Population pharmacokinetics of mefloquine in military personnel for prophylaxis against malaria infection during field deployment.

OBJECTIVE: The purpose of this study was to determine the population pharmacokinetics of mefloquine in healthy military personnel during prophylaxis for malaria infections. METHODS: The subjects were 1,111 Australian soldiers participating in two studies: a randomised double-blinded study (group A, 161 subjects) and an open-label study (group B, 950 subjects). Following a loading dose (250 mg mefloquine base daily, 3 days), subjects received an oral weekly maintenance dose of 250 mg over 6 months. Blood was collected after the last split loading dose then at weeks 4, 8 and 16 for group A, and at weeks 13 and 26 for group B. Plasma mefloquine concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic modelling was performed using NONMEM. RESULTS: A two-compartment model with inter-occasion variability (IOV) for clearance satisfactorily described the pharmacokinetics. Typical values were clearance (CL/F, 2.09 l/h), central volume of distribution (V1/F, 528 l), absorption rate constant (KA, 0.24 h(-1)), inter-compartmental clearance (Q/F, 12.5 l/h), peripheral volume of distribution (V2/F, 483 l) and elimination half-life (t (1/2), 14.0 days). Weight had a positive influence on central volume but was insufficient to warrant dosage adjustments. The inter-individual variability (coefficient of variation, CV%) for CL/F and V1/F was 24.4% and 29.6%, respectively. The IOV for CL/F was 17.8%. The proportional residual error (CV%) for groups A and B was 11.5% and 19.5%, respectively, and the additive error standard deviation (SD) was 57 ng/ml and 149 ng/ml, respectively. CONCLUSION: The typical parameter values were comparable with those estimated in much smaller cohorts of healthy subjects and in malaria patients treated with single-dose mefloquine. The lower unexplained variability in the blinded study suggested these subjects may have been more compliant in taking their medication than soldiers in the open-label study.

Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics.

OBJECTIVES: To compare the relative systemic dose potency and tolerability of inhaled formoterol and salbutamol and to describe elimination of formoterol, particularly any enantioselectivity. METHODS: Twelve healthy subjects, aged 18-28 years, completed three open study days, and eleven asthmatic patients, aged 20-56 years, completed four double-blind study days in randomised, placebo-controlled and crossover fashions. The healthy subjects inhaled 13.5 + 13.5 + 27 microg formoterol (Oxis) via Turbuhaler and 300 + 300 + 600 microg salbutamol (Ventoline) via a pressurised metered dose inhaler (pMDI). The asthmatics, being on formoterol 9 microg twice daily via Turbuhaler during the study, inhaled the same single doses as the healthy subjects plus 900 + 900 + 1800 microg salbutamol via pMDI. Doses were given cumulatively 30 min apart on separate study days. Placebo was a day of no treatment in the healthy subjects. Double dummies were used for the asthmatics. Cardiovascular and metabolic effects were evaluated. Elimination of formoterol was addressed in the healthy subjects. RESULTS: Formoterol was estimated to be 28-109 times as potent as salbutamol, depending on the systemic effect variable. The duration of systemic action seemed to differ marginally at approximately equieffective doses of formoterol and salbutamol. Systemic effects were well tolerated and tended to be more pronounced in the healthy subjects than in the asthmatic patients. The half-life of the pharmacologically more active (R;R)-formoterol was longer than that of (S;S)-formoterol. CONCLUSIONS: Systemically, formoterol was shown to be 28-109 times as potent as salbutamol. Equieffective doses seemed to have a similar duration of effect. Formoterol and salbutamol were well tolerated by healthy subjects up to the tested total doses of 54 microg and 1200 microg, respectively, and by asthmatic patients up to the tested total doses of 54 microg and 3600 microg, respectively. Elimination of formoterol was enantioselective.

Integration of press-fit implants in cortical bone: a study on interface kinetics.

The early healing phase of hard tissue implants is important to their long-term success. Problems during this phase can result in a so-called primary biological failure. In 24 New Zealand white rabbits, the healing in cortical bone of noncoated TiAlV and cpTi cylinders and of TiAlV cylinders plasma-spray-coated with hydroxyapatite (HA) of fluorapatite (FA) was investigated histologically and histomorphometrically after 3, 7, 14, and 28 days. Histomorphometry consisted of bone contact measurements and the use of a new semi quantitative scoring system that discriminated various tissues in contact with the implant. The results demonstrated that the most important parameter in initial implant healing is the bone itself and not the characteristics of the implanted material. For all implants, healing was characterized by a sequence of hematoma formation, bone resorption, and new bone formation where the initial press-fit situation revealed more bone-implant contact than after 7 and 14 days. There were only minor differences between the implant types: the new bone formation directly on the implant surface was qualitatively histologically superior to the CaP-coated implants, but this could be confirmed with the scoring method only for the HA-coated implants. It is concluded that initial press-fit fixation in cortical bones is not an end situation; rather, what happens is that as a result of interface remodeling, early postoperatively implant integration in the bone will decrease temporarily prior to a subsequent phase of new bone formation.