Discovery of altered pharmacokinetics of CGP 15 210 G in poor hydroxylators of debrisoquine during early drug development.

The pharmacokinetics of CGP 15 210 G, a new 5-HT uptake inhibitor in poor and extensive metabolisers of debrisoquine, give indirect evidence of an association between its metabolism and polymorphic hydroxylation of the debrisoquine type.

Non-linear elimination processes of theophylline.

After intravenous and oral administration of theophylline to four healthy subjects, the plasma concentration-time curve of theophylline could be described by linear pharmacokinetics, although total clearance in all subjects decreased when the dose was increased; the doses were theophylline 193.2 mg and 386.4 mg i.v. and 161 mg and 322 mg p.o. Total clearance was 65.5 +/- 11.3 ml/min. Renal clearance changed from 15.2 +/- 9.5 ml/min in the first two hours after administration to 4.9 +/- 5.5 ml/min between 16 and 24 h (p less than 0.001). 1,3-dimethyluric acid (DMU), the major metabolite of theophylline, was determined in urine and in plasma. The renal clearance of DMU was constant at 496.7 +/- 180 ml/min. There was some evidence that at high plasma concentrations of theophylline the formation of DMU might be a zero-order process. The renal excretion rate of 1-methyluric acid (1-MU) paralleled that of DMU, which is in accordance with the assumption that DMU is demethylated to 1-MU. 3-methylxanthine (3-MX) was excreted in urine at a constant rate over 10 h, the rate being equivalent to the dose, which is contrary to the assumption of Michaelis-Menten-kinetics. 3-methyluric acid was found to be a minor metabolite of theophylline and 1-methylxanthine (1-MX) could not be detected. The cumulative amounts excreted in urine, expressed as a percentage of the dose and corrected for molecular weight, were theophylline 16.6 +/- 6.5%, DMU 44.3 +/- 7.0%, 1-MU 24.3 +/- 4.8%, 3-MX 12.9 +/- 3.4% and 3-MU 2.2 +/- 1.8%.

[The effects of nicotine on the circulation and metabolism after cigarette smoking with reference to the plasma levels of nicotine and COHb (author's transl)]. / Nikotinwirkungen nach Zigarettenrauchen auf Kreislauf und Stoffwechsel unter Berücksichtigung der Plasmanikotin- und CO-Hb-Spiegel.

The effects after smoking cigarettes with different nicotine content (1.5 mg and 0.08 mg nicotine/cigarette) were investigated in 6 healthy habitual smokers. Carboxyhemoglobin (COHb) and plasma nicotine levels were determined at the same time as circulatory parameters, heart rate and blood pressure together with metabolic parameters like blood sugar, lactate, free fatty acids and plasma dopamine-beta-hydroxylase (DBH) and plasma cortisol. With the exception of COHb the parameters investigated were shown to be dependent on the nicotine levels. For blood pressure, heart rate and lactate the peaks appeared simultaneously with the maximum nicotine levels, whereas for DBH, cortisol, blood sugar and the free fatty acids there was a delayed reaction in comparison with the nicotine levels. The parameters investigated are not affected by COHb with levels up to 5.6 +/- 0.5%. These results show that after cigarette smoking, nicotine causes considerable changes in the circulation and metabolism.

Acute cardiovascular reactions after cigarette smoking.

The effect of cigarette smoking on the cardiovascular system was determined in the following way: Two cigarettes of relatively high (1.54 mg) and very low (0.08 mg) nicotine content were smoked and compared to sham smoking. After inhalation under standardized conditions there was a relatively high increase of the plasma nicotine levels and a subsequent exponential decrease. Two hours after smoking the levels were still elevated. After 2 low nicotine cigarettes there was a significant small short-term increase. The changes of the pulse rate were directly related to the nicotine levels and the pulse pressure transit time from the heart to the calf and the digital blood flow was indirectly related to them. The regulation of these parameters is exactly related with the nicotine levels probably through the release of catecholamines. The cardiovascular reactions after smoking may indicate the additional myocardial work load after cigarettes of different nicotine content.

Evaluation of smoking-induced effects on sympathetic, hemodynamic and metabolic variables with respect to plasma nicotine and COHb levels.

