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.

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.

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.

Efficacy of spiramycin as an alternative to amoxicillin in the treatment of acute upper respiratory tract infections.

This 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 degrees 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.

Epidemiology of rhinitis in Thais: characteristics and risk factors.

A questionnaire survey was performed on 3,124 subjects living in Bangkok and its vicinity. The cumulative prevalence of chronic rhinitis (CR) was 13.15% (95% CI = 13.13-13.17). The characteristics of CR subjects, i.e. age group, current occupation, associated allergy, family history of atopy, cigarette smoking and drinking habits were totally different from the non CR group, except for sex preponderance. The possible risk factors for developing CR in this group were high income occupation, presence of associated allergy, family history of atopy, smoking and drinking habits. When CR subjects were further classified into "allergic" and "non-allergic" CR groups by using the presence of associated eye symptoms and known provoking factors as the differential criteria, there was no significant difference in all parameters compared between the two groups, i.e. age, sex, current occupation, associated allergy, family history of atopy, smoking and drinking habits, frequency of occurrence of each nasal symptom, seasonal variation of the symptoms, effect of moving to live in the big city, presence of pets in the house and effect of changing occupation, except for the number of nasal symptoms which was significantly higher in the "allergic" CR group.

A non-comparative trial of the efficacy and safety of fexofenadine for treatment of perennial allergic rhinitis.

An open-label, non-comparative study was performed in three Otolaryngology centers in Bangkok, Thailand, to assess the efficacy, safety and tolerability of fexofenadine in Thai patients with perennial allergic rhinitis. Altogether 101 perennial allergic rhinitis patients were included, 33 males and 68 females. Mean age was 33 years, average duration of symptoms was 6 years. All patients received fexofenadine hydrochloride 120 mg once daily (OD) in the morning for 2 weeks. Patients recorded their allergy symptoms daily using a 5 point rating scales in the diary card. At the end of 2 weeks, patients and investigators assessed the overall efficacy of treatment. Adverse events and onset of symptom relief were also recorded by every patient. Blood test and ECG were performed before and after treatment in one center (Siriraj Hospital). Total symptom scores and nasal scores decreased significantly from a baseline at 1 week and 2 weeks after treatment (p < 0.05). The mean onset of symptom relief was 2 hours and 12 minutes. The global assessment of the treatment by patients and investigators showed significant concordance. There was no significant change in either the vital signs, laboratory tests or ECG. The incidence of treatment related adverse events was 8% but all were mild and easily tolerated. Drowsiness was reported from only one patient. This study suggests that fexofenadine 120 mg once daily was an effective, safe and well tolerated treatment for perennial allergic rhinitis in Thai patients.

Desensitization of nitrate-induced venodilation: reversal with oral N-acetylcysteine in humans.

The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

Lack of role of endothelium-derived relaxing factor in effects of alpha-adrenergic agonists in cutaneous veins in humans.

In some blood vessels, the alpha 2-adrenergic agonist clonidine simultaneously activates vasoconstrictive alpha-adrenoceptors on smooth muscle cells and endothelial alpha 2-adrenoceptors mediating release of endothelium-derived relaxing factor (EDRF), with the net vascular response representing a balance between these two counteracting pathways. To investigate whether clonidine's modest constrictor effect in human veins is due to simultaneous release of EDRF, the dorsal hand vein compliance technique was used to measure vascular responses in healthy volunteers. Clonidine-induced venoconstriction was not potentiated by methylene blue, an inhibitor of EDRF-mediated relaxation. After preconstriction with angiotensin II, clonidine did not cause venodilation but rather promoted further constriction, which could be reversed by the alpha 1-antagonist labetalol. However, in veins preconstricted with the full alpha 1-agonist phenylephrine, clonidine induced venodilation, suggesting that clonidine is a partial agonist at venous alpha 1-adrenoceptors. In conclusion, we found no evidence for endothelial alpha 2-adrenoceptor-mediated release of EDRF in human hand veins. The results further suggest that postjunctional alpha 1-adrenoceptors participate in clonidine-induced venoconstriction in humans.