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"Kelebihan besi dapat menyebabkan kerusakan organ akibat pembentukan radikal bebas dan ferroptosis, terutama pada hati sebagai organ utama penyimpanan besi. Efikasi deferiprone sebagai kelator standar yang paling banyak digunakan di Indonesia untuk menurunkan kadar besi hati masih tidak adekuat dan memiliki potensi hepatotoksik. Penelitian ini bertujuan untuk melihat efek kombinasi deferiprone dengan ekstrak etanol buah Phaleria macrocarpa (PM) yang sudah terbukti mampu mengkelat besi untuk mengatasi kelebihan besi pada tikus model hemosiderosis serta melihat interaksi senyawa aktif ekstrak PM dengan transporter uptake besi (DMT-1 dan ZIP-14) secara in-silico. Tikus dibagi menjadi enam kelompok, yaitu normal (N), kontrol negatif (KN), deferiprone (D), kombinasi deferiprone dosis lazim+ekstrak PM (DPM1) dan kombinasi deferiprone setengah dosis lazim+ekstrak PM (DPM2). Induksi kelebihan besi dilakukan dengan injeksi iron-dextran (intraperitoneal) selama 8 minggu. Terapi dimulai pada minggu ke-4 hingga ke-8. Parameter yang diukur meliputi kadar besi dan malondialdehid (MDA) hati, aktivitas ALT dan AST plasma, kadar GSH, TNF-α, ekspresi mRNA GPx4 pada hati, serta pemeriksaan histopatologi. Penelitian in-silico dilakukan dengan pendekatan homology modeling dan molecular docking. Hasil penelitian pada tikus menunjukkan bahwa seluruh kelompok terapi belum mampu menurunkan kadar besi hati secara bermakna dibandingkan kelompok KN, tetapi kelompok DPM-2 menunjukkan penurunan kadar besi yang paling baik. Secara histopatologis, terjadi penurunan akumulasi besi yang bermakna pada kelompok DPM-2. Penurunan kadar besi tersebut disertai dengan penurunan kadar MDA, ALT dan AST yang lebih baik dibandingkan monoterapi dengan deferiprone. Terapi kombinasi menyebabkan peningkatan GSH yang tidak bermakna dan belum mampu meningkatkan ekspresi mRNA GPx4. Hasil molecular docking menunjukkan bahwa beberapa senyawa di dalam ekstrak PM dapat berinteraksi dengan transporter DMT-1 dan ZIP-14 dengan binding energy yang cukup baik. Efek inhibisi terhadap transporter harus dibuktikan lebih lanjut secara in-vitro atau in-vivo.

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Iron overload can lead to organ damage through the formation of free radicals and ferroptosis, particularly affecting the liver as the primary iron storage organ. The efficacy of deferiprone, the most commonly used standard chelator in Indonesia for reducing liver iron levels, remains inadequate and poses potential hepatotoxic risks. This study aims to investigate the effects of combining deferiprone with ethanol extract of Phaleria macrocarpa fruit (PM), which has demonstrated iron-chelating properties, in addressing iron overload in a rat model of hemosiderosis. Additionally, the study examines the interaction of active compounds in PM extract with iron uptake transporters (DMT-1 and ZIP-14) through in-silico methods. Rats were divided into six groups: normal (N), negative control (KN), deferiprone (D), combination of standard dose deferiprone and PM extract (DPM1), and combination of half-dose deferiprone and PM extract (DPM2). Iron overload was induced via intraperitoneal injection of iron-dextran for 8 weeks. Therapy commenced from week 4 to week 8. Parameters measured included liver iron and malondialdehyde (MDA) levels, plasma ALT and AST activities, liver GSH levels, TNF-α levels, and mRNA GPx4 expression, and histopathological examination. In-silico studies employed homology modeling and molecular docking approaches. Results indicated that none of the therapy groups significantly reduced liver iron levels compared to the KN group, but the DPM2 group showed the most substantial reduction in iron levels. Histopathological analysis revealed a significant decrease in iron accumulation in the DPM2 group. This iron reduction was accompanied by better reductions in MDA, ALT, and AST levels compared to deferiprone monotherapy. The combination therapy resulted in a non-significant increase in GSH levels and did not enhance mRNA GPx4 expression. Molecular docking results indicated that several compounds in the PM extract could interact with DMT-1 and ZIP-14 transporters with favorable binding energies. To confirm whether these interactions can result in transporter inhibition, further validation through in-vitro or in-vivo studies is necessary."

