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Abstrak :
ABSTRAK Ruang Lingkup dan Cara Penelitian: Dengan berkembangnya teknologi formulasi obat dan juga kemajuan di bidang pengobatan, telah dibuat teofilin dalam bentuk sediaan lepas lambat (SLLB). Hal ini menguntungkan bagi pasien, karena selain kepatuhan dapat ditingkatkan kadar obat dalam darah dapat terkendali dengan baik. Bioavailabilitas dan bioekivalensi obat SLLB perlu diketahui dengan baik. Untuk teofilin hal ini terutama karena, disamping indeks terapi sempit juga adanya perbedaan antar individu dalam parameter farmakokinetik. Oleh sebab itu telah dilakukan penelitian terhadap tablet Uniphyllin® Continus® yang merupakan teofilin bentuk SLLB baru dibandingkan dengan teofilin sediaan biasa. Penelitian dilakukan terhadap 13 sukarelawan sehat, pria dewasa. Minggu I diberikan teofilin sediaan biasa selama 3 hari, 4x150 mg/hari (9 dosis). Pada minggu II diberikan sediaan lepas lambat selama 3 hari, 2 x 300-400 mg/hari (5 dosis). Pada hari ke-3 dalam keadaan puasa, sebelum dan sesudah makan obat, diambil darah dari vena kubiti. Pada sediaan biasa darah diambil pada jam 0; 0,5; 1; 1,5; 2; 2,5; 3; 6; 9; dan 11. Pada sediaan lepas lambat darah diambil pada jam 0; 2; 3; 4; 5; 7; 9; 12; 15 dan 24. Kadar teofilin plasma diukur dengan metoda enzyme immunoassay-turbidimetry (ACA IV). Dari kadar yang didapat dihitung berbagai parameter farmakokinetik. Hasil dan Kesimpulan: Data farmakokinetik diperoleh dari 12 subyek (satu subyek dibatalkan berhubung efek samping yang berat), sebagai berikut : Cmax tablet sediaan lepas lambat (SLLB) 12,17 μg/mL dan pada sediaan biasa (SBS) 15,75 μg/mL, kedua nilai Cmax berbeda bermakna (p < 0,01). Cmin pada SLLB 8,10 μg/mL dan pada SBS 10,39 µg/mL, kedua nilai berbeda bermakna (p <0,01). Nilai tmax SLLB adalah pada jam ke-4 sedang pada SBS pada jam ke-1,13; keduanya berbeda sangat bermakna (p<0,001). Hasil indeks fluktuasi (IF) antara SLLB dan SBS tidak berbeda (p >0,05; IF SLLB = 0,42 dan IF SBS = 0,44). Dari data farmakokinetik terlihat tablet Uniphyllin® Continus® merupakan suatu sediaan lepas lambat. Variabilitas parameter antar subyek disebabkan oleh variabilitas metabolisme obat, sehingga menimbulkan fluktuasi kadar obat. Oleh karena itu, pada kondlsi tertentu sebaiknya penggunaan teofilin diikuti dengan pemeriksaan kadar obat dalam darah.

