Rianto Setiabudy

Randomized, Open Label Trial of Primaquine Against Vivax Malaria Relapse in Indonesia

ABSTRACT Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.

Dapsone N‐acetylation, metoprolol α‐hydroxylation, and S‐mephenytoin 4‐hydroxylation polymorphisms in an Indonesian population: A cocktail and extended phenotyping assessment trial

We examined dapsone N‐acetylation and metoprolol α‐hydroxylation and S‐mephenytoin 4‐hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n = 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (all rs values >0.84; p < 0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsone N‐acetylation and S‐mephenytoin 4‐hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and pro‐bit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor α‐hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype of S‐mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol α‐hydroxylation polymorphism, with no apparent antimode derived from white populations.

Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia

BackgroundChloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002.MethodsPatients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia.Results42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16%) showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood). The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306). Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65%) subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384).ConclusionThese findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago.

Lack of a relationship between the serum concentration of aminoglycosides and ototoxicity in neonates.

INTRODUCTION Gentamicin and the other aminoglycosides are toxic antibiotics, but they are urgently needed to treat newborns with neonatal sepsis. Aminoglycosides are well known for their nephrotoxicity and ototoxicity. The aminoglycoside dosage currently applied in Indonesia is derived from studies done in Caucasian populations. The safety and efficacy of this dosage regimen, however, has never been evaluated to date. The pharmacokinetic profile of drugs may vary between populations and this may be influenced by genetic factors, lifestyle, drug interactions, etc. The detection of aminoglycoside toxicity in newborns is usually problematic. The present study aims to know the proportion of ototoxicity in newborns in the Cipto Mangunkusumo Hospital treated with gentamicin or amikacin in relation to their trough serum concentration. METHODS The serum level of gentamicin and amikacin were quantified using Liquid Chromatography Tandem Mass Spectrometry (LC-MSMS), and is assumed to be safe if the trough serum concentrations are < 2 mcg/ml and effective if it is between 5 - 12 mcg/ml. For amikacin the desired trough serum concentrations are < 10 mcg/ml and the peak is between 20 - 30 mcg/ml. The hearing function was assessed by Distortion Product Otoacoustic Emission (DPOAE) instrument. This study is registered with the www.clinicaltrials.gov NCT01624324. CONCLUSION Our study indicated that there was no relationship between aminoglycosides serum trough concentration and ototoxicity in neonates with neonatal sepsis.

New Insight into the Molecular Drug Target of Diabetic Nephropathy

Diabetic nephropathy (DN) lowered quality of life and shortened life expectancy amongst those affected. Evidence indicates interaction between advanced glycation end products (AGEs), activated protein kinase C (PKC) and angiotensin II exacerbate the progression of DN. Inhibitors of angiotensin-converting enzyme (ACEIs), renin angiotensin aldosterone system (RAAS), AGEs, and PKC have been tested for slowing down the progression of DN. The exact molecular drug targets that lead to the amelioration of renal injury in DN are not well understood. This review summarizes the potential therapeutic targets, based on putative mechanism in the progression of the disease.

Pilot Study of Isoniazid Acetylation in Melanesian Healthy Subject from Indonesia

Objective: Isoniazid (INH) is metabolized by N-acetyl transferase-2 into acetyl isoniazid (Ac-INH). The acetylation rate is different in each ethnic, therefore it is very interesting to study of INH acetylation. The aims of this study were to synthesize Ac-INH and the produced Ac-INH was used as a working standard for the pilot study of INH acetylation in Melanesian healthy subjects from Indonesia. Methods: Ac-INH can be simply synthesized by acetylation reactions between INH and acetic anhydride. The synthesis results were characterized by organoleptic observation, purity test, UV-Vis spectrophotometry analysis, FTIR analysis, and mass spectrometry analysis. The pilot study of INH acetylation used high performance liquid chromatography to analyze the levels of INH and Ac-INH in blood of Melanesian healthy subjects. The acetylation rate of INH was determined by the ratio between Ac-INH and INH concentrations at 3 h after administration of INH. Results: The acetylation reaction to synthesize Ac-INH has been performed at temperature of 60°C for 30 min. The obtained Ac-INH had the same quality specifications with reference standard of Ac-INH. The average of ratio between of Ac-INH and INH concentrations was Conclusion: The obtained Ac-INH could be used for pilot study of INH acetylation by calculating the ratio of Ac-INH and INH concentrations in plasma subject. The subject has to be increased to represent the Melanesian population from Indonesia. Key words: Isoniazid, Acetyl isoniazid, Acetylation rate, Melanesia

Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria

Key Points Question How is natural variation in cytochrome P450 2D6 activity associated with therapeutic efficacy of primaquine phosphate against latent Plasmodium vivax malaria? Findings In this nested case-control study of 57 patients who had participated in a clinical trial of primaquine for radical cure of acute P vivax malaria, exposure to low levels of cytochrome P450 2D6 activity determined by genotype or measured by dextromethorphan metabolism phenotype was associated with a significantly increased likelihood of relapse of malaria in the year after directly observed high-dose primaquine therapy. Meaning Impaired cytochrome P450 2D6 activity was significantly associated with high risk of therapeutic failure of primaquine, and this finding suggests cytochrome P450 2D6 involvement in producing a therapeutically active metabolite.

