Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines.

Metabolic oxidative profiles of diazepam (I) were obtained by aromatic C-4'-hydroxylation, N-1-demethylation, and 3-hydroxylation using a supernatant of rat liver. Incubation of 3-methyldiazepam (VI), which suppressed 3-hydroxylation, and N-1-nor-3-methyldiazepam (VII), were used to separately investigate these three oxidative pathways. Treatment of animals with phenobarbital enhanced N-1-demethylation and 3-hydroxylation, and to a variable extent C-4'-hydroxylation. Application of metyrapone reduced metabolite formation by 3-hydroxylation and N-1-demethylation, but had no effect on C-4'-hydroxylation. Metyrapone inhibition was more pronounced following than prior to phenobarbital treatment. C-2-hydroxylation was studied using medazepam (XX) incubations. This pathway was increased by phenobarbital pretreatment and reduced by metyrapone inhibition which was again more pronounced following than prior to phenobarbital pretreatment. These results support earlier conclusions on the heterogeneity of liver microsomes and suggests the presence of different species of hepatic microsomal terminal oxidases. Phenobarbital treatment and metyrapone change the metabolic profile via induction and inhibition, respectively, and, thus, in the case of 1,4-benzodiazepines, the formation of metabolites with varying pharmacological activity. This could become important in clinical situations as a diagnostic mean to determine induction under various treatment or, possibly, during cumulation of metabolites with a long half-life.

Effects of thiopentone and etomidate on median nerve somatosensory evoked responses.

Somatosensory evoked potentials (SEP) after median nerve stimulation were recorded in 40 patients during infusion of either 15 mg/kg bw thiopentone or 1 mg/kg bw etomidate (n = 10) within 15 min and after 0.3 mg/kg bw etomidate (n = 20). Marked alterations of SEP waveforms and changes in latencies were observed in all patients. Central conduction time (CCT) was significantly correlated to plasma thiopentone concentration. Infusion of high doses of thiopentone and etomidate was followed by a complete loss of middle and long latency components. Amplitude of the primary cortical SEP N20 was found to be unchanged after thiopentone and to be increased after etomidate, indicating the synchronizing properties of this drug. A pronounced increase in SEP latencies and CCT and waveform alterations have to be considered during hypnotic drug administration in intensive care medicine and intraoperatively.

Aerosolized amiloride: dose effect on nasal bioelectric properties, pharmacokinetics, and effect on sputum expectoration in patients with cystic fibrosis.

Aerosolized amiloride normalizes the excessive sodium absorption cystic fibrosis (CF) respiratory epithelium. The aims of this study were to assess the dose-effect relationship and the duration for which amiloride inhibits Na+ transport, to determine acute and chronic pharmacokinetics, and to test the effect of acute aerosolized amiloride on the amount of sputum expectorated. The effect of inhaled amiloride was assessed principally by nasal potential difference (PD) measurements. Amiloride serum levels were measured in 23 patients after inhalation of different doses of aerosolized amiloride. Twenty CF patients inhaled amiloride (10(-3)M) or a placebo in a double-blinded, randomized order, and sputum production was quantitated. The results of this study showed that maximal initial PD inhibition was achieved by 6 x 10(-3)M of amiloride. The duration of inhibition of PD (effective time until return to 50% delta PD [ET50] after nasal administration) was dose dependent (10(-3)M, 39 +/- 0.8 minutes; 10(-2)M; 133 +/- 14 minutes). Amiloride serum levels were below 2.5 ng/ml in 20 of 28 patients; levels were above 5 ng/ml only within 4 hours after high dose inhalation (10(-2)M). In the double-blinded, crossover study, more sputum was expectorated after amiloride inhalation as compared with that after a placebo (P < 0.05). In conclusion, the bioelectric effects of amiloride and serum levels after inhalation are dose dependent, and amiloride is effective at inducing sputum expectoration in CF.

[Health education for chronic liver and pancreatic diseases: Discussion groups "chronic liver disease" (CL), "chronic pancreatic disease" (CP)]. / Schulung bei Leber- und Pankreaserkrankungen: Gesprächsgruppe "Chronische Lebererkrankungen" (CL) /"Chronische Pankreaserkrankungen" (CP).

