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"Artemisinin-based Combination Theraphy (ACT) telah digunakan sebagai terapi utama untuk mengobati malaria falciparum tanpa komplikasi di Indonesia sejak 2004. Dihydroartemisinin-piperaquine (DHP) diangkat sebagai terapi utama untuk semua kasus malaria tanpa komplikasi sejak tahun 2016, termasuk kasus malaria vivax. Tujuan dari penelitian ini adalah untuk mengevaluasi polimorfisme nukleotida tunggal pada class domain propeller gen diantara kasus malaria tanpa komplikasi yang disebabkan Plasmodium vivax dari Provinsi Jambi dan Papua, Indonesia. IsolatP. vivax diambil dari April 2016 hingga April 2018. Melalui deteksi kasus aktif dan pasif malaria vivax tanpa komplikasi, sebanyak 41 isolat dari Provinsi Jambi dan 55 isolat dari Provinsi Papua terekrut pada penelitian ini. Domain propeller gen pvk12 diamplifikasi dengan metode nested PCR lalu disekuensing untuk mengevaluasi polimorfisme nukleotida tunggal. Hasil dari penelitian ini menunjukkan tidak ditemukan polimorfisme domain propeller pada kodon M448, T517, F519, I568, D605, D691, dan I708 dari seluruh isolat yang diteliti. Polimorfisme pada kodon S578Y dari domain propeller gen pvk12 ditemukan pada satu isolat dari Provinsi Jambi.

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Artemisinin-based combination therapy (ACT) has been adopted as first line therapy for uncomplicated falciparum malaria in Indonesia since 2004. Dihydroartemisininpiperaquine (DHP) has been adopted as first line therapy for all uncomplicated malaria cases in Indonesia since 2016.

The present study aims is to evaluate the single nucleotide polymorphisms in propeller domain gene among uncomplicated of Plasmodium in Jambi and Papua Provinces, Indonesia. The P. vivax isolates were collected from April 2016 to April 2018. A total of 41 P. vivax isolates from Jambi and 55 isolates from Papua were collected from uncomplicated vivax malaria cases enrolled through active and passive case detections. Amplification by nested PCR used to amplify gene propeller domain and sequencing is used to evaluate single nucleotide polymorphism.

The overall results indicated that no polymorphisms of propeller domain pvk12 gene at codon M448, T517, F519, I568, D605, D691, and I708 were observed in all isolates. Polymorphism at codon S578Y of propeller domain gene was found in one isolate from Jambi Province."

"Pendahuluan: Artesunat amodiakuin (AS-AQ) merupakan artemisinin-based combination therapy (ACT) yang digunakan sebagai lini pertama di berbagai daerah endemik di Indonesia. Studi sebelumnya pada pasien malaria falsiparum tanpa komplikasi di Sumba Indonesia menunjukkan gagal terapi sebesar 11,1%. Diduga salah satu penyebab kegagalan terapi adalah polimorfisme gen sitokrom P450 2C8 (CYP2C8), CYP1A1 dan CYP1B1. Penelitian ini bertujuan untuk mempelajari peran polimorfisme pada gen pemetabolisme artesunat amodiakuin terhadap kegagalan terapi amodiakuin. Metodologi: Analisis polimorfisme CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 dan CYP1B1*3 dilakukan pada pasien malaria falsiparum yang mendapatkan AS-AQ di Sumba Indonesia (N=110). Single nucleotide polymorphisms (SNPs) dianalisis menggunakan polymerase chain reaction (PCR) dilanjutkan dengan retriction-fragment length polymorphism (RFLP) dan sekuensing. Hasil: Tidak ditemukan alel CYP2C8*2 dan alel CYP2C8*3 pada sampel penelitian (N=110). Frekuensi alel CYP1A1*2, CYP1B1*2 dan CYP1B1*3 berturut-turut sebanyak 5%, 23,6% dan 4,1%. Tidak ditemukan kemaknaan pada analisis haplotipe CYP1B1*2 (p=0,13, 95% CI: 0,11 – 1,34) dan CYP1B1*3 (p=0,34, 95% CI: 0,44 – 11,34). Hanya ditemukan tipe heterozigot pada alel CYP1A1*2 dan CYP1B1*3. Kesimpulan: Tidak ditemukan hubungan antara alel CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 dan CYP1B1*3 dengan kegagalan terapi amodiakuin di Sumba, Indonesia.

