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Apium graveolens L. (seledri) merupakan obat herbal yang digunakan untuk pengobatan hipertensi. Penelitian terdahulu melaporkan bahwa penggunaan bersama herbal dengan obat sintetik dapat menyebabkan terjadinya perubahan pada farmakokinetik dan farmakodinamik obat sintetik. Informasi mengenai interaksi antara obat herbal dengan obat sintetik masih terbatas sehingga perlu diketahui efektivitas dan keamanan penggunaan kombinasi tersebut. Penelitian ini bertujuan untuk membuktikan adanya interaksi farmakodinamik dan farmakokinetik kombinasi kaptopril dan ekstrak seledri yang diberikan secara oral sebagai antihipertensi. Penelitian ini merupakan penelitian eksperimental yang terbagi menjadi dua bagian. Bagian pertama adalah pengujian interaksi farmakokinetik dengan mengambil darah tikus pada titik waktu tertentu setelah pemberian obat dan ekstrak seledri. Konsentrasi kaptopril diukur menggunakan kromatografi cair kinerja ultra tinggi-tandem spektrometri massa (KCKUT-SM/SM), selanjutnya dihitung K_e, C_max, AUC, T_max, dan T_1/2. Bagian kedua yaitu pengujian interaksi farmakodinamik untuk efek antihipertensi dengan metode pengukuran tekanan darah secara non-invasive pada ekor. Tekanan darah diukur sebelum perlakuan, setelah induksi NaCl 4%, dan setelah pemberian bahan uji. Pengambilan sampel urin dan darah untuk pengujian kadar natrium, kalium, volume urin, kadar kreatinin, aktivitas enzim ALT (SGPT), dan enzim penghambat konversi angiotensin. Hasil uji pada profil farmakokinetik kaptopril berbeda antara pemberian tunggal dengan kombinasi ekstrak seledri. Pemberian kaptopril 2,5 mg/kg bb bersamaan dengan ekstrak seledri 40 mg/kg bb tanpa jeda waktu menurunkan C_max dan AUC serta memperpanjang waktu T_max dan T_1/2. Pemberian ekstrak seledri 1 jam sebelum kaptopril (10 mg/kg bb) pada kombinasi, meningkatkan C_max dan AUC, serta memperpanjang T_1/2. Tekanan darah tikus yang mendapat kombinasi kaptopril dosis 5 mg/kg bb dengan ekstrak seledri dosis 40 mg/kg bb menurun lebih besar dibandingkan dengan pemberian kaptopril tunggal. Penurunan tekanan darah pada kelompok kombinasi kaptopril dan ekstrak seledri diikuti dengan peningkatan volume urin. Kadar natrium urin dan serum, serta kadar kalium serum cenderung mengalami peningkatan pada semua kelompok perlakuan namun tidak berbeda bermakna dengan kelompok normal. Kadar kalium urin cenderung mengalami penurunan kecuali pada kelompok kombinasi kaptopril (5 mg/kg bb) dan ekstrak seledri (40 mg/kg bb). Kreatinin serum cenderung meningkat pada kelompok kombinasi kaptopril dengan ekstrak seledri tetapi masih dalam rentang normal. Kreatinin urin dan bersihan kreatinin pada tikus yang mendapat kombinasi kaptopril dan ekstrak seledri tidak berbeda dengan kelompok normal.  Kadar SGPT cenderung menurun pada semua kelompok kombinasi kaptopril dan ekstrak seledri, namun tidak berbeda bermakna dengan kelompok normal. Kesimpulan hasil penelitian ini adalah pemberian kombinasi kaptopril dosis 2,5 mg/kg bb dan 10 mg/kg bb dengan ekstrak seledri dosis 40 mg/kg bb secara oral dapat mengubah farmakokinetik kaptopril.  Pemberian kombinasi kaptopril dosis 5 mg/kg bb dan ekstrak seledri dosis 40 mg/kg bb menurunkan tekanan darah kembali normal pada tikus hipertensi yang diinduksi NaCl.