"Latar Belakang: Phaleria macrocarpa (PM) mengandung mangiferin yang memiliki kemampuan sebagai kelator besi dengan membentuk kompleks. Kompleks dapat menekan akumulasi besi pada pasien talasemia yang rutin transfusi. Kondisi besi berlebih dapat mempengaruhi terjadinya cedera organ ginjal. Penelitian bertujuan untuk mengetahui efektivitas ekstrak etanol buah PM sebagai agen kelator besi diamati pada organ ginjal tikus model besi berlebih. Metode: 30 tikus Sprague-Dawley dibagi acak 6 kelompok: normal (N), besi berlebih (KN), besi berlebih diobati Deferiprone dosis 462,5 mg/kgBB (D), besi berlebih diobati mangiferin dosis 50mg /kgBB (M), besi berlebih diobati ekstrak PM dosis 100mg/kgBB (PM100), besi berlebih diobati ekstrak PM dosis 200mg/kgBB (PM200). Injeksi besi diberikan 2kali/minggu selama 3 minggu dilanjutkan 8 minggu bersama pengobatan. Kadar besi ginjal diukur menggunakan AAS. Kadar urea dan kreatinin plasma serta TNF-α ginjal diukur menggunakan kit. Hasil: Mangiferin dari ekstrak terdeteksi pada ginjal tikus model besi berlebih diukur dengan HPLC. Mangiferin dan PM tidak dapat menurunkan kadar besi di organ ginjal dan kadar ureum plasma signifikan. Pengaruh mangiferin dan PM pada kadar kreatinin plasma tidak linier. Mangiferin dan PM dapat menurunkan kadar TNF-α ginjal signifikan dengan KN dan D.Kesimpulan: Mangiferin dan PM memiliki potensi kelator besi dan menurunkan respon inflamasi pada kondisi besi berlebih.

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Background: Mangiferin, active compound in Phaleria macrocarpa (PM), has been shown as an iron chelating agent by forming complexes. The complex can reduce iron accumulation in thalassemia patients receive transfusions. Renal organ failure can be impacted by the high iron. This study aims to determine the effectiveness of ethanolic extract of PM fruit as iron chelating agent observed in the kidney of iron overload rat.

Methods: 30 Sprague-Dawley divided randomly six groups: normal (N), iron-overload (KN), iron-overload treated Deferiprone dosage 462,5 mg/kgBW (D), iron-overload treated mangiferin dosage 50mg/kgBW (M), iron-overload treated PM extract dosage 100mg/kgBW (PM100) and iron-overload treated with PM extract dosage 200mg/kgBW (PM200). Iron injection was administered twice/week for 3 weeks, continued 8 weeks with treatment. Kidney iron levels of rats measured using AAS. Plasma urea and creatinine levels as well as renal TNF-α measured using kit.

Results: Mangiferin from extract was detected in the kidney of rat iron overload models which measured using HPLC. Mangiferin and PM cannot significantly reduce plasma urea and kidney iron levels. Effect of mangiferin and PM on plasma creatinine levels not linearly. Mangiferin and PM can reduce renal TNF-α levels significantly.

Conclusion: Mangiferin and PM have ability as iron chelator and reduce inflammatory response caused iron overload."

"ABSTRAKTransfusi darah dibutuhkan dalam meningkatkan kualitas hidup pasien thalassemia mayor, namun dapat menyebabkan kelebihan zat besi, sehingga diperlukan terapi kelasi besi, seperti deferipron dan deferasirox. Tujuan penelitian ini adalah menganalisis obat yang lebih cost-effective dengan metode Analisis Efektivitas-Biaya AEB karena masing-masing obat memiliki perbedaan efektivitas dan biaya obat yang signifikan. Data diambil secara retrospektif dan pengambilan sampel dilakukan secara total sampling berdasarkan catatan rekam medik dan sistem informasi rumah sakit. Pasien yang diikutsertakan merupakan pasien anak-anak pengguna deferipron n=33 dan deferasirox n=27 yang rutin melakukan transfusi darah pada tahun 2016. Efektivitas pengobatan diukur berdasarkan perubahan kadar serum ferritin. Biaya didapatkan dari median total biaya pengobatan, meliputi biaya obat, alat kesehatan, tindakan, administrasi dan jasa dokter, laboratorium serta kantong darah. Berdasarkan hasil penelitian, deferasirox 1.164 ng/mL lebih efektif dari deferipron 692 ng/mL dan median total biaya pengobatan deferasirox lebih mahal. Hasil akhir menunjukkan bahwa rasio efektivitas-biaya deferasirox Rp 65.816,68 lebih rendah dari deferipron Rp 74.956,60 , namun keduanya tidak ada yang mendominasi sehingga tidak dapat ditentukan terapi yang lebih cost-effective. Bila pengobatan deferipron dipilih, perlu dikeluarkan biaya tambahan sebesar Rp 52.416,64 untuk peningkatan satu unit efektivitas dan pengambil kebijakan di pelayanan kesehatan harus mempertimbangkan apakah biaya lebih tersebut sebanding dengan peningkatan efektivitasnya.

