The calculation of pharmacokinetic/pharmacodynamic surrogates from concentrations in serum has been shown to yield important information for the evaluation of antibiotic regimens. Calculations based on concentrations in serum, however, may not necessarily be appropriate for peripheral-compartment infections. The aim of the present study was to apply the microdialysis technique for the study of the peripheral-compartment pharmacokinetics of select antibiotics in humans. Microdialysis probes were inserted into the skeletal muscle and adipose tissue of healthy volunteers and into inflamed and noninflamed dermis of patients with cellulitis. Thereafter, volunteers received either cefodizime (2,000 mg as an intravenous bolus; n = 6), cefpirome (2,000 mg as an intravenous bolus; n = 6), fleroxacin (400 mg orally n = 6), or dirithromycin (250 mg orally; n = 4); the patients received phenoxymethylpenicillin (4.5 x 10(6) U orally; n = 3). Complete concentration-versus-time profiles for serum and tissues could be obtained for all compounds. Major pharmacokinetic parameters (elimination half-life, peak concentration in serum, time to peak concentration, area under the concentration-time curve [AUC], and AUC/MIC ratio) were calculated for tissues. For cefodizime and cefpirome, the AUCtissue/AUCserum ratios were 0.12 to 0.35 and 1.20 to 1.79, respectively. The AUCtissue/AUCserum ratios were 0.34 to 0.38 for fleroxacin and 0.42 to 0.49 for dirithromycin. There was no visible difference in the time course of phenoxymethylpenicillin in inflamed and noninflamed dermis. We demonstrated, by means of microdialysis, that the concept of pharmacokinetic/pharmacodynamic surrogate markers for evaluation of antibiotic regimens originally developed for serum pharmacokinetics can be extended to peripheral-tissue pharmacokinetics. This novel information may be useful for the rational development of dosage schedules and may improve predictions regarding therapeutic outcome.

Our results indicate that befunolol, metipranolol, timolol, clonidine, and dipivefrin reduce choroidal and optic disc blood flow. This could be caused by drug diffusion to the choroid, which may cause vasoconstriction. Ocular blood flow reduction was not observed with betaxolol, levobunolol, or pilocarpine. The lack of effect of all drugs under study on central retinal blood flow velocity might partially be the result of autoregulative mechanisms. Because optic nerve head blood flow likely plays a critical role in the clinical course of glaucoma, the use of antiglaucoma drugs, which reduce blood flow, should be reconsidered.

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1 COS-7 cells transfected with the cDNA of the human dopamine transporter (DAT cells) or the human noradrenaline transporter (NAT cells) were loaded with [ 3 H]-dopamine or [ 3 H]-noradrenaline and superfused with bu ers of di erent ionic composition. 2 In DAT cells lowering the Na + concentration to 0, 5 or 10 mM caused an increase in 3 H-e ux. Cocaine (10 mM) or mazindol (0.3 mM) blocked the e ux at low Na + , but not at 0 Na + . Lowering the Cl 7 concentration to 0, 5 or 10 mM resulted in an increased e ux, which was blocked by cocaine or mazindol. Desipramine (0.1 mM) was without e ect in all the conditions tested. 3 In NAT cells, lowering the Na + concentration to 0, 5 or 10 mM caused an increase in 3 H-e ux, which was blocked by cocaine or mazindol. Desipramine produced a partial block, its action being stronger at 5 or 10 mM Na + than at 0 mM Na + . E ux induced by 0, 5 or 10 mM Cl 7 was completely blocked by all three uptake inhibitors. 4 In cross-loading experiments, 5 mM Na + -or 0 Cl 7 -induced e ux was much lower from [ 3 H]-noradrenaline-loaded DAT, than NAT cells and was sensitive to mazindol, but not to desipramine. E ux from [ 3 H]-dopamine-loaded NAT cells elicited by 5 mM Na + or 0 Cl 7 was blocked by mazindol, as well as by desipramine. 5 Thus, cloned catecholamine transporters display carrier-mediated e ux of amines if challenged by lowering the extracellular Na + or Cl 7 , whilst retaining their pharmacological pro®le. The transporters di er with regard to the ion dependence of the blockade of reverse transport by uptake inhibitors.

Secretoneurin (SN) is a neuropeptide derived from secretogranin II that is found in brain and endocrine tissues. The aim of the present study was to determine the influence of this novel peptide on dopamine (DA) release from rat striatum using the microdialysis technique. Rat SN (1–30 µmol/L added to the dialysis buffer) enhanced DA outflow of awake rats in a concentration‐dependent way without marked effects on the outflow of 3,4‐dihydroxyphenylacetic acid or homovanillic acid. The increase in extracellular DA content caused by the peptide was observed throughout the entire period of administration (up to 4 h). Human SN and its 15‐amino‐acid C‐terminal sequence also increased DA outflow, but the effects were smaller than those of rat SN. Two other peptides derived from secretogranin II were without effect on DA efflux. These results establish that SN has a pronounced effect on DA release under in vivo conditions.