Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Helmet-induced skull base fracture in a motorcyclist.

Observations after a fatal motorcycle accident suggested that the face bar of a full-face helmet may transmit an impacting force to the skull base via the chin strap and the mandibular rami and condyles, bypassing the energy-absorbing facial bones. If this mechanism is confirmed, the structural properties of these face bars will need to be reassessed.

Current clinical applications and dose regimens of metronidazole and related nitroimidazoles.

Metronidazole, in particular, and the other nitroimidazoles (tinidazole, ornidazole) available in Australia are well established drugs for the treatment of protozoal (trichomonal or amoebic) infections; recent data testify to their efficacy in the prevention and therapy of anaerobic infections. Administration by oral and rectal routes is indicated rather than by the intravenous route on the basis of efficacy, safety and cost; this recommendation is applicable to both loading and maintenance dosing. Intravenous administration should be restricted to emergency preoperative loading (single 500-mg dose); to patients with proven anaerobic infections; patients with serious sepsis associated with an unidentified organism; patients who are unable to take medication by mouth and those without a functional rectum or with diarrhoea; and patients with leukaemia who are vomiting. These drugs are remarkably safe under conditions of acute use if the intravenous route is avoided. However, extreme caution in their long-term use and use in obstetric and paediatric patients should be exercised until toxicological issues are resolved. It is concluded that the nitroimidazoles are effective, cheap and safe drugs for the short-term treatment of protozoal and bacterial (anaerobic) infections.