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Introduction: Artesunate amodiaquine (AS-AQ) is one of the ACT used in many endemic areas in Indonesia. Previous study in Sumba showed that there were 11,1% treatment failure with AS-AQ in uncomplicated malaria falciparum patients. Polymorphisms in cytochrome P450 2C8 (CYP2C8), CYP1A1 and CYP1B1 genes are thought to be the major factors in the treatment failure of amodiaquine. The aim of this study was to analyze the role of polymorphisms in the genes encoding amodiaquine metabolizing enzymes (CYP2C8, CYP1A1, CYP1B1) in the treatment failure of amodiaquine.

Methodology: Polymorphisms of CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 and CYP1B1*3 were studied in patients with malaria falciparum treated with AS-AQ in Sumba Indonesia (N=110). Single nucleotide polymorphisms (SNPs) were analyzed using polymerase chain reaction (PCR) continued with restriction-fragment length polymorphism (RFLP) and sequencing.

Results: There were no CYP2C8*2 and CYP2C8*3 alleles found in the samples (N=110). The frequency of CYP1A1*2, CYP1B1*2 and CYP1B1*3 alleles were 5%, 23,6% and 4,1%, respectively. There were no significant difference in haplotype analysis of CYP1B1*2 (p value=0,13, 95% confidence interval=0,11 – 1,34) and CYP1B1*3 (p value=0,34, 95% confidence interval=0,44 – 11,34). Heterozygote types were found in CYP1A1*2 and CYP1B1*3 alleles.

Conclusions: There were no associations between CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 and CYP1B1*3 alleles with treatment failure of amodiaquine in Sumba, Indonesia."

"[ABSTRAKLatar belakang: Salah satu tantangan terbesar dalam upaya pengobatan malaria adalahterjadinya penurunan efikasi pada penggunaan obat antimalaria, seperti kasus resistensi.Kejadian resistensi terhadap beberapa jenis obat mendorong penemuan obat antimalariabaru terus dilakukan. Beberapa studi yang telah dilakukan menyebutkan bahwaandrografolid (ANDRO) memiliki efek sebagai antimalaria. Dehidroksiandrografolid(DeOH-AND) adalah senyawa yang memiliki kemiripan struktur dengan ANDRO.Penelitian ini bertujuan untuk mengetahui efek DeOH sebagai antiplasmodium danmekanisme kerjanya.Metode: Penelitian ini merupakan penelitian eksperimental dengan teknik in vitro. Padapenelitian ini digunakan galur parasit Plasmodium falciparum 3D7 (chloroquinesensitive). Percobaan dilakukan untuk menjawab tiga tujuan penelitian; pertamabertujuan untuk mengetahui potensi DeOH-AND sebagai antiplasmodium denganmelakukan uji IC50, uji hambatan bergantung stadium parasit dan melihat morfologi selparasit menggunakan mikroskop cahaya dan TEM (Transmission Electron Microscope).Kedua bertujuan untuk mengetahui efek sitotoksik DeOH-AND terhadap sel mamaliayang diujikan pada sel hati galur sel HepG2 dan sel darah merah. Ketiga, bertujuan untukmempelajari pengaruh DeOH-AND terhadap status oksidatif parasit dilihat dari kadarROS intraseluler parasit, rasio GSH/GSSG dan aktivitas enzim SOD.Hasil: DeOH-AND memiliki aktivitas antiplasmodium dengan nilai IC50 sebesar 4 μMsedangkan kontrol klorokuin yang digunakan memiliki nilai IC50 sebesar 0.06 μM(60x10-9 M). Kedua senyawa ini dapat menghambat pertumbuhan sel parasit pada stadiumring, tropozoit dan skizon. Hasil pengamatan menggunakan mikroskop cahaya dan TEMmempelihatkan kerusakan pada sel parasit bila dibandingkan dengan kontrol. SenyawaDeOH-AND tidak toksik terhadap sel hati (HepG2) dengan nilai CC50 yakni 394.67 μMserta tidak toksik pada sel darah merah. Hasil percobaan bagian ketiga menunjukkanbahwa DeOH-AND tidak mempengaruhi kadar ROS, rasio GSH/GSSG serta aktivitasenzim SOD.Kesimpulan: Senyawa DeOH-AND memiliki potensi sebagai antiplasmodium dan tidakmemiliki efek toksik terhadap sel mamalia baik hati (HepG2) dan sel darah merah.DeOH-AND tidak mempengaruhi status oksidatif parasit secara signifikan.

