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Abstrak :
Relaps masih menjadi masalah dalam eradikasi malaria vivaks. Primakuin adalah satu-satunya antihipnozoit yang saat ini tersedia di pasaran. Efikasi primakuin diperoleh oleh farmakokinetik dan farmakodinamik obat. Kemampuan CYP2D6 memetabolisme primakuin menjadi bentuk aktif akan memengaruhi kadar primakuin dan efikasi klinisnya. Pada penelitian ini dilakukan analisis farmakokinetik dan farmakodinamik primakuin dengan pendekatan populasi pada subjek dengan malaria vivaks; serta menganalisis hubungan variasi jumlah salinan gen CYP2D6 dengan kejadian relaps. Subjek studi adalah 174 orang Tentara Nasional Indonesia yang terinfeksi malaria vivaks dan diterapi dengan kombinasi skizontisida dan primakuin selama 14 hari. Kejadian relaps diamati selama satu tahun. Model farmakokinetik-farmakodinamik primakuin yang dikembangkan dengan metode mixed effect non linier menggunakan piranti lunak NONMEM versi 7.4.1. Kuantifikasi jumlah salinan gen CYP2D6 dilakukan pada 49 subjek. Jumlah salinan ditentukan berdasarkan nilai Cq hasil amplifikasi intron 6 dengan qPCR real-time. Jumlah salinan dihitung sesuai dengan rumus 2-ΔΔCq x jumlah salinan DNA Kalibrator, ΔΔCq = ΔCq (kalibrator)  ΔCq (sampel) dan ΔCq = Cq (CYP2D6) - Cq (RNAse P). Hubungan jumlah salinan gen CYP2D6 dan kejadian relaps malaria vivaks dianalisis dengan uji Chi-square. Hasil penelitian menunjukkan bahwa kadar primakuin plasma paling baik dideskripsikan oleh model satu kompartemen dengan penyerapan orde pertama. Berat badan diimplementasikan sebagai fungsi alometrik pada clearance (CL) dan distribusi volume (Vd). Piperakuin maupun pironaridin menurunkan CL dan Vd primakuin sebesar 3354%. Faktor genetik CYPD6 tidak memengaruhi CL primakuin. Risiko kejadian relaps malaria vivaks dideskripsikan dengan model constant hazard pada model time-to-event. Peningkatan satu poin skor aktivitas gen CYP2D6 menurunkan risiko relaps sebesar 88,3%, sehingga dapat disangkal bahwa faktor genetik CYP2D6 menjadi salah satu faktor yang dapat memengaruhi risiko kambuh vivaks malaria. Tidak didapatkan hubungan antara AUC primakuin dan kejadian relaps, sehingga hasil ini tidak dapat digunakan untuk menghitung dosis primakuin yang optimal. Kuantifikasi jumlah salinan gen CYPD6 dilakukan pada 21 subjek relaps dan 28 subjek kontrol. Mayoritas subjek memiliki jumlah salinan ≥ 2 (39 dari 49 orang). Tidak ditemukan hubungan antara jumlah salinan gen CYP2D6 dan kejadian relaps (p = 0,155). Relapse is still a problem in vivax malaria eradication. Primakuine is the only antihipnozoite currently available on the market. The efficacy of primaquine is obtained by the pharmacokinetics and pharmacodynamics of the drug. The ability of CYP2D6 to metabolize primaquine to its active form will affect primakuine levels and clinical efficacy. In this study, a pharmacokinetic and pharmacodynamic analysis of primaquine was carried out with a population approach in subjects with vivax malaria; and to analyze the relationship between variations in the number of copies of the CYP2D6 gene with the incidence of relapse. Study subjects were 174 Indonesian National Armed Forces infected with vivax malaria and treated with a combination of schizonticides and primaquine for 14 days. Relapse incidence was observed for one year. The primakuine pharmacokinetic-pharmacodynamic model was developed using a non-linear mixed effect method using NONMEM software version 7.4.1. Quantification of the number of copies of the CYP2D6 gene was performed in 49 subjects. The number of copies is determined based on the Cq value of the intron 6 amplification with real-time qPCR. The number of copies is calculated according to the formula 2-ΔΔCq x number of copies of the DNA Calibrator, ΔΔCq = ΔCq (calibrator)  ΔCq (sample) and ΔCq = Cq (CYP2D6) - Cq (RNAse P). The association between copy number of CYP2D6 gene and the incidence of vivax malaria relapse was analyzed using Chi-square test. The results showed that plasma primquine levels were best described by a one-compartment model with first-order absorption. Body weight is implemented as an allometric function on clearance (CL) and volume distribution (Vd). Piperakuine and pyronaridin reduce CL and Vd primakuin by 3354%. CYPD6 genetic factor does not affect CL primaquine. The risk of vivax malaria relapse was described using the constant hazard model in the time-to-event model. One point increase in the CYP2D6 gene activity score reduced the risk of relapse by 88.3%, so it can be denied that CYP2D6 genetic factor is one of the factors that can affect the risk of malaria vivax relapse. There was no relationship between AUC of primaquine and the incidence of relapse, so these results cannot be used to calculate the optimal primquine dose. CYPD6 gene copy count quantification was performed in 21 relapsed subjects and 28 control subjects. The majority of subjects had a number of copies ≥ 2 (39 of 49 people). No association was found between the number of copies of the CYP2D6 gene and the incidence of relapse (p = 0.155).

