Supornchai Kongpatanakul

Where do developing World clinicians obtain evidence for practice: a case study on pneumonia

There are few data on the practice of evidence based medicine in the developing world, nor on the actual sources of evidence that clinicians use in practice. To test the hypothesis that there was variation between and within developing countries in the proposed management of a patient with hospital acquired pneumonia, and that part of the variation can be explained by the sources of evidence used. Questionnaire responses to hypothetical case history. Investigators from 6 centres within the International Clinical Epidemiology Network (INCLEN) in China, Thailand, India, Egypt, and Kenya. Doctors chosen to represent primary and secondary hospital practice in the regions of the study centres. Investigations and initial treatments which would be ordered for a hypothetical 60-year-old woman who develops pneumonia 5 days after hospital admission, whether local data on antibiotic sensitivities are available and where information would be obtained to guide management. Chest x-ray and sputum gram stain/culture were consistently the most commonly ordered investigations, there being much greater variation in the initial treatment choices with either penicillin, a third-generation cephalosporin or aminoglycoside being the most popular choice. Textbooks were the commonest form of information source, and access to a library, textbooks and journals were statistically significantly associated with appropriate choice of investigations, but not treatment. Access to local antibiotic sensitivities was associated with appropriate initial treatment choice. Improving access to information in the literature and to local data may increase the practice of evidence-based medicine in the developing world.

Comparative study of dihydroartemisinin and artesunate safety in healthy Thai volunteers.

OBJECTIVE As part of new drug development initiatives in Thailand, a new tablet formulation of dihydroartemisinin (DHA, an antimalarial drug) has been developed. Our previous bioequivalence study indicated that the new and reference DHA formulations were well tolerated; however, a significant decrease in hemoglobin was detected after a single 200-mg oral dose. To explore further, a clinical study with an emphasis on hematological parameters was conducted. METHODS A single-center, randomized, single-blind, cross-over clinical study was conducted in 18 healthy volunteers with a dosage of 300 mg daily for 2 days. Artesunate was used as a comparator. Adverse events were monitored and laboratory parameters on study Days 0, 2, 5, and 7 post drug administrations were analyzed. RESULTS Eighteen volunteers completed both rounds of the study. Both drugs were well tolerated. All adverse events were mild. Significant decrease in hemoglobin compared to baseline was detected for both drugs 7 days after administration (DHA: 0.48 g/dl, p = 0.007; artesunate 0.38 g/dl, p = 0.001). Transient bone marrow suppression was evidenced by reduction of reticulocytes with a lowest number on study Day 5 (artesunate 75% reduction in reticulocyte count; DHA 47%, p < 0.001 for both drugs compared to baseline). CONCLUSION The present study confirmed our previous finding on significant decrease in hemoglobin. Artesunate appeared to have more negative effects on the numbers of reticulocytes and white blood cells than DHA. Systemic laboratory and toxicity profiles presented in this study may be used as a framework for future clinical studies of artemisinin and its derivatives.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers

Abstract. Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

Association of Nevirapine Levels with Rash or Hepatotoxicity Among HIV-Infected Thai Women.

Background: We performed a nested case-control study of Thai women prescribed nevirapine-based antiretroviral therapy (ART) to determine if development of rash or hepatotoxicity during the first 24 weeks of treatment is associated with plasma nevirapine concentrations. Method: From May 2005-January 2007, we enrolled 217 women initiating nevirapine-based ART in Thailand. Cases (n = 54) were women who during the first 24 weeks of treatment with nevirapine developed rash (any grade, n = 42) or hepatotoxicity (≥grade 2, n = 22, [10 had both]). Controls were the next enrolled woman who was confirmed not to meet the case definition during the first 24 weeks. Nevirapine concentrations after the two week lead-in dose of 200 mg once daily were compared between cases and controls by Wilcoxon rank-sum tests. Results: We found no difference in Week 2 pre-dose nevirapine concentrations: cases median = 3,528 ng/mL (n = 24), controls median = 3,150ng/mL (n = 30), p = 0.5. Cases had higher post-dose nevirapine concentrations (median = 6,150 ng/mL, n = 21) than controls (median = 4,746 ng/mL, n = 20, p = 0.02). When limited to cases who developed a rash at Week 2, we found no differences in the pre-dose (median = 3,270 ng/mL, n = 12, p = 0.9) or post-dose nevirapine concentration (median = 5,443 ng/mL, n = 9, p = 0.4) compared with controls. Conclusions: We cannot conclude definitively that nevirapine concentrations at two weeks of therapy are associated with rash or hepatotoxicity. It is unlikely that therapeutic drug monitoring at that time will improve identification of patients at risk for rash or hepatotoxicity.

