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The receptor involved in the serotonin (5-hydroxytryptamine 5-HT)-induced vasodilatation in the human forearm has not yet been identified. Experimental data point to the 5-HT2Breceptor located on the endothelium. RS-127445 (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropyl-pyrimidine) is a novel potent and selective 5-HT2Breceptor antagonist. The effect of oral RS-127445 (500 mg) on 5-HT-induced vasodilatation was studied in a double-blind, randomized, placebo-controlled, crossover study in six healthy volunteers. On each study day 5-HT (0.5 ng/kg/min) was infused into the brachial artery for 8 min, before drug administration and at intervals of 20, 65, 110, 230, and 470 min after oral ingestion. At each infusion, plasma samples for study drug assay were taken and forearm blood flow was assessed using venous occlusion plethysmography. Although (log) drug concentrations exceeded pKi, there was no correlation between RS-127445 concentrations and 5-HT-induced vasodilatation. 5-HT-induced vasodilatation did not differ between treatments and time points. It appears that there is no functional involvement of 5-HT2Breceptors in 5-HT-mediated vasodilatation in the human forearm.

A randomized, single-centre, cross-over study was designed to compare the bioavailability of two pharmaceutical formulations of recombinant human follicle stimulating hormone (recFSH; Puregon®): (i) a dissolved cake injected by a normal syringe; and (ii) a ready-for-use solution injected using a device referred to as Puregon®Pen. Twenty-two healthy female volunteers underwent one of two administration sequences: Puregon®Pen/syringe or syringe/Puregon®Pen, by which they received a single subcutaneous dose of recFSH (150 IU). Endogenous gonadotrophin production had been previously suppressed using an oral contraceptive (Lyndiol®). Pharmacokinetic parameters characterizing rate [peak concentration (Cmax) and time of peak concentration (tmax)] and extent [area under the curve (AUC) and clearance (CL)] of absorption were obtained from 20 subjects. After injection with both formulations, serum FSH concentrations reached a peak of 3.4 IU/l at 13 h after injection. The elimination half-life was approximately 34 h, irrespective of formulation. A difference of approximately 18% was found between serum FSH concentrations obtained using the two formulations, which was caused by differences between the anticipated and the actual volume injected with the normal syringe. After correction for injection losses by weighing the amount injected with a normal syringe, the two formulations were found to be bioequivalent with respect to Cmax, AUC and CL. For tmax, bioequivalence could not be proven due to high intra-subject variability and broad absorption peaks of FSH. Both methods were well tolerated, local reactions being generally mild and short-lived.

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 ± 1.13 h versus3.85 ± 0.40 h) and serum trough concentrations (46 ± 14 mg/L versus23 ± 7 mg/L) of CAZ were significantly (p< 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 ± 25.1 mL/h versus205.7 ± 55.4 mL/h), CAZ clearance per kg (40.9 ± 6.1 mL/h/kg versus60.8 ± 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 ± 0.43 versus4.73 ± 0.89) were significantly (p< 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.