Abstrak :
Anredera cordifolia (Ten.) Steenis (binahong) merupakan salah satu bahan alam yang memiliki potensi dan digunakan untuk pengobatan tradisional. Efek farmakologi tanaman binahong dapat digunakan sebagai alternatif menurunkan kadar glukosa darah. Penelitian terdahulu melaporkan bahwa penggunaan bersama herbal dengan obat sintetik dapat menyebabkan terjadi perubahan pada farmakodinamika dan farmakokinetika obat sintetik. Informasi mengenai interaksi antara obat herbal dengan obat sintetik masih terbatas sehingga perlu diketahui efektivitas penggunaan kombinasi tersebut. Penelitian ini bertujuan untuk membuktikan adanya interaksi farmakodinamika dan farmakokinetika kombinasi ekstrak daun binahong dengan glibenklamid yang diberikan secara oral sebagai antidiabetes. Penelitian ini dilakukan secara ekperimental dan non ekperimental. Penelitian eksperimental dibagi menjadi dua bagian. Bagian pertama adalah pengujian interaksi farmakodinamika untuk efek antidiabetes dengan metode pengukuran kadar glukosa secara enzimatik. Kadar glukosa darah diukur sebelum perlakuan, setelah induksi pakan tinggi lemak (sukrosa 20 %, lemak sapi 20 %, mentega 10% dan pakan standar 50 %) dan setelah pemberian sediaan uji. Pengambilan sampel darah digunakan untuk pengujian TTGO, profil asam amino dan profil asam lemak. Bagian kedua adalah pengujian interaksi farmakokinetika dengan mengambil darah tikus pada titik tertentu setelah pemberian ekstrak daun binahong dan obat glibenklamid. Konsentrasi glibenklamid diukur dengan menggunakan kromatografi cair kinerja ultra tinggi-tandem spektrometri massa (KCKUT-SM/SM), selanjutnya dihitung nilai AUC, Tmaks, Cmaks, T1/2 dan Ke. Penelitian non ekperimental dilakukan drug design untuk memprediksikan ikatan antara kandidat molekul obat glibenklamid dan vitexin (senyawa yang terdapat dalam ekstrak binahong) sebagai antidiabetes dengan protein target CYP3A4 secara in silico dengan menggunakan molecular docking serta memprediksi interaksi antarprotein. Hasil uji pada farmakodinamika diperoleh kadar glukosa darah pada kombinasi glibenklamid (4,5 mg/kgBB) dengan ekstrak daun binahong dosis 1 (17,5 mg/kgBB), dosis 2 (35 mg/kgBB) dan dosis 3 (70mg/kgBB) dapat menurunkan kadar glukosa darah kembali normal namun persentase penurunan kadar glukosa pada hari ke 21 terbesar terdapat pada kelompok kontrol positif. Pada pengujian tes toleransi glukosa kelompok kombinasi memperoleh nilai AUC sebanding dengan nilai AUC kelompok positif yang diberi glibenklamid. Hasil penelitian pada profil asam lemak dan profil asam amino menunjukkan kelompok kombinasi obat dengan ekstrak daun binahong mengalami penurunan asam lemak dan peningkatan asam amino. Hasil uji profil farmakokinetika glibenklamid berbeda antara pemberian tunggal dengan kombinasi ekstrak daun binahong. Pemberian glibenklamid (4,5 mg/kgBB) dengan ekstrak daun binahong (70mg/kgBB) dapat menurunkan AUC dan Cmaks serta memperpanjang Tmaks. Hasil energi bebas gibs (ΔG) pada molecular docking diperoleh nilai glibenklamid dan vitexin yang berikatan dengan reseptor CYP3A4 dengan score ChemPLP sebesar -4,4 kkal/mol, glibenclamid dengan reseptor -3,2 kkal/mol dan vitexin dengan reseptor yaitu -3,2 kkal/mol, dapat disimpulkan bahwa pemberian kombinasi glibenklamid (4,5 mg/kgBB) dengan ekstrak daun binahong dosis 1 (17,5 mg/kgBB), dosis 2 (35 mg/kgBB) dan dosis 3 (70mg/kgBB) secara oral dapat menurunkan kadar glukosa darah pada tikus yang diinduksi pakan tinggi lemak. Persentase penurunan kadar glukosa darah lebih tinggi pada kelompok yang hanya diberikan glibenklamid 4,5 mg/kgBB (kelompok positif), sementara pada kelompok pemberian tunggal (ekstrak binahong dosis 1,2 dan 3), mengalami penurunan kadar glukosa tetapi tidak lebih tinggi persentase penurunan kadar glukosa darah dibandingkan dengan kelompok kontrol positif. Pada uji farmakokinetika pemberian kombinasi glibenklamid (4,5 mg/kgBB) dengan ekstrak daun binahong (70 mg/kgBB) secara oral dapat menurunkan kadar obat glibenklamid dalam plasma tikus. ......Anredera cordifolia (Ten.) Steenis (binahong) is a natural ingredient with potential and is used in traditional medicine. The pharmacological effect of the binahong plant can be used as an alternative to lower blood glucose levels. Previous studies have reported that the concomitant use of herbs with synthetic drugs can cause changes in the pharmacodynamics and pharmacokinetics of synthetic drugs. Information regarding the interaction between herbal medicines