The article deals with our experience in the educational programs for patients with chronic liver diseases and chronic pancreatic diseases.The structure of our educational programs is modular, the main event is the discussion group "Chronic Liver Diseases" (CL) (2 meetings are headed by physicians, 1 by psychologists, duration in all 3,6 hours) respectively the discussion group "Chronic Pancreatic Diseases" (CP) (2 meetings headed by physicians, 1 by nutrition consultants, duration in all 2,6 hours). As needed, additional modules can be added, for example specific seminars in case of alcohol abuse or educational programs for diabetics. The average number of participants is between 7 - 15 persons in the discussion group CL, respectively 11 - 20 in the discussion group CP. An overhead projector is used to address the various topics, the patients are encouraged to actively participate in the discussion. The contents can be found in a structured curriculum and focus on anatomical basics, diagnostic and therapeutic aspects, physical fitness and performance in professional life.

Influence of increased catecholamine levels in blood plasma during cold-adaptation and intramuscular infusion on thresholds of thermoregulatory reactions in guinea-pigs.

Catecholamines and some of their metabolites were determined in urine and blood plasma of guinea-pigs before, during and after acclimation to a cold or warm environment. During adaptation to 5 degrees C the amounts of noradrenaline in plasma and 24-h urine samples continuously increased up to 600% compared with values obtained at an ambient temperature of 22 degrees C. Higher levels of dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol further indicated an increased turnover of noradrenaline during cold adaptation. Acclimation to an ambient temperature of 28 degrees C reduced the peripheral release of noradrenaline in comparison to the release observed at 22 degrees C. Cold-induced increases in metabolic rate and electrical muscle activity both occur at a considerably lower mean body temperature in cold-than in warm-adapted guinea-pigs. The shift of thermoregulatory cold defence reactions to a lower mean body temperature could also be observed in warm-adapted animals after intramuscular infusion of noradrenaline in amounts comparable to those released during cold adaptation. It is concluded that high peripheral sympathetic activity directly or indirectly inhibits noradrenergic neurons in the lower brain stem that modulate the thermoregulatory control system by means of their afferents to the hypothalamus. As a consequence of this peripheral influence the thermoregulatory set point is shifted to a lower mean body temperature.

[Monitoring long-term therapy with theophylline preparations in children with asthma]. / Die Uberwachung der Langzeittherapie mit Theophyllin-Präparaten bei Kindern mit Asthma.

In 78 children (4 to 17 years of age) with moderate or severe asthma who were additionally treated with sustained-release theophylline preparations, different ways of drug monitoring were examined. Analysis of plasma and saliva theophylline was performed by means of high performance liquid chromatography. Saliva theophylline turned out to permit a reliable prediction of plasma theophylline, if an individual regression is calculated for each patient, basing on 3 simultaneously performed measurements of theophylline levels in saliva and plasma within the therapeutic range of 8 to 20 mg/l. In 25 patients theophylline levels were determined in venous and capillary blood. There was an excellent agreement (r = 0.97). Thus, a convenient monitoring of theophylline treatment in children is possible.

[Somatosensory evoked potentials under thiopental and etomidate]. / Somatosensorisch evozierte Potentiale unter Thiopental und Etomidat.

The somatosensory evoked potential in response to median nerve stimulation was recorded in 42 patients during infusion of either 15 mg/kgbw thiopentone (TH) or 1 mg/kgbw etomidate (E) within 15 min and before and after injection of 0.3 mg/kgbw etomidate bolus. Cortical and cervical responses were analysed simultaneously and central conduction time (CCT) was calculated. Marked alterations of waveforms and an increase in latency of the primary cortical SEP and of CCT were observed in all patients. Infusion of TH or E was followed by a diminution of middle and long latency components. Amplitude of the cortical N20 was found to be unchanged during and after TH and to be increased after infusion or injection of E, indicating the synchronizing properties of this drug. The cervical SEP (N14) remained entirely unchanged in response to both agents. During hypnotic drug administration a pronounced increase in latencies and CCT as well as a decrease in the number of identifiable peaks has to be considered when SEP monitoring is performed intraoperatively or in intensive care treatment.

Screening, identification and quantitation of benzodiazepines in serum by solid phase extraction on a cyanopropyl phase using high performance liquid chromatography and photodiode array detection.

