LIPOPHILICITY, AQUEOUS SOLUBILITY, AND DEGREE OF IONIZATION OF ATRACTYLODIN AND β-EUDESMOL, THE BIOACTIVE COMPOUNDS ISOLATED FROM ATRACTYLODES LANCEA

Objective: The study aimed to evaluate the critical physicochemical properties (lipophilicity, aqueous solubility, and degree of ionization) of atractylodin and β-eudesmol using in vitro testing. Methods: Lipophilicity (Log P and Log D) was determined using the shake-flask method (n-octanol/water partition). Aqueous solubility was determined using kinetic solubility assay in media with pH ranging from 1.2 to 7.4. The degree of ionization (pKa) was determined using the potentiometric titration method. Results: Log P and Log D values of 3.0-5.0 suggested moderate lipophilicity of both compounds. Both exhibited low aqueous solubility over the investigated pH range (0.08-0.93 and 1.97-32.48 μg/ml for atractylodin and β-eudesmol, respectively). Based on the pKa values of 9.63 (atractylodin) and 9.12 (b-eudesmol), both are classified as basidic compounds. Conclusion: Atractylodin and β-eudesmol are classified as BCS class II drugs. The physicochemical parameters of both compounds obtained from the current study will be further applied for in silico prediction of their ADME (absorption, distribution, metabolism, and excretion) properties. In addition, PBPK modeling will be used for the prediction of optimal dose regimens of the capsule formulation of the standardized extract of Atractylodes lancea for first-in-human (FIH) and phase II studies in patients with cholangiocarcinoma

Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy (ACT) is presently recommended by the World Health Organization as first-line treatment for uncomplicated <it>Plasmodium falciparum </it>malaria in several countries, as a mean of prolonging the effectiveness of first-line malaria treatment regimens. A three-day course of artesunate-mefloquine (4 mg/kg body weight once daily for three consecutive days, plus 15 and 10 mg/kg body weight mefloquine on the first and second days) has been adopted by Malaria Control Programme of Thailand as first-line treatment for uncomplicated falciparum malaria all over the country since 2008. The gametocytocydal anti-malarial drug primaquine is administered at the dose of 30 mg (0.6 mg/kg) on the last day. The aim of the present study was to assess patient compliance of this combination regimen when applied to field condition.</p> <p>Methods</p> <p>A total of 240 patients (196 males and 44 females) who were attending the malaria clinics in Mae-Sot, Tak Province and presenting with symptomatic acute uncomplicated falciparum malaria, with no reappearance of <it>Plasmodium vivax </it>parasitaemia during follow-up were included into the study. The first dose of the treatment was given to the patients under direct supervision. All patients were given the medication for self-treatment at home and were requested to come back for follow-up on day 3 of the initial treatment. Baseline (day 0) and day 3 whole blood mefloquine and plasma primaquine concentrations were determined by high performance liquid chromatography.</p> <p>Results</p> <p>Two patients had recrudescence on days 28 and 35. The Kaplan-Meier estimate of the 42-day efficacy rate of this combination regimen was 99.2% (238/240). Based on whole blood mefloquine and plasma primaquine concentrations on day 3 of the initial treatment, compliance with mefloquine and primaquine in this three-day artesunate-mefloquine combination regimen were 96.3% (207/215), and 98.5% (197/200), respectively. Baseline mefloquine and primaquine levels were observed in 24 and 16% of the patients.</p> <p>Conclusion</p> <p>The current first-line treatment and a three-day combination regimen of artesunate-mefloquine provides excellent patient compliance with good efficacy and tolerability in the treatment of highly multidrug resistance falciparum malaria. Previous treatment with mefloquine and primaquine were common in this area.</p

Health and Gross National Happiness: review of current status in Bhutan

Worldwide, contemporary measures of the success of health development programs have been mostly in terms of the reduction of mortality and morbidity as well as increasing longevity. While these goals have yielded much-needed health improvements, the subjective outcomes of these improvements, as experienced by individuals and the communities, have not been considered. Bhutan, under the overarching policy of Gross National Happiness, has provided due consideration to these subjective indicators. Here, we report on the current status of health and happiness in Bhutan as revealed by conventional objective indicators and subjective Gross National Happiness indicators. The current literature on health in Bhutan in relation to the Gross National Happiness Survey conducted by the Centre of Bhutan Studies has been reviewed. Bhutan has made great strides within a short period of modernization, as shown by both objective and subjective indicators. Tremendous challenges lie ahead to achieve the ultimate goal of health and happiness, and how Bhutan articulates its path to modernization may be a lesson for the rest of the world

Study on association between genetic polymorphisms of haem oxygenase-1, tumour necrosis factor, cadmium exposure and malaria pathogenicity and severity

