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The relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for >28 days. All patients received a 7-day oral quinine regimen either alone (n ‫؍‬ 22) or in combination with rifampin (n ‫؍‬ 8). The median fever clearance time was 58.5 h, and the mean ؎ standard deviation parasite clearance time was 73 ؎ 24 h. After recovery, six patients had recrudescences of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 g ⅐ day/ml had a relative risk of 5.3 (95% confidence interval ‫؍‬ 1.6 to 17.7) of having a subsequent recrudescence of infection (P ‫؍‬ 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 g/ml and an MIC of 0.7 g/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).The cinchona alkaloids have been important antimalarial drugs for more than 350 years. The principal alkaloid, quinine, still remains effective against chloroquine-resistant falciparum malaria, and it is widely used. Development of quinine resistance in Plasmodium falciparum has been relatively slow and incomplete by comparison with those of the other principal antimalarial drugs, e.g., chloroquine, mefloquine, and sufadoxine-pyrimethamine. In areas with multidrug-resistant strains, 7-day regimens of quinine and tetracycline still provide cure rates well over 90% in patients with uncomplicated falciparum malaria (4, 5). To date there is no convincing evidence of high-grade quinine resistance in the treatment of severe malaria (9). The pharmacokinetic properties of and therapeutic responses to quinine vary with age, pregnancy, immunity, and disease severity (2,8,14). As patients recover from malaria, the total apparent volume of distribution of quinine expands and systemic clearance increases (13). As a result, concentrations in plasma fall. In areas with resistant strains of P. falciparum in order to achieve good therapeutic responses in children, the dose of quinine must be increased after the 3rd day of treatment to compensate for this decline in the concentration in plasma which occurs with recovery (2). These observations suggest that quinine concentrations must remain above levels which inhibit parasite multiplication throughout the course of treatment to eradicate the infection from the body (14). Knowledge of the in vivo minimum parasiticidal concentrations and MICs (14) of quinine in patients with malaria are necessary for optimization of d...

We have investigated the effect of herbal teas (peppermint, chamomile and dandelion) on the activity of hepatic phase I and phase II metabolizing enzymes using rat liver microsomes. Female Wistar rats were divided into six groups (n = 5 each). Three groups had free access to a tea solution (2%) while the control group had water. Two groups received either green tea extract (0.1%) or aqueous caffeine solution (0.0625%). After four weeks of pretreatment, different cytochrome P450 (CYP) isoforms and phase II enzyme activities were determined by incubation of liver microsomes or cytosol with appropriate substrates. Activity of CYP1A2 in the liver microsomes of rats receiving dandelion, peppermint or chamomile tea was significantly decreased (P < 0.05) to 15%, 24% and 39% of the control value, respectively. CYP1A2 activity was significantly increased by pretreatment with caffeine solution. No alterations were observed in the activities of CYP2D and CYP3A in any group of the pretreated rats. Activity of CYP2E in rats receiving dandelion or peppermint tea was significantly lower than in the control group, 48% and 60% of the control, respectively. There was a dramatic increase (244% of control) in the activity of phase II detoxifying enzyme UDP-glucuronosyl transferase in the dandelion tea-pretreated group. There was no change in the activity of glutathione-S-transferase. The results suggested that, like green and black teas, certain herbal teas can cause modulation of phase I and phase II drug metabolizing enzymes.

1 In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37°C) and tracer-labelling with [I4C]-phenytoin was 6.7%-33.3% with a median of 11.9%. 2 The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P < 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. 3 An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = -0.83, P < 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. 4 Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P < 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. 5 The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.