Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal) were determined in a balanced crossover study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. Serum concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability was calculated model-independently. The extent of the absolute bioavailability (F) of tramadol in the suppositories, based on AUC data, was 77.0% (point estimate; n = 10) with a 95% confidence interval of 70.8-83.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2933 +/- 304 h.ng/ml (rectal) and 3775 +/- 446 h.ng/ml (i.v.) [mean +/- SD; n = 10]. Optimal curve fitting of the serum concentration data after rectal administration presupposed the existence of two absorption sites with different absorption rates and lag times. Under this premise the absorption half-lives were t1/2,ka;1 = 1.7 h (median; range: 1.1-3.1 h) and t1/2,ka;2 = 0.98 h (0.35-1.9 h), and the corresponding lag times were t0;1 = 0 h (0-0.37 h) and t0;2 = 0.66 h (0.31-3.5 h). The relative portion of the more rapidly absorbed quantity of tramadol varied between 9.2 and 50% (median: 28%). The maxima of the serum concentration curves were reached 2-6 h after rectal administration; the means of the individual maxima were 294 +/- 50 ng/ml (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) were 1.38 +/- 0.47 h (rectal; n = 10) and 1.78 +/- 0.63 h (i.v.; n = 7). In the terminal phase the biological half-life (t1/2, beta) was 5.7 +/- 1.0 h (rectal) and 5.7 +/- 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCl, probably due to a reduced first-pass metabolisation after rectal administration.

[Causes of pediatric mortality in a medieval skeletal series]. / Ursachen von Kindersterblichkeit in einer hochmittelalterlichen Skelettserie.

Critical episodes in the life of prehistoric children can be traced by comprehensive palaeopathological investigations of frequently occurring symptoms like criba orbitalia, porotic hyperostosis and Harris' lines, combined with the evaluation of growth curves. Among the children of a skeletal sample excavated in Schleswig (northern Germany, 11th/12th century AD), two periods of growth retardation were observed. The first one, starting between 1 and 2 years of age, is due to malnutrition already set on in the second part of the first year of life and a high morbidity at weaning age. After a catch-up growth between 6 and 7 years of age, living conditions became even worse for the 8 to 10 year old children. It is presumed that an inadequate nourishment did not fit the requirements of the prepuberal organism, especially regarding the considerable high working-burden of children in medieval times after completing their 7th year of life. The combined effect of malnutrition and diseases is responsible for the high mortality of the children in medieval Schleswig.

Causes of infant mortality in the Middle Ages revealed by chemical and palaeopathological analyses of skeletal remains.

In most prehistoric and historic populations, mortality of small infants is very high. Causes of death are mainly discussed in analogy to the situation in modern preindustrial societies. The children are at high risk to fall ill or even die especially in times of weaning. Trace element analysis of the skeletal remains of small infants excavated in Schleswig (northern Germany, 11th/12th century AD) led to the estimation of weaning age as well as to the reconstruction of a stepwise substitution of mothers' milk by other food items. Subsequent palaeopathological analysis confirmed high mortality in this age-group. Thus, causes of death of small infants in a medieval town can be outlined.

Bioavailability of enteral tramadol formulations. 1st communication: capsules.

The absolute bioavailability of tramadol hydrochloride (rac-1(e)-(m-methoxyphenyl)-2-(e)-(dimethylaminomethyl)cyclohexan- 1(a)-ol hydrochloride, CG 315) after the oral administration of Tramal capsules was determined in a balanced cross-over study in 10 male volunteers. Each volunteer received two single doses of 100 mg tramadol hydrochloride, one by oral (2 Tramal capsules) and one by intravenous route (2 ampoules of Tramal 50 solution for injection). The formulations were administered in the morning on an empty stomach, and the interval between the two applications was one week. Serum concentrations of tramadol were determined by gas chromatography-mass spectrometry and the bioavailability was ascertained by calculation of the areas under the serum concentration curves. The absolute bioavailability of tramadol in Tramal capsules was 68 +/- 13% (means +/- SD; n = 10) with a range of 41-84% and a 95% confidence interval of 55.0-79.2%. The areas under the serum concentration curves of tramadol hydrochloride (AUC) were 2488 +/- 774 ng X h/ml (p.o.) and 3709 +/- 977 ng X h/ml (i.v.). Peak serum concentrations of 280 +/- 49 ng/ml were reached 2 h after oral administration of two Tramal capsules; a serum concentration of 100 ng/ml (assumed as the threshold value for analgesic efficacy) was reached after 0.68 +/- 0.17 h and was maintained for 9.0 +/- 2.2 h. The half-life of absorption was 0.38 +/- 0.18 h and the lag-time 0.48 +/- 0.14 h. In the terminal phase the biological half-lives of tramadol were 5.1 +/- 0.8 h (p.o.) and 5.2 +/- 0.8 h (i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

[Bioavailability of penicillin V in aqueous dosage forms]. / Bioverfügbarkeit von Penicillin V in einer wässrigen Zubereitungsform.

