Somruedee Chatsiricharoenkul

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.

Activation of Indoleamine 2,3-Dioxygenase in Patients with Scrub Typhus and Its Role in Growth Restriction of Orientia tsutsugamushi

Background Our earlier genome-wide expression study revealed up-regulation of a tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO1), in patients with scrub typhus. This gene has been previously reported to have anti-microbial activity in a variety of infectious diseases; therefore, we aimed to prove whether it is also involved in host defense against Orientia tsutsugamushi (OT) infection. Methodology/Principal Findings Using LC-MS, we observed an increased ratio of serum L-kynurenine to serum L-tryptophan in patients with scrub typhus, which suggests an active catalytic function of this enzyme upon the illness. To evaluate the effect of IDO1 activation on OT infection, a human macrophage-like cell line THP-1 was used as a study model. Although transcription of IDO1 was induced by OT infection, its functional activity was not significantly enhanced unless the cells were pretreated with IFN-γ, a potent inducer of IDO1. When the degree of infection was evaluated by quantitative real-time PCR, the relative number of OT 47 kDa gene per host genes, or infection index, was markedly reduced by IFN-γ treatment as compared to the untreated cultures at five days post-infection. Inhibition of IDO1 activity in IFN-γ treated cultures by 1-methyl-L-tryptophan, a competitive inhibitor of IDO1, resulted in partial restoration of infection index; while excessive supplementation of L-tryptophan in IFN-γ treated cultures raised the index to an even higher level than that of the untreated ones. Altogether, these data implied that IDO1 was partly involved in restriction of OT growth caused by IFN-γ through deprivation of tryptophan. Conclusions/Significance Activation of IDO1 appeared to be a defensive mechanism downstream of IFN-γ that limited intracellular expansion of OT via tryptophan depletion. Our work provided not only the first link of in vivo activation of IDO1 and IFN-γ-mediated protection against OT infection but also highlighted the promise of this multifaceted gene in scrub typhus research.

Maternal Vitamin D Status and Its Related Factors in Pregnant Women in Bangkok, Thailand.

Background There are few data focusing on the prevalence of vitamin D deficiency in tropical countries. Objectives We determined the vitamin D status in pregnant women and examined the factors associated with vitamin D deficiency. Design and Methods A cross-sectional study of 147 pregnant Thai women aged 18–45 years at Siriraj Hospital (a university hospital in Bangkok, Thailand) was undertaken. Clinical data and plasma levels of 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (iPTH), calcium, albumin, phosphate and magnesium were obtained in pregnant women at delivery. Results The prevalence of hypovitaminosis D [defined as 25(OH)D <75 nmol/L] in pregnant women at delivery was 75.5% (95% confidence interval (CI), 67.7–82.2%). Of these, vitamin D insufficiency [defined as 25(OH)D 50–74.9 nmol/L] was found in 41.5% (95% CI, 33.4–49.9%) and vitamin D deficiency [25(OH)D <50 nmol/L] was found in 34.0% (95% CI, 26.4–42.3%) of women. The mean 25(OH)D concentration was 61.6±19.3 nmol/L. The correlation between 25(OH)D and iPTH was weak (r = –0.29, P<0.01). Factors associated with vitamin D deficiency by multiple logistic regression were: pre-pregnancy body mass index (BMI in kg/m2, odds ratio (OR), 0.88, 95% CI 0.80–0.97, P = 0.01) and season of blood collection (winter vs. rainy, OR, 2.62, 95% CI 1.18–5.85, P = 0.02). Conclusions Vitamin D deficiency is common among pregnant Thai women. The prevalence of vitamin D deficiency increased in women who had a lower pre-pregnancy BMI and whose blood was collected in the winter. Vitamin D supplementation may need to be implemented as routine antenatal care.

A Case-Control Study of Involvement of Oxidative DNA Damage and Alteration of Antioxidant Defense System in Patients with Basal Cell Carcinoma: Modulation by Tumor Removal.

Oxidative damage has been suggested to play a role in the pathogenesis of basal cell carcinoma (BCC). This study illustrated an involvement of oxidative DNA damage and changes in antioxidant defenses in BCC by conducting a case-control study (24 controls and 24 BCC patients) and assessing urinary 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dGuo), plasma antioxidant defenses including catalase (CAT), glutathione peroxidase (GPx), NQO1, and total superoxide dismutase (SOD) activities, and glutathione (GSH) levels before surgery and 1 month after surgery. 8-oxo-dGuo expressions as well as protein and mRNA expressions of DNA repair enzyme hOGG1 and antioxidant defenses (CAT, GCLC, GPx, Nrf2, and MnSOD) in nonneoplastic epidermis of control and BCC tissues were also determined. This study observed induction in urinary 8-oxo-dGuo, increased 8-oxo-dGuo expression, and reduced hOGG1 protein and mRNA in BCC tissues, decreased activities of CAT, GPx, and NQO1, but elevated SOD activities and GSH levels in BCC patients and reduction of all antioxidant proteins and genes studied in BCC tissues. Furthermore, decreased plasma antioxidant activities in BCC patients were restored at 1 month after operation compared with preoperative levels. Herein, we concluded that BCC patients were associated with oxidative DNA damage and depletion of antioxidant defenses and surgical removal of BCC correlated with improved redox status.

Prevalence and risk factors for chloroquine maculopathy and role of plasma chloroquine and desethylchloroquine concentrations in predicting chloroquine maculopathy.

To determine the prevalence and to identify the risk factors of chloroquine maculopathy (CM), and to evaluate the association of plasma chloroquine (CQ) and desethylchloroquine (DCQ) levels and CM.

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.