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Apium graveolens L. (celery) is commonly used as herbal medicine for antihypertension. There was evidence that herb combines with the synthetic drug may affect the pharmacokinetics and pharmacodynamics of the synthetic drug. Information about the interaction between herbal medicines and synthetic drugs is still limited, therefore it will be necessary to explore the clinical results when using these combinations. This study aimed to investigate the pharmacodynamic and pharmacokinetic interaction of oral administration of combined captopril and celery as antihypertensive agent in animal model. The study was divided into two parts. In the first part which was the pharmacokinetics study, blood samples were collected at a various time points after herb-drug combination administration. The blood values of K_e, C_max, AUC, T_max, and T_1/2 of captopril were obtained by using LC-MS/MS method. The second part was the pharmacodynamic study. The blood pressure was measured bymeans of non-invasive tail method and recorded before and after treatment of induction of 4% NaCl solution and herb-drug administration. The urine and blood were collected and the sodium and potassium concentration, cumulative urine volume, creatinine, the activities of glutamic pyruvic transaminase enzyme and angiotensin converting enzyme inhibition were measured. The results of the pharmacokinetic study showed that concomittant administration of 2.5 mg/kg bw of captopril and 40 mg/kg bw of celery extract decreased C_max, K_e, AUC and increased T_1/2 and T_max of captopril. When 40 mg/kg bw of celery extract was given 1 hour before 10 mg/kg bw of captopril, the C_max, T_1/2, AUC of captopril were increased and K_e was decreased compared with captopril alone. The combination 5 mg/kg bw of captopril and 40 mg/kg bw of celery extract decreased the blood pressure in hypertensive rats better than 5 mg/kg bw of captopril alone. The decreased in blood pressure was followed by an increase in urine volume. Urinary and serum sodium, serum potassium levels tended to increase in all treatment groups, but they were not significantly different from the normal group. Urinary potassium levels tended to decrease except in the combined 5 mg/kg bw of captopril and 40 mg/kg bw of celery extract. In conclusion, oral administration of combination of 2,5 mg/kg bw and 10 mg/kg bw captopril with 40 mg/kg bw celery extract changes the pharmacokinetics of captopril, whereas the administration of combination of 5 mg/kg bw captopril and 40 mg/kg bw celery extract decreased the blood pressure to normal value in NaCl-induced hypertension rats.

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Latar belakang: Kurkumin memiliki aktivitas antikanker yang poten, namun profil farmakokinetik dan ketersediaan kurkumin di organ target sangat rendah. Nanopartikel kurkumin dibuat untuk meningkatkan aktivitas kurkumin sehingga dapat meningkatkan efek obat pada proses angiogenesis dan proliferasi sel pada tikus model kanker ovarium.

Metode: Nanopartikel kurkumin dibuat dengan metode gelasi ionik menggunakan kitosan sebagai polimer. Profil farmakokinetika kurkumin dan nanokurkumin dilakukan pada tikus dengan pemberian dosis oral sebesar 100 mg/kgBB. Sampel darah diambil pada sembilan  waktu dan konsentrasi kurkumin dalam plasma dianalisis menggunakan UPLC-MS/MS. Pengujian nanokurkumin sebagai ko-kemoterapi secara in vivo pada kanker ovarium dilakukan pada tikus model kanker ovarium dengan induksi DMBA. Tikus model kanker ovarium diberikan terapi cisplatin atau kombinasi cisplatin dan kurkumin, atau kombinasi cisplatin dan nanokurkumin. Efek antikanker dilihat dari pengukuran marker antiproliferasi (Ki67), marker apoptosis serta jalur sinyal TGF-b/PI3K/Akt dan IL-6/JAK/STAT3.