The Role of Mangiferin in the Prevention of Experimentally Induced Iron Overload in an Animal Model

BACKGROUND The leaves, fruit peels, and bark of mango trees (Mangifera indica L) contain mangiferin as an active compound with known anti-oxidative and iron chelating properties. This study aims to evaluate the benefits of mangiferin in the management of iron overload. METHODS Thirty rats were divided into five groups: normal control, rats with iron overload, and rats with iron overload treated with oral mangiferin doses of 50, 100, or 200 mg/kg BW, respectively. The iron overload in this rat model was induced by means of 15 mg intraperitoneal iron dextran, twice a week for 4 weeks. Plasma mangiferin was measured using high performance liquid chromatography, plasma ferritin by using enzyme linked immunosorbent assay, and iron contents of plasma, urine, and tissues by using atomic absorbance spectrophotometry. RESULTS Plasma mangiferin concentration at doses of 50, 100, or 200 mg/kg BW were 416.10±112.04, 310.55±134.18, and 450.11±165.99 ng/mL, respectively. At 50 mg/kg BW, mangiferin significantly decreased plasma ferritin levels (from 7051.14±1368.24 to 5543.80±1225.53 ng/mL, (p=0.037). Mangiferin also showed tendency to increase urinary iron excretion and to decrease cardiac and hepatic iron accumulation. CONCLUSION In our model, oral administration of mangiferin showed non-linear pharmacokinetics and low bioavailability. At a dose of 50 mg/kg BW, mangiferin decreased plasma ferritin levels significantly. Mangiferin did not prevent the increase of plasma iron, although it exerted tendency to increase urinary iron excretion and to decrease iron accumulation in liver and heart.

Model Skoring Untuk Memprediksi Anemia Defisiensi Besi pada Bayi 0-6 Bulan

Latar belakang. Anemia defisiensi besi (ADB) merupakan salah satu masalah kesehatan gizi di Indonesia. Data SKRT tahun 2001 menunjukkan prevalensi ADB pada bayi 0-6 bulan 61,3%. Belum dijumpai pemeriksaan laboratorium sederhana yang dapat memprediksi seorang bayi berusia 0-6 bulan menderita ADB. Tuj uan. Mencari model skoring untuk memprediksi ADB pada bayi 0-6 bulan. Metode. Desain penelitian adalah studi kohort prospektif dengan pembanding eksternal. Ada 211 bayi yang ikut penelitian, terdiri dari 143 bayi yang lahir dari ibu tanpa anemia dan 68 bayi yang lahir dari ibu dengan anemia. Pemeriksaan darah tepi lengkap, gambaran darah tepi, feritin, sTfR dilakukan saat bayi berusia 0 bulan, 1, 2, 3, 4, 5, 6, dan 12 bulan. Diagnosis ADB berdasarkan 1) kadar Hb 14%, 5) Indeks Mentzer >13; 6) Indeks RDW >220. Hasil. Faktor risiko terjadi ADB pada bayi berusia 0-6 bulan adalah diet ibu dan jenis kelamin bayi. Berdasarkan faktor risiko dibuat model skoring dan klasifikasi risiko untuk memprediksi seorang bayi berusia 0-6 bulan akan menderita ADB atau tidak. Kesimpulan. Model skoring untuk memprediksi ADB pada bayi berusia 0-6 bulan dapat digunakan untuk deteksi dini ADB. (

Butyrylcholinesterase and C5+ variant in a Javanese ethnic group in Indonesia

OBJECTIVE This study was designed to investigate the butyrylcholinesterase (BChE) and C5 variant phenotypes in a Javanese ethnic group in Indonesia. BLOOD-DONORS, MATERIALS AND METHODS: Random blood samples from a Javanese ethnic group were obtained from the Indonesian Red Cross Service. The donors were 40.09 +/- 9.53 years old, consisting of 358 (89.45%) males and 42 females (10.55%). The plasma content of BChE was determined spectrophotometrically using benzoylcholine as substrate, and phenotyping of BChE was performed using the inhibitors 10 microM dibucaine and 50 microM sodium fluoride. Phenotyping of the C5+ variant was carried out by means of polyacrylamide gel electrophoresis using a 7.5% (w/v) acrylamide slab gel and a 3% (w/v) acrylamide stacking gel, and stained with fast red azo dye. RESULTS The results show that of 398 samples studied, the average activities of BChE are 1.00 +/- 0.22 U/ml. 377 individuals (94.72%) show normal activities, whereas 21 individuals (5.78%) are below normal (< 0.690 U/ml). The mean +/- SD of dibucaine number (DN) is 83 +/- 5 and the fluoride number (FN) is 66 +/- 6. From this population we identified one individual with UA phenotype (total activity: 0.310 U/ml, DN: 62, and FN: 50). The frequency of C5+ variant in the population as detected by acrylamide electrophoresis is 21%. CONCLUSION Our data indicate that the atypical allele of BChE is rare and that the C5+ variant is detected in high frequency in the ethnic Javanese of Indonesia.