A randomized, open-label, 2-period, crossover bioequivalence study of two oral formulations of 75 mg oseltamivir in healthy Thai volunteers.

AIM Oseltamivir, an ester prodrug of its active carboxylate metabolite, is an effective neuraminidase inhibitor used to treat influenza A and B virus infections. The purpose of this study was to compare the bioavailability of two 75 mg oral formulations of oseltamivir: a generic drug, GOP-A-Flu (test, Government Pharmaceutical Organization, Thailand) and Tamiflu (reference, Hoffmann-La Roche Ltd., Nutley, NJ, USA) in healthy volunteers. SUBJECTS AND METHODS A single-dose, randomized, 2-sequence, crossover study was conducted in 24 healthy Thai volunteers. Each volunteer received a 75 mg capsule of the reference or test drugs under fasting conditions. Blood samples were collected before dosing and at various time points up to 48 hours after dosing and analyzed for plasma oseltamivir and oseltamivir carboxylate concentrations. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-infinity, tmax and t1/2 were analyzed using the non-compartmental method. Drug safety was assessed. RESULTS 23 volunteers completed both treatment periods. The geometric mean ratios (test/reference) between the two formulations of oseltamivir were 96.83% (90% CI, 76.85 - 123.15%) for Cmax 103.66% (86.44 - 113.56%) for AUC0-t, and 103.98% (86.44 - 113.56%) for AUC0-infinity. Those of oseltamivir carboxylate were 102.17% (90% CI, 90.90 - 109.10%) for Cmax, 103.95% (90.90 - 109.10%) for AUC0-t, and 103.95% (90.92 - 109.08%) for AUC0-infinity. No significant difference of the tmax of oseltamivir and oseltamivir carboxylate between the two formulations was detected (p > 0.05). Both formulations were well-tolerated. CONCLUSION Although the Cmax of oseltamivir was the only parameter not entirely within the equivalence criteria, the two capsule formulations were considered bioequivalent in terms of rate and extent of absorption regarding its active carboxylate metabolite.

Efficacy of Spiramycin as an Alternative to Amoxicillin in the Treatment of Acute Upper Respiratory Tract Infections

SummaryThis study compared the efficacy of spiramycin with that of amoxicillin in treating patients with acute community-acquired upper respiratory tract infections (URTIs). The study was an open, randomised, comparative parallel design and patients received either spiramycin 3 MIU (2 tablets, 500mg or 1.5 MIU per tablet) twice daily after meals, i.e. 6 MIU/day for 7 days or amoxicillin (500 mg/capsule) 1 capsule three times daily after meals, i.e. 1500 mg/day for 7 days. Patients attending the ENT outpatient clinic at Siriraj Hospital in Bangkok for treatment of acute URTIs were included in the study after giving their informed consent. Eligible patients comprised those aged 18 years and over, of either gender, who had at least two of the following symptoms: fever (≥38°C oral), nasal discharge/obstruction, sore throat, cough and/or hoarseness of voice that did not require parenteral drug therapy or hospitalisation. A total of 99 patients were included in this study, 49 patients received spiramycin and 50 received amoxicillin. Of the 45 assessed patients treated with spiramycin, 40 were judged by the investigators as a ‘success’ (89%), and five were judged a ‘non-success’ (11%), compared with 48 assessed patients in the amoxicillin group where 40 patients were classified as a ‘success’ (83.3%) and 8 were judged a ‘non-success’ (16.7%). No statistically significant differences between treatments were demonstrated regarding the overall efficacy of treatment.This study demonstrated that the prescribed regimens of spiramycin and amoxicillin were similarly effective in the treatment of adult acute URTIs. The tolerability of both drugs was also similar. Furthermore, it was noted that the convenient twice-daily dosage regimen of spiramycin may allow better patient compliance.