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ABSTRACTBackground: One of the biggest challenges in malaria treatment is the occurrence ofdecreasing efficacy on antimalarial drugs like resistancy cases. Insidence of some drugresistance encourages the new antimalarial drugs continue to discover. Severeal studiesmentioned that andrographolide (ANDRO) has an antimalarial effect.Dehidroksiandrographolide (DeOH) is a compound which has structural similarities withANDRO. This study aims to determine the effect of DeOH as antiplasmodium and itsmechanism.Methods: This is an experimental study using in vitro techniques. In this study were usedPlasmodium falciparum 3D7 strains (chloroquine sensitive). The experiments has three aims;the first part was aimed to known about the potential of DeOH-AND as an antiplasmodiumusing IC50 assay technique, stage dependent antiplasmodium activity, and analyse the P.falciparum morphology using light microscope and TEM (Transmission ElectronMiscroscope) technique. The second parts was aimed to investigate the cytotoxic effect ofDeOH-AND on mamalian cell (hepar cell-HepG2 and red blood cell). And the third aims isto investigate the effect of DeOH-AND on parasite oxidative stress status with analyse theintracellular ROS (Reactive Oxygen Species) concentration, GSH/GSSG ratio and SOD(Superoxide Dismutase) enzyme activity.Results: DeOH-AND has antiplasmodium activity with IC50 value of 4 μM whereaschloroquine has IC50 values of 0.06 μM (60x10-9M). These compounds was found to inhibitthe ring, tropozoit and skizon stage of the parasite. Treated P. falciparum 3D7 parasites showthe crisis of their morphology cell which compared with untreated parasites (control). DeOHANDis not toxic to liver cells (HepG2) with CC50 values 394.67 and also not toxic to redblood cells which were seen from the results of hemolysis potential test. DeOHantiplasmodium effect were seen on all stage of the parasite (either ring, trophozoit andschizont) and caused parasite cell damage effect activity at all stages of the parasite (eitherring, trophozoit and schizonts) and shown to cause damage. The third experiment showed thatDeOH-AND did not affect the intracellular ROS (Reactive Oxygen Species) concentration,GSH/GSSG ratio and also SOD enzyme activity.Conclusions: DeOH compounds has antiplasmodium activity. These compound has no toxiceffect on both of the liver cells (HepG2) and red blood cells. DeOH-AND did not affect parasitoxidative status with significantly, Background: One of the biggest challenges in malaria treatment is the occurrence ofdecreasing efficacy on antimalarial drugs like resistancy cases. Insidence of some drugresistance encourages the new antimalarial drugs continue to discover. Severeal studiesmentioned that andrographolide (ANDRO) has an antimalarial effect.Dehidroksiandrographolide (DeOH) is a compound which has structural similarities withANDRO. This study aims to determine the effect of DeOH as antiplasmodium and itsmechanism.Methods: This is an experimental study using in vitro techniques. In this study were usedPlasmodium falciparum 3D7 strains (chloroquine sensitive). The experiments has three aims;the first part was aimed to known about the potential of DeOH-AND as an antiplasmodiumusing IC50 assay technique, stage dependent antiplasmodium activity, and analyse the P.falciparum morphology using light microscope and TEM (Transmission ElectronMiscroscope) technique. The second parts was aimed to investigate the cytotoxic effect ofDeOH-AND on mamalian cell (hepar cell-HepG2 and red blood cell). And the third aims isto investigate the effect of DeOH-AND on parasite oxidative stress status with analyse theintracellular ROS (Reactive Oxygen Species) concentration, GSH/GSSG ratio and SOD(Superoxide Dismutase) enzyme activity.Results: DeOH-AND has antiplasmodium activity with IC50 value of 4 μM whereaschloroquine has IC50 values of 0.06 μM (60x10-9M). These compounds was found to inhibitthe ring, tropozoit and skizon stage of the parasite. Treated P. falciparum 3D7 parasites showthe crisis of their morphology cell which compared with untreated parasites (control). DeOHANDis not toxic to liver cells (HepG2) with CC50 values 394.67 and also not toxic to redblood cells which were seen from the results of hemolysis potential test. DeOHantiplasmodium effect were seen on all stage of the parasite (either ring, trophozoit andschizont) and caused parasite cell damage effect activity at all stages of the parasite (eitherring, trophozoit and schizonts) and shown to cause damage. The third experiment showed thatDeOH-AND did not affect the intracellular ROS (Reactive Oxygen Species) concentration,GSH/GSSG ratio and also SOD enzyme activity.Conclusions: DeOH compounds has antiplasmodium activity. These compound has no toxiceffect on both of the liver cells (HepG2) and red blood cells. DeOH-AND did not affect parasitoxidative status with significantly]"