Hasil: Diperoleh ukuran partikel nanokurkumin sebesar 19,43±11,24 nm, dengan efisiensi penjerapan 99,97%, dan loading capacity 11,34%. Sifat mukoadhesif nanokurkumin lebih baik dibandingkan dengan kurkumin. Evaluasi profil farmakokinetik pada tikus diperoleh bahwa nanokurkumin meningkatkan AUC, Cmax, Tmax dan menurunkan klirens. Pada uji aktivitas in vivo,  pemberian cisplatin dan ko-kemoterapi nanokurkumin menyebabkan penurunan yang signifikan pada volume dan berat ovarium. Penemuan ini sesuai dengan penurunan ekspresi protein TGF-β, PI3K dan p-Akt/Akt. Efek ko-kemoterapi nanokurkumin juga dapat dapat menurunkan ekspresi protein IL-6, JAK, dan p-STAT3/STAT3. Pemberian cisplatin dan nanokurkumin juga menyebabkan peningkatan marker apoptosis yang signifikan seperti Bax, kaspase-9 dan kaspase-3 serta menurunkan ekspresi Bcl-2.

Kesimpulan: Nanokurkumin dapat memperbaiki profil farmakokinetika kurkumin, sehingga dapat diaplikasikan pada strategi ko-kemoterapi kanker ovarium dengan menghambat proliferasi melalui penghambatan jalur sinyal PI3K/Akt, JAK/STAT3, peningkatan apoptosis marker Bax, kaspase-3 dan kaspase-9 serta menurunkan ekspresi Bcl-2.

Kata kunci: kurkumin, kitosan, nanopartikel, kanker ovarium, PI3K/Akt, JAK/STAT

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Background: Curcumin has a potent anticancer activity. However, its systemic bioavailability and its concentration in organ is extremely low. The modification of curcumin to curcumin nanoparticles was expected to increase the activity of curcumin on angiogenesis and cell proliferation process in rat ovarian cancer.

Methods: Nanocurcumin were made using ionic gelation methods. The pharmacokinetic profiles of curcumin particles and nanoparticles were then assessed in rats by administering a single oral dose of 100 mg/kg BW. Blood samples were taken from nine predetermined time points, and curcumin plasma concentrations were then analyzed using UPLC-MS/MS. Nanocurcumin was tested as a co-chemotherapy in vivo and was carried out on ovarian cancer animal models, induced with 7,12-dimethylbenz(a)anthracene (DMBA). The ovarian cancer animal models were then treated with cisplatin, or cisplatin and curcumin, or combination of cisplatin with nanocurcumin. The anticancer effect of nanocurcumin as co-chemotherapy was investigated with the measurement of antiproliferation marker (Ki67), apoptotic markers as well as the expression of TGF-b/PI3K/Akt dan IL-6/JAK/STAT3.

Result: The particle size of the curcumin nanoparticles obtained were 19,43±11,24 nm. Entrapment efficiency (EE) of curcumin nanoparticles were exceeding 99.97%, and drug loading capacity (DLC) was 11.34%. The mucoadhesive properties of the nanoparticles were superior to that of curcumin particles. Pharmacokinetic evaluation in rats revealed that curcumin nanoparticles resulted in an increase of AUC, Cmax, Tmax, and lower Cl. The administration of cisplatin and nanocurcumin co-chemotherapy caused a significant reduction in ovarian volume and weight. These findings followed with decreased protein expression of TGF-β, PI3K and p-Akt/Akt. The co-chemotherapy effect nanocurcumin is also investigated as a mechanism of action via IL-6, JAK, p-STAT3/STAT3 expressions.  Treatments of cisplatin and nanocurcumin resulted in a significant increase in apoptotic markers such as Bax, caspase-9, and caspase-3 expressions and decreased Bcl-2 expression.