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ABSTRACT Comparative Study Of Plasma Concentration Of Theophylline Using Sustained Released Tablet Uniphyllin® Continus® 300-400 Mg With Plain Capsules Of Theophylline150 MgScope and Method of Study: Advances in drug formulation and therapeutics make it possible to produce various controlled-release (CR) theophylline preparations. Such dosage form has been advocated to be more advantageous than the conventional form as it may in-crease patient?s compliance, and the plasma concentration of the drug to be more controllable. The bioavailability and bioequivalence of sustained released drugs should be carefully observed. This is particularly important for theophylline, because not only it has a narrow margin of safety but also the capacity to metabolize the drug varies markedly between individuals. Uniphyllin® Continus®, a controlled release theophylline preparation, is to be marketed soon here. The aim of the present study is to confirm its controlled release characteristics compared with a conventional release (CVR) dosage form. Thirteen healthy Indonesian volunteers participated in this study. They were given 150 mg of CVR theophylline 4 times daily for 9 dosages. Venous blood samples were taken at 0; 0.5; 1; 1.5; 2; 2.5; 3; 6; 9 and 11 hours after the last dosage. After a wash-out period of two weeks, the subjects took the CR tablets twice daily for 5 dosages. Subjects with body weights less than 70 kg were given 300 mg tablets, and heavier subjects were given 400 mg tablets. Blood samples were drawn at 0; 2; 3; 4; 5; 7; 9; 12; 15 and 24 hours. Plasma theophylline concentration was determined by enzyme immunoassay-turbidimetric method (ACA IV, Dupont). Findings and Conclusions: Data was analyzed from 12 subjects (one subject dropped due to serious adverse reactions). The mean of peak concentrations (Cmax) of the CR and CVR dosage forms were 12.17 and 15.75, μg/mL, respectively (p <0.01). Trough concentrations (Cmin) of the CR and CVR forms were 8.10 and 10.39 µg/mL, respectively (p < 0.01). The time to attain Cmax (tmax) for the CR and CVR forms were 4 and 1.13 hours, respectively (p < 0.001). The fluctuation index (FI) of the CR and CVR forms were 0.42 and 0.44, respectively; which are not significantly different. The pharmacokinetic data show that Uniphyllin® Continus® tablet is a slow sustain released tablet. Variability between subjects caused by variability in drug metabolism produce fluctuations in the plasma concentration of the drug.

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ABSTRAK
Ruang lingkup dan cara penelitian : Sediaan teofilin oral biasanya diberikan setelah makan untuk mengurangi gangguan saluran cerna. Beberapa laporan menunjukkan bahwa makanan mempengaruhi pola absorpsi dan bioavalabilitas teofilin dari beberapa sediaan lepas lambat. Euphyllin retard, satu-satunya sediaan teofilin lepas lambat yang beredar di Indonesia, belum mempunyai data mengenai hal ini.

Penelitian ini dilakukan dengan disain menyilang, tersamar tunggal dan acak pada 10 orang sukarelawan, dalam keadaan puasa dan setelah makan. Darah diambil dari vena kubiti sebelum makan obat dan pada jam-jam ke 1, 2, 3, 4, 5, 6, 8, 10, 12, dan 24 setelah makan obat. Kadar serum teofilin diukur dengan cara enzyme-multiplied immunoassay tehnique {EMIT) dan digunakan untuk menghitung luas area kurva kadar teofilin dalam plasma terhadap waktu dari 0 sampai 24 jam (AUCO_24 jam) dan menentukan kadar puncak teofilin dalam plasma (Cmax) dan waktu untuk mencapai (tax).

Uji statistik t berkaitan digunakan untuk membandingkan AUCO_24 jam dan kadar serum pada berbagai waktu pengamatan dan uji Wilcoxon untuk data berkaitan digunakan untuk membandingkan Cmax dan tmax yang dicapai teofilin pada pemberian tanpa dan dengan makan .

Hasil dan kesimpulan: Pada penelitian ini, didapatkan bahwa pola absorpsi dan bioavailbilitas Euphyllin dalam keadaan puasa berbeda dengan pemberian setelah makan. Pemberian Euphyllin retard setelah makan dibandingkan dengan pemberian pada perut kosong memperlihatkan :

a. AUCO-24jam yang lebih tinggi 83,5% (p = 0.02)

b. Kadar serum pada jam ke 4 sampai dengan jam ke 10 lebih tinggi 113.9 - 157.6% (p<0.01)

c. Cmax teramati lebih tinggi 138.5% (p < 0.02), sedangkan tmax tidak berbeda bermakna.