"ABSTRAKMalaria masih menjadi salah satu masalah di dunia. Salah satu tantangan dalam eliminasi malaria adalah timbulnya resistensi obat antimalaria. Terjadinya resistensi telah mendorong usaha untuk penemuan kandidat obat antimalaria. Beberapa studi yang dilakukan memperlihatkan adanya aktivitas antimalaria dari produk fermentasi Streptomyces sp. Streptomyces sp. menghasilkan beberapa metabolit sekunder yang diantaranya memilki aktivitas antimalaria yaitu prodigiosin. Penelitian ini bertujuan untuk mengetahui efektivitas produk fermentasi Streptomyces sp. sebagai antimalaria, mekanisme kerja hambatannya dan sifat toksisitasnya terhadap sel HepG2. Penelitian ini merupakan penelitian eksperimental dengan teknik in vitro, menggunakan galur parasit Plasmodium falciparum 3D7 drug sensitive . Penelitian dilakukan untuk mengetahui potensi produk fermentasi Streptomyces sp. sebagai antimalaria dengan melakukan uji IC50, dan mekanisme kerja dengan Transmission Electron Microscopy TEM . Dilakukan pula uji toksisitas produk fermentasi Streptomyces sp. pada sel HepG2. Produk fermentasi Streptomyces sp. memiliki aktivitas sebagai antimalaria dengan nilai IC50 sebesar 0,001 ?g/mL, sedangkan kontrol kuinidin yang digunakan memiliki nilai IC50 sebesar 0,054 ?g/mL dan prodigiosin 0,022 ?g/mL. Hasil pengamatan dengan TEM menunjukkan tidak terbentuknya hemozoin. Produk fermentasi Streptomyces sp. bersifat tidak toksik terhadap sel hati HepG2 dengan nilai CC50 1380 ?g/mL. Produk fermentasi Streptomyces sp. memiliki potensi sebagai antimalaria dan tidak memiliki efek toksik terhadap sel HepG2

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ABSTRACTMalaria remains one of the problem in the world. One of the challenge in malaria elimination is the emergence of antimalarial drug resistance. The occurance of drug resistance has been encouraging efforts to find antimalarial drugs candidate. Some studies showed that there was antimalarial activity from Streptomyces sp. fermentation. Streptomyces sp. produced some secondary metabolite, which include prodigiosin who had antimalarial activity. This research aim to know the activity of Streptomyces sp. fermentation product as antimalarial, worked mechanism and toxicity on HepG2 cell. This research was experimental research with in vitro technique using Plasmodium falciparum 3D7 drug sensitive parasite. The research was done to know potency of Streptomyces sp. fermentation product as antimalarial by IC50 test, and worked mechanism by Transmission Electron Microscopy TEM . Toxicity tests was also done on HepG2 cell. Streptomyces sp. fermentation product has activity as antimalarial with IC50 value 0,001 g mL, quinidine control has IC50 value 0,054 g mL and prodigiosin 0,022 g mL. Observation with TEM showed no formation of hemozoin. Streptomyces sp. fermentation product was not toxic for HepG2 sel with CC50 value 1380 g mL. Streptomyces sp. fermentation product has a potency as antimalarial and not toxic for HepG2 cell."