The bioavailability of Megacillin-oral-Trockensaft (active substance: potassium salt of phenoxymethylpenicillin, penicillin V potassium) was compared with that of another commercially available drug containing the same active substance. In a cross-over study, 12 healthy volunteers were administered by oral route 10 ml of each preparation (equivalent to 600 000 U = 392.2 mg potassium salt of phenoxymethylpenicillin) under standardized experimental procedure. Relative bioavailability was assessed by determination of phenoxymethylpenicillin concentrations in the plasma, employing both microbiological assay as well as high-performance liquid chromatography, by computation of the areas under the plasma concentration curves, and by calculation of the time periods necessary for the attainment of maximum plasma concentrations. In order to assess differences between the two forms in duration of efficacy, calculation of time intervals were based on plasma concentrations which were above 0.5; 1.0 or 1.5 micrograms/ml, respectively. Results of this comparative study indicate that Megacillin-oral-Trockensaft is superior to the other commercial preparation. The considerably better bioavailability of Megacillin-oral-Trockensaft is attributed to a substantially higher absorption rate and to a 2.4 times greater extent of absorption. Due to the distinct advantage in the bioavailability of Megacillin-oral-Trockensaft peak plasma concentrations of phenoxymethylpenicillin 5-6 fold higher and are reached faster when compared with those following intake of the other form tested. In practice, the superior bioavailability of Megacillin-oral-Trockensaft guarantees quicker initiation of therapeutic activity and greater safety (higher plasma concentrations, prolonged effect).

[On separation of isomeres, structural elucidation and pharmacological characterization of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (author's transl)]. / Uber die Isomerentrennung, Strukturaufklärung und pharmakologische Charakterisierung von 1-(m-Methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol.

1-(m-Methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (L 201) was split into the cis- and trans-isomers and the conformations of the two isomers were determined by 13C-NMR-spectroscopy. Molecule models showed that both conformeres were similar to the geometrical structure of morphine. The adaptation of the morphine structure was better with the more active trans-isomer than with the cis-isomer. Tramadol, the trans-isomer, was separated into its optical antipodes. When tested for analgesia in the electro-stimulation test with mice, all compounds showed analgetic activity. The trans-isomer was more active than the cis-isomer and the (+)-form of the trans-isomer was more active than the (--)-form. Given by s.c. route, the (+)-transisomer E 382 was 1/3 as active as morphine. However, the Straub-tail reaction and the withdrawal jumping tests yielded more favourable results with L 201 and tramadol than with E 382.

[General pharmacological studies on tramadol, a potent analgetic agent (author's transl)]. / Allgemeine pharmakologische Untersuchungen mit Tramadol, einem stark wirkenden Analgetikum.

The general pharmacological properties of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal) are described and compared with those of other strong narcotic analgetics. In behavioral studies tramadol in high doses had a primarily stimulating effect in mice and rats and a sedative effect in rabbits and dogs. The Straub tail phenomenon, a reaction typical for mice administered morphine, was observed only after subtoxic doses of tramadol. In i.v. doses tramadol generally caused a weak central inhibition of non-stimulated and electrically stimulated brain activity in unanesthetized rabbits. Muscle tone and motor coordination in rats and mice were only slightly affected by the drug, in contrast to the effect of morphine. Unlike other strong analgesics tramadol in doses of 5--20 mg/kg i.v. did not cause respiratory depression and even clearly increased respiratory volume and rate in conscious rabbits and anesthetized dogs. In cats and dogs i.v. doses of tramadol up to 10 mg/kg were well tolerated in the cardiovascular system. Tramadol has a slight, papaverine-like spasmolytic effect and no effect on gastrointestinal motility or urinary and electrolyte excretion. The drug showed no antipyretic properties in rabbits. It inhibited edema in rats and guinea pigs but had no antiproliferative effect in the cotton pellet test in rats. Tramadol did not inhibit monoamine oxidase activity or cause enzyme induction in the rat liver.

[Pharmacological investigations with the combination sulfamoxole/trimethoprim, a new broadspectrum chemotherapeutic agent (author's transl)]. / Pharmakologische Untersuchungen zur Verträglichkeit der Kombination Sulfamoxol/Trimethoprim (CN 3123), eines neuen Breitbandchemotherapeutikums

Investigations were conducted with the combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) in a dose ratio of 5:1, with respect to pharmacological activity and possible side effects. The effects obtained with the combination CN 3123 were compared with those of the single substances. In a dose range comparable to that as used in clinical treatment, there were no effects on cardiovascular or respiratory functions, on functions of autonomic and central nervous system, on contractility of smooth muscles and on data of clinical chemistry such as urine and electrolyte excretion, blood sugar, blood coagulation and liver function tests. Doses which are 5 to 10 times higher than the initial dose or 10 to 20 times higher than the maintenance dose used in man caused an increase of urine and sodium excretion without influencing potassium and chloride output. There were no signs of sedation as alteration of motility or EEG patterns, but in mice and rats there was an increase in both duration and depth of anaesthesia caused by barbiturates or ether. Only in a dose range 30 to 40 times higher than the initial dose for man there were some slight alterations with respect to cardiovascular system and liver function tests. In vitro, with high concentrations of CN 3123 there was a weak, unspecific spasmolytic effect on the isolated ureter and an increase in the refractory period of the guinea pig atrium. There were no hints that the side effects seen with separate administration of high or very high doses of sulfamoxole or trimethoprim were increased or poteniated by their simultaneous administration. Slight side effects in animals were only observed with doses exceeding the tenfold of the doses for therapeutic use in men. Therefore, the therapeutic range of CN 3123 seems to be more than adequate.