Importance of plasma protein binding of antituberculosis drugs on the response to shortcourse chemotherapy

Recently, there has been an increasing concern over the consequences of altered plasma protein binding of drugs in disease states, malnutrition and concomittant drug use on the therapeutic efficacy and toxicity of many antituberculous drugs. The increasing awareness of the problems associated with altered plasma protein binding necessitates studying the plasma protein binding profile of drugs used in short- course therapy for tuberculosis since such a study has not been done regardless of the fact that malnutrition and multiple drug use is often unavoidable and where drug resistance and hepatotoxicity has been a major issue. A total of 5 clinically healthy volunteers and 18 smear-positive tuberculosis patients, who were undertaking a short-course chemotherapy at the Union Tuberculosis Institute, were recruited and the plasma protein level and their binding property to rifampicin, isonazid and pyrazinamide at steary-state were studied. The findings showed that although the total plasma protein level was not significantly reduced, there is decrease in the mean albumin level in relation to the globulin level in tuberculous patients. The protein binding profile showed rifampicin to be highly bound (74-87 per cent) and pyrazinamide to be moderately bound (22-40 per cent ) to plasma proteins but no significant binding was seen with isoniazid (0.7-2.4 per cent ). All 3 drugs achieved adequate serum concentration well above the MIC throughout the study accompanied by rapid clinical improment and sputum conversion to negativity in 88.9 per cent of patients within one month of treatment. No sign of hepatic toxicity was seen in the study. Two patients (11.1 per cent ) had relapse after completion of therapy. The study highlights the importance of plasma protein binding of drugs and its influence on the metabolism and interaction between drugs used concomitantly in short-course chemotherapy. The study also showed that addition of pyrazinamide in short-course chemotherapy is very effective and well tolerated but increase in dosage of pyrazinamide during the twice-weekly phase may be necessary to prevent relapse.

Comparative multiple-dose pharmacokinetics of chloroquine in P. vivax malaria patients and healthy volunteers

Recent evidence of the emergence of resistance of P. vivax to chloroquine in Myanmar has increased the importance and urgency of understanding the cause of resistance as well as the need for devising the strategies to limit its spread. A comparative multiple-dose pharmacokinetic study was conducted on 5 clinically healthy volunteers and 10 malaria patients with P. vivax, admitted to the No. 2 Miliysty Hospital, Yangon, with the object to study whether there is any pharmacokinetic-dynamic relationship underlying the response of patients to standard chloroquine (1500 mg given over 3 days) therapy. Serum chloroquine concentrations reached well above the MIC level in all subjects with the patients' serum concentration (both peak and trough) and the AUC being significantly (2-3 times) higher than jnormal volunteers (p < 0.02). Both the clearance and the volume of distribution were also significantly lower in the malaria patients as compared to the healthy volunteers (p < 0.05). The elimination half-life (T1/2el) was shorter in malaria patients but the difference was not statistically significant. No significant difference was seen with other pharmacokinetic parameters, between normal volunteers and patients and between patients who do and do not recrudescenced. The study supports the emergence of chloroquine-resistant P. vivax in Myanmar and also excludes the possibility of apparent resistance due to pharmacokinetic causes, especially reduced bioavailability.

Pharmacokinetics of mefloquine in uncomplicated plasmodium falciparum malaria patients in Myanmar

With the aim to study the pharmacokinetic basis underlying the therapeutic outcome of mefloquine in malaria patients, a single oral dose of 1000 mg mefloquine hydrochloride (Mepha) was administered to 24 patients with acute uncomplicated falciparum malaria and 10 healthy volunteers and was followed-up till day 42. The drug serum levels at various time intervals were analysed by a Waters HPLC and the pharmacokinetic profile studied. The study shows that although Myanmar malaria patients had a slower rate of absorption (T1/2ab = 6.38 + 0.60 hour; Tmax =1.31 + 0.12 days), the peak serum level reached was much higher (Cmax = 2.24 + 0.05 ug/ml) than those of the westerners.