Plasma exchange (PE) is currently being used to treat a variety of disorders involving immune complexes, such as polyarteritis nodosa. This procedure removes endogenous toxic components that accumulate in patients with this disease, but it also removes drugs. Plasma-protein binding and the volume of distribution (V) are two kinetic parameters which strongly affect the efficiency of drug removal by PE. Drugs that are highly bound to plasma proteins and have a low V may show a marked decrease in plasma levels as a result of PE. Because ceftriaxone exhibits saturable plasma-protein binding, which influences its pharmacokinetic parameters, particularly its V, we evaluated its removal during PE therapy in this nonrandomized crossover study. Twelve polyarteritis nodosa patients undergoing PE were studied. Each patient was given ceftriaxone intravenously in doses of 1 and 3 g on days 4 and 11, respectively, immediately before (n = six patients; group I) and 6 h before (n = six patients; group II) PE. Plasma was assayed for ceftriaxone by high-pressure liquid chromatography. The mean amounts eliminated +/- standard deviations were 230.8 +/- 38.5 mg (1 g) and 750.0 +/- 168.5 mg (3 g) for group I and 161.0 +/- 66.0 mg (1 g) and 347.0 +/- 121.0 mg (3 g) for group II. The drug fractions eliminated by PE were 23.0% +/- 3.9% (1-g dose) and 24.9% +/- 5.6% (3-g dose) for group I (P > 0.05), and 16.6% +/- 5.9% (1-g dose) and 11.5% +/- 4.0% (3-g dose) for group II (P < 0.05). These results showed that the drug fraction eliminated decreased when V increased only when the distribution phase of ceftriaxone had been completed (group II). These findings suggest that PE may influence ceftriaxone disposition and that it would be better to administer the drug after PE to assure its therapeutic efficacy.

Cimetidine (400 mg b.d.), ranitidine (150 mg b.d.) and placebo were administered for 1 week to 6 healthy male volunteers in a randomized double-blind cross-over fashion. Hormonal concentrations before and after a TRH test were assessed before and after each treatment. A spontaneous decrease in the hormonal response to TRH was observed after placebo treatment. Both cimetidine and ranitidine induced a significant increase in basal prolactin (PRL) values. Neither TSH nor T₃ were modified by cimetidine or by ranitidine. The basal concentration of reverse T₃ was increased during cimetidine treatment. There was a significant rise in post-TRH T₄ after cimetidine and ranitidine administration. These results suggest a role for histamine H₂ receptors in the secretion of PRL and T4. Moreover, cimetidine affects the hepatic metabolism of thyroid hormones.

Very often, an impact on the intracellular metabolism of iodothyronines and more precisely on microsomal deiodinases is evoked to explain thyroid hormone (TH) serum level alterations occurring with numerous drugs. Among them, three at least are also known to interfere with other hepatic microsomal enzymes, amiodarone (AMI), phenobarbital (PHE) and propranolol (PRO). Starting from this statement, we have examined the effects of 5 macrolides on TH serum level and on hepatic 5' type 1 deiodinase (5'DI) in vivo in rat. Rats were treated orally for eight days either with 200 mg/kg macrolides--erythromycine (ERY), troleandomycine (TRO), josamycine (JOS), midecamycine (MID) and spiramycine (SPI)--, or with AMI (45 mg/kg), PHE (50 mg/kg) or PRO (20 mg/kg), these 3 latter drugs for comparative purpose. Total T4, T3 and rT3 were determined by RIA. Hepatic 5'DI was evaluated by measuring released radioactive iodide from a reverse T3 monolabelled with 125I used substrate. Compared to control group, ERY and TRO decreased T4 (respectively by 28 and 16%) and from these two, only TRO decreased T3 (23%). With JOS, the only major modification was an increment of T3 (26%). AMI gave a typical alteration with a high T4 (130%), a low T3 (26%) and a high rT3 (376%). 5'DI was statistically inhibited by AMI (85%), JOS (49%), TRO (43%) and ERY (35%). The other drugs showed no significant effect. So, three macrolides have both altered TH serum level and 5'DI, findings which have never been reported before. The precise mechanism of this action remains unknown and the resulting effect, being far from the one observed with AMI, tends to demonstrate, for macrolides, an absence of correlation between the extent of 5'DI inhibition and TH serum profile. Besides, comparative analysis of the results observed with macrolides, AMI, PHE and PRO argues against any relationship between 5'DI and cytochrome-P450 monooxygenases.

Objective:To study the elimination of teicoplanin during plasma exchange, a procedure currently used to treat a variety of disorders involving immune complexes. Teicoplanin is a glycopeptide antibiotic that exhibits a long terminal half-life (100-150 h) and is highly bound t o plasma proteins (unbound fraction (f,)=0.2).Methods: Twelve adults with systemic polyarteritis nodosa, cryoglobulinemia-induced vasculitis or dysglobulinemic neuropathy undergoing plasma exchange were studied. Each patient received intravenous teicoplanin, 6 mg/kg body weight, immediately before plasma exchange. Plasma was assayed for teicoplanin by high-pressure liquid chromatography.Results: A high level of protein binding of teicoplanin was measured within this patient population (98%). The mean quantity of teicoplanin eliminated (2SD) was 74.6234.6 mg. The mean drug fraction eliminated by plasma exchange (?SD) was 19.5?5.6%. Mean fu value as determined by ultrafiltration (2SD) was 2.221.7%. Conclusions:These results show that plasma exchange influences teicoplanin pharmacokinetics, with a clinically significant quantity being eliminated. If trough teicoplanin concentrations of around 10 mg/L are desired, it is recommended that teicoplanin dosage be supplemented or given after plasma exchange.level of 20-25 mg/L is recommended [6]. When teicoplanin levels are measured by microbial assay, the optimal range is 25% higher (manufacturer's recom-213