Conclusion: Nanocurcumin is an effective formulation to improve pharmacokinetics profile. Nanocurcumin as a co-chemotherapy  can be considered as a potential co-chemotherapy in ovarian cancer. The improved mechanism of actions are shown by the proliferation inhibition, downregulation of PI3K/Akt, JAK/STAT3 signaling pathways, and Bcl-2 expression and increasing apoptosis through the expression of Bax, caspase-9 and caspase-3.

Keywords: curcumin, chitosan, nanoparticles, ovarian cancer, PI3K/Akt, JAK/STAT

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"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.

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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."

"Peneliti terdahulu melaporkan adanya penggunaan bersama salah satu jamu yang mengandung daun kemuning dengan simvastatin memungkinkan potensi adanya interaksi. Penelitian ini bertujuan untuk mengetahui adanya interaksi farmakodinamika dan farmakokinetika simvastatin kombinasi dengan ekstrak daun kemuning sebagai antihiperlipidemia. Pengujian dilakukan 2 tahap yaitu farmakodinamika dan farmakokinetika. Pengujian farmakodinamika meliputi kadar profil lipid darah, asam lemak dan asam amino. Hewan coba dibagi menjadi 9 kelompok yaitu kelompok normal, negatif, positif simvastatin (9 mg/kg BB), ekstrak daun kemuning dosis 1 (157,5 mg/kg BB), dosis 2 (315 mg/kg BB) dan dosis 3 (630 mg/kg BB) serta kelompok kombinasi simvastatin dengan ekstrak daun kemuning dosis 1, dosis 2, dan dosis 3. Pengukuran kadar profil lipid menggunakan spektrofotometer klinikal. Pengujian farmakokinetika diberikan simvastatin 9 mg/kg BB dan kombinasi simvastatin dengan ekstrak daun kemuning 630 mg/kg BB. Konsentrasi simvastatin dalam plasma diukur menggunakan LCMS/MS selanjutnya dihitung nilai AUC, Tmaks, Cmaks. T1/2, Cl/F dan Vz/F. Penelitian secara in-silico menggunakan molecular docking dan molecular dynamic. Pemberian ekstrak daun kemuning maupun kombinasi simvastatin dengan ekstrak daun kemuning mampu menurunkan kadar profil lipid darah kembali normal namun persentase penurunan tertinggi pada kelompok simvastatin. Pada uji farmakokinetika dapat menurunkan kadar simvastatin dalam plasma tikus dan mempengaruhi aktivitas enzim CYP3A4 secara in silico.

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Previous researchers reported the joint use of one of the herbs containing kemuning leaves with simvastatin allow for potential interactions. This study aimed to determine the pharmacodynamic and pharmacokinetic interactions of simvastatin in combination with kemuning leaf extract as an antihyperlipidemic agent. The research was conducted pharmacodynamics and pharmacokinetics. Pharmacodynamic testing was carried out to test blood lipid profile levels, fatty acid and amino acid profiles. The experimental animal were divided into 9 groups: normal, negative, positive simvastatin (9 mg/kg BW), kemuning leaf extract dose 1 (157,5 mg/kg BW), dose 2 (315 mg/kg BW) and dose 3 (630 mg/kg BW) and the combination group of simvastatin with kemuning leaf extract dose 1, dose 2, and dose 3. Blood lipid profile levels test used a clinical spectrophotometer. Pharmacokinetic testing was given with simvastatin 9 mg/kg BW and a combination of simvastatin with kemuning leaf extract 630 mg/kg BW. The concentration of simvastatin in plasma was measured using LCMS/MS and then the AUC, Tmax, Cmax, T1/2, Cl/F and Vz/F values were calculated. In-silico study was conducted using molecular docking and molecular dynamics. Administration of kemuning leaf extract or the combination of simvastatin with kemuning leaf extract was able to reduce blood lipid profile levels back to normal, but the percentage of reduction was highest in the simvastatin group. In pharmacokinetic tests, can reduce simvastatin levels in the plasma of the rats and influence the activity of the CYP3A4 enzyme in silico."