A screening procedure for benzodiazepines in serum is presented. The compounds are extracted over a cyanopropyl phase followed by identification and determination via high performance liquid chromatography and photodiode array detection. Diazepam (CAS 439-14-5), flunitrazepam (CAS 1622-62-4), nordazepam (CAS 1088-11-5), oxazepam (CAS 604-75-1) and temazepam (CAS 846-50-4) are quantified. Retention data of 42 benzodiazepines and their metabolites as well as hydrolysis products are listed. This assay leads to an expansion of a known systematic toxicological analysis system to identify pharmaceuticals, drugs of abuse and pesticides.

Determination of uracil and thymine and their nucleosides and nucleotides in picomole amounts by gas chromatography mass spectrometry selected ion monitoring.

A stable isotope dilution method is presented by which uracil (Ura) and thymine (Thy) can be determined with high precision and sensitivity at the picomole level utilizing stable isotope dilution and gas chromatography electron impact mass spectrometry in the selected ion monitoring mode. [15N2]Ura and [2H3]Thy served as internal standards. The molecular ions as well as the [M-CH3]+ ion fragments of silylated Ura and Thy (Ura-TMS and Thy-TMS) were suitable for the assay which provides evidence of specificity, if identical results are obtained at both ions. Nucleosides and nucleotides of Ura and Thy were determined following quantitative hydrolysis in 6 N HCl at 180 degrees C for two hours. Other hydrolysis procedures did not give satisfactory results. Levels of free Ura and Thy were measured in human and rat plasma after solvent extraction with a sensitivity of 20-40 pm ml-1 demonstrating ready applicability of the assay method to biological samples. The potential physiological role of circulating Ura and Thy is discussed.

[Elimination of secretions in CF patients under amiloride inhalation]. / Sekretelimination bei CF-Patienten unter Amiloridinhalation.

Inhaled amiloride reduces active absorption of sodium of respiratory epithelium in CF patients and so, transiently, diminishes loss of water. 10 CF patients, 8 to 28 years of age, were examined on two days. First day, they inhaled in a randomised order isotonic saline and a solution of amiloride hydrochloride (0.3 mg/ml) one after another, each inhalation taking twenty minutes. Second day, inhalations were performed in an inverse order. To intensify the effect of inhalation, the inhalation procedure was combined with "autogenic drainage", a special kind of physiotherapy. Main criterion for evaluation was the amount of expectorated sputum. Mean increase of sputum during amiloride inhalation in comparison to saline was +50.4%. Patients and physiotherapist observed a liquefaction of secretion and a decrease of coughing by amiloride and a support of physiotherapy. These results suggest a beneficial clinical effect of regular amiloride inhalation in CF patients.

Influence of prolonged physical exercise on the erythropoietin concentration in blood.

Erythropoietin (EPO) and red blood cells were studied in 15 well-trained men before and several times after a marathon run. Changes in red blood cells reflected changes of plasma volume. Immediately after the run, red blood cells were increased due to haemoconcentration, whereas 31 h later the values were decreased due to haemodilution. The EPO concentration was increased 3 h, and more impressive 31 h, after the run. This long-lasting increase in EPO concentration after the marathon run would seem to be responsible for the increased red blood cell mass in long distance runners.

Determination of ftorafur and 5-fluorouracil levels in plasma and urine.

A gas chromatographic method was developed for ftorafur (Ft) detection in plasma and urine with a sensitivity of 1 mug/ml. Specific determination of its metabolite 5-fluorouracil (FU) with a sensitivity of 1 ng/ml was achieved by column chromatographic separation from Ft and subsequent gas chromatography-mass spectrometry of bis-silyl-FU in the selected ion mode (GC-MS-SIM) using bis-15N-FU as internal standard. Intravenous injections of 2-14C-Ft and 2',5'-14C-Ft were given to rats and rabbits respectively, and plasma and urine were analyzed for Ft, and 14C activity. Unchanged Ft accounted for most of the 14C activity in plasma, while FU concentrations were below 0.15% and 0.4% relative to Ft concentrations in the rabbit and the rat, respectively. 30-60% of the urinary 14C activity was unchanged Ft and less than 0.2% FU. The significance or low FU levels is discussed in view of the hypothesis that Ft acts as a transport form of its metabolite FU.