and synthetic drugs is still limited, so it is necessary to know the effectiveness of using these combinations. This study aims to prove the pharmacodynamic and pharmacokinetic interactions of the combination of binahong leaf extract with glibenclamide administered orally as an anti-diabetic. This research was conducted experimentally and non-experimentally. Experimental research is divided into two parts. The first step is to test the pharmacodynamic interactions for the anti-diabetic effect using the enzymatic method of measuring glucose levels. Blood glucose level pressure was measured before treatment, after induction of a high-fat diet (20% sucrose, 20% beef fat, 10% butter, and 50% standard feed), and after administration of the test preparation. Blood sampling was used for testing OGTT, the amino acid profile, and the fatty acid profile. The second part is testing pharmacokinetic interactions by taking rat blood at a certain point after administration of binahong leaf extract and glibenclamide drug. The concentration of glibenclamide was measured using ultra-high performance liquid chromatography-tandem mass spectrometry (KCKUT-SM/SM), then the AUC, Tmax, Cmax, T1/2, and Ke values were calculated. Non-experimental research was conducted with drug design to predict the bond between candidate drug molecules glibenclamide and vitexin, one of the compounds contained in binahong extract as an anti-diabetic with CYP3A4 target protein in silico, by using molecular docking and predicting interactions between proteins. The results of the pharmacodynamic test obtained blood glucose levels in the combination of glibenclamide (4.5 mg/kg BW) with binahong leaf extract dose 1 (17.5 mg/kg BW), dose 2 (35 mg/kg BW), and dose 3 (70mg/kg BW) can reduce blood glucose levels back to normal, but the percentage of decrease in glucose levels on the 21st day is greatest in the positive control group. In the glucose tolerance test, the combined group obtained an AUC value comparable to the one in the positive group given glibenclamide. The study's results on the fatty acid profile and amino acid profile showed that the combination group of drugs with binahong leaf extract experienced a decrease in fatty acids and an increase in amino acids. The test results of the pharmacokinetic profile of glibenclamide were different between a single administration and a combination of binahong leaf extract. Giving glibenclamide (4.5mg/kg BW) with binahong leaf extract (70mg/kg BW) can reduce AUC and Cmax and prolong Tmax. The results of gibs free energy (ΔG) on molecular docking obtained the values of glibenclamide and vitexin, which bind to the CYP3A4 receptor with a ChemPLP score of -4.4 kcal/mol, glibenclamide with a receptor -3.2 kcal/mol and vitexin with a receptor of-3,2 kcal/mol. Conclusion The results of this study show that the administration of a combination of glibenclamide (4.5 mg/kg BW) with binahong leaf extract dose 1 (17.5 mg/kg BW), dose 2 (35 mg/kg BW) and dose 3 (70mg/kg BW) orally can lower blood glucose levels in rats induced by a high-fat diet, but the percentage reduction in blood glucose levels was better in the group that was only given glibenclamide 4.5 mg/kgBW (positive group), while in the group that was only given binahong extract doses of 1,2 and 3 also experienced a decrease in glucose levels but the percentage decrease in glucose levels was not greater than the positive control group. In the pharmacokinetic test orally administering a combination of glibenclamide (4.5 mg/kg BW) with binahong leaf extract (70 mg/kg BW) can reduce glibenclamide drug levels in rat plasma.

Abstrak :
This book presents new European work in the area of addiction studies, focusing on the temporal and spatial variances of addiction behaviours and the solution repertoires for dealing with their problematic variants. It contains work in three main research areas. First, it provides insight into the historical and regionally bound language use tied to addiction problems, showing how concepts and ideas have been intertwined with certain trends globally and regionally. Second, it provides a framework for understanding the roles played by different social actors and stakeholders in different European societies when addressing and solving the problems associated with addiction. Third, it reports on perceptions of the problems as an integrated part of epistemic and political systems, as well as part of a popular understanding among lay people.