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A thermostable suppository of artesunate (artesunic acid) has been developed. In Gabon, 12 children with Plasmodium falciparum malaria received two administrations of this suppository in a 4-hr interval. Parasitemia and fever were then measured and the plasma levels of artesunate and its active metabolite, dihydroartemisinin, were determined by means of a reversed phase high-pressure liquid chromatography method using reductive electrochemical detection. Substantial parasite clearance (97-100%) was noted 24 hr after the beginning of the treatment and body temperature had returned to normal. Absorption, metabolism, and elimination of artesunate were rapid. Mean values of maximum plasma levels (Cmax) and maximum concentration peak times (tmax) were evaluated. The Cmax of dihydroartemisinin (0.18 Ϯ 0.10 g/ml [mean Ϯ SE]) was higher than the Cmax of artesunate (0.09 Ϯ 0.04 g/ml) and the tmax of dihydroartemisinin (1.13 Ϯ 0.58 hr) was higher than the tmax of artesunate (0.58 Ϯ 0.19 hr). Plasma levels 30 min after the second suppository administration were not consistently higher than those found 30 min after the first administration.

Studies of isoniazid, the well known antituberculosis drug, have revealed that N-acetylation polymorphism, is of great clinical importance. In humans, N-acetylation is one of the most important pathways in the inactivation of isoniazid. Caffeine, which is also biotransformed by N-acetylation, has been widely used as an in vivo probe for the assessment of N-acetyltransferase polymorphism. The activity of N-acetyltransferase can be estimated from the urinary metabolic ratio of two caffeine metabolites, namely, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), and 1-methylxanthine (1X) after the ingestion of caffeine. In the present study caffeine was used as a metabolic probe to determine N-acetyltransferase polymorphism in 83 healthy Greek volunteers by means of the molar ratio of AFMU and IX determined in urine following ingestion of 200 mg caffeine. Frequency distribution analysis of the metabolic ratios AFMU/1X revealed two distinct groups with 66.3% (n = 55) slow acetylators and 33.7 % (n = 28) rapid acetylators. No statistically significant difference was detected between slow and fast acetylators in terms of gender, smoking habits and caffeine-intake habits. These results are in agreement with previous studies on N-acetyltransferase activity in Caucasians using caffeine as a metabolic probe. They also agree with reports on N-acetyltransferase activity in Greek tuberculosis patients using isoniazid as a metabolic probe. Thus, the use of caffeine as a metabolic probe is a reliable method for the assessment of N-acetyltransferase activity in the Greek population.

Probably for genetic reasons a substantial part of the Greek population requires Levothyroxine treatment. Since commercially available Levothyroxine was first marketed, the manufacture and storage of the drug in tablet form has been complicated and difficult; and as cases of therapeutic failure have frequently been reported following treatment with this medicinal agent, quality control is an essential factor. Due to the unreliability of Levothyroxine-based commercial products, in the present study we decided to follow the Food and Drug Administration (FDA) guidelines*, and use a Levothyroxine solution as reference product. The bioavailability of the Levothyroxine sodium tablet formulation THYROHORMONE/Ni-The Ltd (0.2 mg/tab) and that of a reference oral solution (0.3 mg/100 ml) under fasting conditions were compared in an open, randomized, single-dose two-way crossover study. Twenty four healthy Caucasian volunteers (M/F=15/9, mean age=32.9+/-7.4yr) participated in the study. Bioavailability was assessed by pharmacokinetic parameters such as the area under plasma concentration-time curve from time zero up to the measurable last time point (AUC(last)) and the maximum plasma concentration (Cmax). Heparinized venous blood samples were collected pre-dose and up to a 48-hour period post-dose. Levothyroxine sodium in plasma samples was assayed by a validated electrochemiluninescent immunoassay technique. Statistical analysis showed that the post-dose thyrotropin-stimulating hormone (TSH) levels decreased significantly (p<0.05). Regarding Levothyroxine (T4), the point estimate of the test formulation to the reference formulation ratios (T/R) for AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.94) and 0.93 with 90% confidence limits (0.91, 0.94), respectively. Regarding triiodo-L-thyronine (T3), the point estimate for the T/R ratios of AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.95) and 0.94 with 90% confidence limits (0.92, 0.95), respectively. The 90% confidence limits for the pharmacokinetic parameters AUC(last) and Cmax lie within the acceptance limits for bioequivalence (0.80, 1.25), for both T3 and T4.

Sulpiride (SU), a widely used benzamide neuroleptic, is known to promote rapid prolactin release. Sulpiride plasma level and the prolactin response to the most commonly used dose, i.e., 50 and 200 mg sulpiride (administered orally), were studied in ten male volunteers.The design of this study permitted the simultaneous measurement of the sulpiride plasma level for 48 hours, by means of a new HPLC-electrochemical detection method, and of the prolactin level, by means of RIA.Pharmacokinetic study of sulpiride showed that the mean concentration and time of peak plasma level of the two doses were different: 77 ng/rnl SV at 2.3 h for the 50 mg dose and 243 ng/ml at 3.5 h for the 200 mg dose. The absorption and elimination rate constants were similar regardless of the dose (k a: 1.05-1.9 h -I; t 1;2~: 25 h).. A linear relationship of the area under the plasmatic concentration versus time curve with the dose was observed. Mean plasma level decreased for both doses to about 14% of peak value at 48 hours.Prolactin serum levels increased from the basal value after SU administration with marked individual differences. The 200 mg dose resulted in earlier prolactin peak levels (54 ng/ml between 30 min and I h) than the 50 mg dose (50 ng/ml between I and 2 h). The prolactin level then decreased and remained constant at about 15 ng/ml for II to 48 h. Prolactin levels returned to basal values (mean: 5 ng/ml) after one week.It is concluded that therapeutic doses of sulpiride induce prolactin secretion that is dose-dependent in a first phase and stimulated independently of the sulpiride concentration in a second phase. A mechanism of indirect action mediated by PRL is suggested to explain the neuroleptic activity of the drug.