over the course of several hours between 3 and 5 blood samples were taken in the post-absorption phase. The hourly elimination rate, calculated by lines of regression, gave a mean value of 0.224 g/kg (s = 0.038 g/kg). This was significantly higher than the elimination rate for non-alcoholics calculated from drinking experiments found in the literature (p less than 0.001). In addition 2 blood samples were taken several hours apart from each of 39 alcoholics. Based on the results of the analysis of the second blood sample, the value of the first blood sample was calculated back using the maximum value formula employed in foro. The calculated maximum values were compared to the analysis values. In 8 cases the analysis value was higher than the calculated maximum value, exceeding it by as much as 0.74 g/kg. It should be considered whether the formula currently employed to calculate the maximum BAC is sufficiently accurate in alcoholic to exclude possible false detrimental values.

[Fatalities in drug dependent patients: suicide or accident?]. / Todesfälle von Drogenkonsumenten: Suizid oder Unfall?

The investigation is based on the evaluation of 87 fatalities arising from drug addiction in autopsy material at the Institute for Forensic Medicine, Tübingen. When considered individually there were 76 cases of intoxication, 10 deaths due to external forces and one death due to natural internal causes as a result of drug abuse. The investigation was mainly concerned with the differentiation between suicide or accidental death in the intoxication group. Amongst the total of 76 cases we found 12 to be indisputable or probable suicides and 44 to be indisputable or probable accidents. The remaining 20 could not be classified with sufficient certainty. With the exception of the existence of a farewell letter there were no single meaningful differentiation criteria. There are indications which in themselves are not strong pointers but which, when considered together, allow a cautious interpretation. Finally the question is discussed as to how far the character changes typical in drug addiction can be explained by a latent suicidal tendency with quoad vitam fatalistic indifference.

[Suicide with a supposedly safe plant growth regulator]. / Selbsttötung mit einem als unschädlich geltenden Pflanzenwachstumsregler.

The suicide of a young man with the plant growth regulator Cycocel (chlorocholine chloride and choline chloride) is reported. Morphological and toxicological findings are presented. According to the manufacturers this product is harmless. So far cautionary labelling is not required. A discussion is given on whether such active substances should be subject to stricter controls.

[Factors influencing ethanol determination in urine using the TDx system]. / Störeinflüsse auf die Athanolbestimmung im Harn mittels TDx.

The quantification of ethanol in urine samples and the susceptibility to trouble by Abbott Radiative Energy Attenuation (REA) was evaluated and compared with results by gas-chromatography (GC) and by ADH-technique. REA technique shows good reproducibility and specificity, but concerning accuracy Abbott's REA gives always lower results comparing those obtained by GC and ADH.

Inhibition of non-specific leukocyte esterase activity. Absence of monocyte esterase activity due to phosphoric and thiophosphoric acid ester intoxication.

In vitro evaluation of the effect of five insecticidal phosphoric and 11 thiophosphoric acid esters on different, non-specific human leukocytes esterases indicated that most of the organic phosphor compounds studied inhibited the activity of neutral alpha-naphthylacetate esterase, alpha-naphthylbutyryl esterase, and naphthol AS acetate esterase, i.e. the monocyte esterases. The extent of inhibition was dose dependent; the inhibiting dose being identical for the various non-specific esterases. Reactivation with Obidoxim was not successful. Monocyte esterase activity in a human survivor of E 605 intoxication was detectable only after serum acetylcholinesterase had returned to normal levels. The organic phosphor compound studied, however, inhibited neither acid alpha-naphthylacetate esterase nor naphthol AS-D chloroacetate esterase activity.

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.

Forensic significance of acetylcholine esterase histochemistry in organophosphate intoxication. Original investigations and review of the literature.

The 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 = E600 and parathion = E605) 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 microgram/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.

[Pharmacokinetic studies after oral and parenteral application of dipotassium chlorazepate (author's transl)]. / Pharmakokinetische Untersuchungen nach oraler und parenteraler Applikation von Dikalium-chlorazepat.

Pharmacokinetic investigations after oral and intravenous application of 50 mg and 100 mg 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carbonic acid (dipotassium clorazepate, DPC, Tranxilium, Tranxène) were conducted with two groups of male subjects (A: N = 7; B: N = 6). DPC and its metabolites, nordiazepam (ND) and oxazepam (OX), were measured in blood and urine. After oral application of DPC the expected metabolite pattern was observed. But after i.v. infection of 50 mg or 100 mg DPC a rapid increase of DPC- and also ND-concentrations in the serum was shown. The pattern of the metabolites excreted in urine differed considerably between the groups with oral and i.v. administration of DPC. The possible causes of rapid biotransformation in the serum are discussed.