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ABSTRAKBlood transfusions are needed in improving the quality of life of major thalassemia patients, but it can lead to excess iron, so it requires iron chelation therapy, such as deferiprone and deferasirox. This study is aimed to analyse whether deferipron or deferasirox is more cost effective with Cost Effectiveness Analysis CEA method because each drug has a significant difference in effectiveness and drug costs. Data were taken retrospectively and sampling was done using total sampling based on medical records and hospital information systems. Patients which included are pediatric patients with deferiprone n 33 and deferasirox n 27 who regulary perform blood transfusion in 2016. The effectiveness is measured by changes in serum ferritin levels and the cost is median of the total cost, summed from the cost of drugs, medical devices, hospitalization, administration, physician, laboratories and blood bags. Based on the results, the effectiveness of deferasirox 1,164 ng mL is greater than deferiprone 692 ng mL and median total cost of deferasirox is more expensive. The final result showed that cost effective ratio of deferasirox Rp 65.816,68 is lower than deferiprone Rp 74.956,60 , but none of both medications is dominant and therefore we could not determine which medication is more cost effective. If deferiprone is selected, it requires extra cost Rp 52.416,64 to increase the effectivity. Policy maker in healthcare facility need to consider if incremental cost of medication is equal to its increased effectiveness."

"ABSTRAK Latar belakang. Kelasi besi diduga berperan terhadap penurunan fungsi ginjal pada pasien thalassemia mayor. Data fungsi ginjal pasien thalassemia mayor yang menggunakan kelasi besi oral di Jakarta masih terbatas. Tujuan. Mengetahui penurunan fungsi ginjal pasien thalassemia mayor yang mendapat kelasi besi oral dan faktor yang memengaruhinya. Metode penelitian. Penelitian dilakukan bulan Maret ndash; Juli 2017 pada pasien thalassemia mayor yang mendapat kelasi besi oral tunggal selama minimal 1 tahun. Fungsi ginjal dinilai dengan laju filtrasi glomerulus berdasarkan formula Schwartz revisi Fungsi tubulus ginjal dinilai dengan peningkatan rasio kalsium kreatinin urin hiperkalsiuria . Hasil penelitian. Total subjek sebanyak 54 orang 28 deferipron, 26 deferasiroks . Proporsi LFG menurun pada kelompok deferipron lebih tinggi dibandingkan deferasiroks 53,6 vs 46,2 . Hiperkalsiuria lebih banyak ditemukan pada kelompok deferasiroks dibandingkan deferipron 12,9 vs 3,6 . Penurunan LFG bermakna pada kelompok deferipron tetapi tidak bermakna pada kelompok deferasiroks. Tidak terdapat perbedaan bermakna LFG dan rasio kalsium kreatinin urin antara kelompok deferipron vs deferasiroks p=0,427; p=0,109 . Usia, hemoglobin, rerata hemoglobin, feritin, dosis kelasi besi dan saturasi transferin hanya memengaruhi fungsi tubular ginjal. Simpulan. Terdapat penurunan fungsi ginjal pada pasien thalassemia mayor yang mendapatkan kelasi besi oral. Fungsi ginjal pada thalassemia perlu dinilai berkala meski penurunannya tidak bermakna secara klinis.Kata kunci: Thalassemia, fungsi ginjal, kelasi besi oralABSTRACT Background. Iron chelator can cause renal dysfunction in thalassemia major patients. Data of renal function in thalassemia major patients who receive oral iron chelator are limited. Objective. To determine kidney dysfunction in thalassemia major patients receiving oral iron chelator and its correlating factors. Methods. The study was conducted in March ndash July 2017 on thalassemia major patients treated with single oral iron chelator for at least 1 year. Renal function determined by glomerular filtration rate measured with revised Schwartz formula. Tubular function determined by increased urine calcium creatinine ratio hypercalciuria . Results. Total subjects were 54 28 deferiprone, 26 deferasirox . Proportion of decreased GFR in deferipron group was higher than deferasirox 53,6 vs 46,2 . Hypercalciuria was higher in deferasirox group than deferiprone 12,9 vs 3.6 . Declining of GFR was significant in deferiprone group but not significant in deferasirox group. There was no significant difference of GFR and urinary creatinine calcium ratio in deferiprone vs deferasirox group p 0.427 p 0.109 . Age, hemoglobin level, mean hemoglobin, ferritin, iron chelator dose and transferrin saturation only affecting kidney tubular function. Conclusions. Renal dysfunction was found in thalassemia major patients receiving oral iron chelator. Kidney function in thalassemia major patients should be monitored periodically eventhough the decline was not significant. Keywords Thalassemia, renal function, oral iron chelator"