<p>Abstract</p> <p>Background</p> <p>Malaria is the most important public health problems in tropical and sub-tropical countries. Haem oxygenase (HO) enzyme and the pro-inflammatory cytokine tumour necrosis factor (TNF) have been proposed as one of the factors that may play significant role in pathogenicity/severity of malaria infection. HO is the enzyme of the microsomal haem degradation pathway that yields biliverdin, carbon monoxide, and iron. In this study, the association between malaria disease pathogenicity/severity and (GT)_nrepeat polymorphism in the promoter region of the inducible HO-1 including the effect of cadmium exposure (potent inducer of HO-1 transcription) as well as polymorphism of TNF were investigated.</p> <p>Methods</p> <p>Blood samples were collected from 329 cases non-severe malaria with acute uncomplicated <it>Plasmodium falciparum </it>malaria (UM) and 80 cases with <it>Plasmodium vivax </it>malaria (VM), and 77 cases with severe or cerebral malaria (SM) for analysis of genetic polymorphisms of HO-1 and TNF and cadmium levels. These patients consisted of 123 (25.3%) Thai, 243 (50.0%) Burmese and 120 (24.7%) Karen who were present at Mae Sot General Hospital, Mae Sot, Tak Province, Thailand.</p> <p>Results</p> <p>The number of (GT)_nrepeats of the HO-1 gene in all patients varied between 16 and 39 and categorized to short (S), medium (M) and long (L) GT_nrepeats. The genotype of (GT)_nrepeat of HO-1 was found to be significantly different among the three ethnic groups of patients. Significantly higher frequency of S/L genotype was found in Burmese compared with Thai patients, while significantly lower frequencies of S/S and M/L but higher frequency of M/M genotype was observed in Burmese compared with Karen patients. No significant association between HO-1 and TNF polymorphisms including the inducing effect of cadmium and malaria pathogenicity/severity was observed.</p> <p>Conclusions</p> <p>Difference in the expression of HO-1 genotype in different ethnic groups may contribute to different severity of malaria disease. With this limited sample size, the finding of the lack of association between malaria disease pathogenicity/severity genetic polymorphisms of HO-1 (GT)_nrepeat as well as TNF observed in this study may not entirely exclude their possible link with malaria disease pathogenicity/severity. Further study in larger sample size is required.</p

Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010

<p>Abstract</p> <p>Background</p> <p>In Thailand, the proportion of <it>Plasmodium vivax </it>infection has become equal to <it>Plasmodium falciparum</it>. Reports of a trend of gradual decline of <it>in vitro </it>sensitivity of <it>P. vivax </it>to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance <it>P. vivax </it>in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with <it>in vitro </it>sensitivity of <it>P. vivax </it>isolates.</p> <p>Methods</p> <p>The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008 - August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females) with mono-infection of <it>P. vivax </it>malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days) and the anti-relapse drug primaquine (15 mg for 14 days). <it>In vitro </it>sensitivity of <it>P. vivax </it>isolates was evaluated by schizont maturation inhibition assay.</p> <p>Results</p> <p>All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of <it>P. vivax </it>parasitaemia nor appearance of <it>P. falciparum </it>occurred during the investigation period. <it>In vitro </it>data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI) values of IC₅₀for chloroquine were 100.1 and 134.7 (1.1-264.9) nM, respectively.</p> <p>Conclusion</p> <p><it>In vivo </it>results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with <it>P. vivax </it>in the Thai-Myanmar border area. <it>In vitro </it>sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of <it>P. vivax </it>is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to the drug policy.</p

Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria

<p>Abstract</p> <p>Background</p> <p>This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria.</p> <p>Methods</p> <p>A total of 70 patients with acute uncomplicated <it>Plasmodium falciparum </it>malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows:</p> <p>Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54).</p> <p>Results</p> <p>Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent C_max: 3.74 <it>vs </it>2.41 μg/ml; C_max-ss: 2.80 <it>vs </it>2.08 μg/ml; C_max-min-ss: 2.03 <it>vs </it>0.71 μg/ml; AUC: 23.31 <it>vs </it>10.63 μg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, C_min-sswas lower in this group (0.80 <it>vs </it>1.37 μg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, V_z/F) and elimination half-life (t_1/2z, t_1/2e) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups.</p> <p>Conclusion</p> <p>The findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300–600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.</p

Antimalarial activity of plumbagin in vitro and in animal models

BACKGROUND: Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. METHODS: In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). RESULTS: Plumbagin exhibited promising antimalarial activity with in vitro IC(50) (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270–640) and 370 (270–490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. CONCLUSIONS: Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability

Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models

<p>Abstract</p> <p>Background</p> <p>Chemotherapy of cholangiocarcinoma (CCA), a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed.</p> <p>Methods/Design</p> <p>The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR), the crude ethanolic extracts of rhizomes of <it>Zingiber officinale </it>Roscoe (Ginger: ZO) and <it>Atractylodes lancea </it>thung. DC (Khod-Kha-Mao: AL), fruits of <it>Piper chaba </it>Hunt. (De-Plee: PC), and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF) were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA) was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification.</p> <p>Results</p> <p>Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight) as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively). PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL), analgesic (CUR and PPF), antipyretic (CUR and AL), antihypertensive (ZO and AL), and anti-ulcer (CUR, ZO, and AL) activities.</p> <p>Conclusion</p> <p>Plants used in Thai traditional medicine for the treatment of various ailments may provide reservoirs of promising candidate chemotherapeutics for the treatment of CCA.</p