The effect of smoking cigarettes containing 1.5 mg and 0.08 mg nicotine per cigarette and of sham-smoking was studied in six healthy habitual smokers. Levels of carboxyhemoglobin (COHb) and plasma nicotine were measured simultaneously with hemodynamic variables, such as heart rate and blood pressure, and with the metabolic parameters, plasma DBH, cortisol, blood glucose, lactate and free fatty acids. All variables, with the exception of COHb are dose related to plasma nicotine levels. Blood pressure, heart rate and lactate show simultaneous peaks together with maximal nicotine levels, while DBH and cortisol, blood glucose and free fatty acids show a delayed reaction compared to nicotine concentrations. No effects of COHb, even with levels up to 5.6 +/- 0.5% have been observed on the variables investigated. These results demonstrate, that it is nicotine which induces considerable hemodynamic and metabolic alterations after smoking.

[Pharmacological study on treptilamine in man/study on tolerability (author's transl)]. / Humanpharmakologische Untersuchungen zu Treptilamin Eine Verträglichkeits-Studie.

N,N-Diethyl-N-(2-[alpha(tricyclo[2,2,1,0(2,6]hept-3-ylidene)-benzyloxy]-ethyl)amine hydrochloride (treptilamine) which in experiments on animals showed distinct spasmolytic effects, has been investigated first in 6 volunteers with regard to compatibility using different doses p.o. and i.v. In connection with this previous study a double blind study including placebo was performed for verification of the observed effects. In the plot study 30, 40 and 50 mg were applied orally and 10, 15 and 20 mg treptilamine were used i.v. The double blind study was designed for 20 volunteers at dosages of 40 mg p.o. and 15 mg i.v. against placebo. In the pilot study systolic blood pressure decreased significantly 5 to 15 min after i.v. application of the substance for 5 or 30 min. The range of accommodation was restricted depending on the dose used. No alteration of circulation was observed after oral application at any dose. All volunteers felt tired. A significant decrease of systolic blood pressure (15 mmHg for 10 min immediately after application) occurred after 15 mg of substance were applied i.v. in the double blind study. No effect on circulation could be seen after placebo. The range of accommodation was restricted in a significant way both after i.v. application (40%) and after oral application (30%). Two of five volunteers recorded a burning sensation in the venous wall which was followed by drowsiness. One volunteer felt increasingly tired after oral application. No influence of the substance could be seen on the clinicochemical parameters examined.

High-performance liquid-chromatographic determination of free nicotinic acid and its metabolite, nicotinuric acid, in plasma and urine.

We report a liquid-chromatographic procedure for determining free nicotinic acid and a metabolite, nicotinuric acid, in plasma and urine. Five-tenths milliliter of urine or deproteinized plasma is evaporated and the residue analyzed isocratically by reversed-phase ion-pair chromatography, with measurement of the eluted nicotinic acid and nicotinuric acid at 254 nm. Nicotinic acid, nicotinuric acid, and the internal standard (isonicotinic acid) have retention times of 7.8, 8.4, and 6.8 min, respectively, in plasma, and 12.3, 13.1, and 10.8 min in urine, because of double column length. Day-to-day reproducibilities (CV) for nicotinic acid and nicotinuric acid within 7.5% are attainable for the concentration ranges 0.1--20 mg/liter, equivalent to 0.81--162 micromol of nicotinic acid and 0.55--11 micromol of nicotinuric acid per liter for plasma; in urine for the range 0.5--100 mg/liter, equivalent to 4--810 micromol of nicotinic acid and 2.8--555 micromol of nicotinuric acid per liter. Metabolites of nicotinic acid such as nicotinamide, N-methylnicotinamide, 2-hydroxypyridine-5-carboxylic acid, and other structurally related substances do not interfere.

Gas-liquid chromatographic determination of nicotine and cotinine in plasma.

We report a procedure for determining nicotine and cotinine in plasma. Nicotine is extracted from 1 ml of plasma with diethyl ether, back extracted, and analyzed by gas-liquid chromatography with a nitrogen/phosphorus detector. Nicotine and its internal standard, modaline, had retention times of 1.9 and 2.9 min, respectively. Cotinine is then extracted from the same plasma with dichloromethane and similarly analyzed. Cotinine and its internal standard, lidocaine, had retention times of 3.8 and 4.9 min. Day-to-day reproducibilities (CV) within 14% for nicotine and within 6% for cotinine are attainable for the respective concentration ranges 1-100 microgram/liter and 1-200 microgram/liter. Nornicotine and related alkaloids do not interfere. The sensitivity was such that less than 0.1 microgram (0.62 nmol) of nicotine and 0.1 microgram (0.62 nmol) of nicotine and 0.1 microgram (0.57 nmol) of cotinine could be detected per liter.