Abstrak :
Sistem pelepasan obat terkendali adalah proses untuk menjaga konsentrasi senyawa aktif dari obat di dalam tubuh. Dosis dari obat dapat dilepaskan di antara batas toksik dan batas terapi, dan mengurangi efek samping dan kerusakan pada jaringan normal. Eksperimen mengenai pelepasan obat terkendali ini secara in vivo memakan waktu dan biaya. Karena itu, pemodelan diperlukan sebelum eksperimen dilakukan. Pemodelan yang dilakukan adalah pelepasan theophylline dengan meninjau pengaruh difusifitas dan ukuran dari obat tersebut. Theophylline memiliki jarak batas terapi dan toksik yang sempit, sehingga pelepasannya di dalam tubuh perlu di kontrol. Simulasi dilakukan dengan bantuan software COMSOL Multiphysics. Dari simulasi, didapatkan pada variasi D = 2 x 10-10 m2/s dan r = 0,007 m adalah variabel yang paling mendekati profil pelepasan yang diinginkan. Controlled drug release is a process to keep active substance concentration of drugs inside the body. Dosage from the drugs can be released between the toxic and therapeutic limit, and decrease the side effects and the damage on normal tissue. The experiment about drug release in vivo is time and money consuming. So, modeling is needed before the experiment is conducted. The modeling that is conducted is theophylline release with diffusivity and size of the drug as consideration. Theophylline has a narrow therapeutic and toxic limit, so the release in body should be controlled. Simulation is conducted using COMSOL Multiphysics software. From simulation, at the variation D = 2 x 10-10 m2/s and r = 0,007 m is the nearest desired release profile.

Abstrak :
In order to make use of pregelatinized Manihot starch in controlled release tablet, the research was done by heating the starch suspension up to its gelatinized temperatur, then dried. The particle size of pregelatinized Manihot starch used were (100-150 mesh) : (150-250 mesh) : smaller than 200 mesh = 3,5 : 1 : 1. The effect of pregelatinized Manihot starch on physical characteristic of Theophyllin controlled relase tablet was known by using 4 formulas containing variety of pregelatinized starch as follows: 30%, 40%, 50%, and 60%. Evaluation on the tablet results including tablet mass and size uniformity, hardness and friability. The result showed that pregelatinized Manihot starch in variable content on these tablet formulas fulfilled the requirement of tablet physical characteristics.

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Curcumin analog (Pentagamavunon-0/PGV-0) can inhibit steroidogenesis of luteal cell culture. Corpus luteum secretes progesterone by LH stimulation. The main transduction signal of luteal cells steroidogenesis is through the cAMP/PKA. The objective of this study was to know the effect of PGV-0 on cAMP and progesterone concentration of luteal cell culture containing theophylline. The subject was corpus luteum of rat Sprague Dawley strain induced with PMSG (10 IU). PGV-0 was given shortly after the stimulation of LH and or PGF2α with or without theophyline. The cell culture then put into the incubator for 24 hours. Concentration of cAMP was assessed by ELISA whereas the progesterone concentration was determined by RIA. The result showed that LH stimulation caused cAMP and progesterone increase significantly. The inhibition of PGF2α on cAMP and progesterone concentrations showed no significant difference compared to the control. Theophylline increased the cAMP and progesterone concentration significantly but not to LH stimulation. PGV-0 did not inhibit cAMP concentration but PGV-0 inhibited the progesterone concentration by LH stimulation. In conclusion, PGV-0 inhibits signal transduction of lutheal cell in down stream cAMP.

Abstrak :
Sediaan obat lepas terkendali merupakan sediaan yang dapat melepaskan kandungan obatnya secara terkendali. Kopolimerisasi poli(vinhl alkohol)(PVA) 10% dengan N-isopropitakrilamida (NIPAAm) 5% meriggunakan radiasi sinar gamma C060 dosis 30 kGy dengan laju dosis 8 kGy/jam dapat menghasilkan hidrogel. Hidrogel PVA-ko-NIPAAm yang memiliki sifat fisik yang baik yaltu elastis clan peka suhu ml, dipelajari pula rasio 'swelling'nya pada berbagai suhu. Imobilisasi teofilin kedalarn hidrogel dilakukan dengan metode absorbsi clan simultan, dengan dosis 50, 100, clan 150 mg per sediaan hidrogel (berat 1 000 mg, diameter 30,67 mm pada 28°C) clan diuji penglepasannya pada pH 1,2; 6,8; 7,4; clan 10,0 menggunakan alat uji disolusi. Hasil penelitian menunjukkan bahwa hidrogel PVA-ko-NIPAAm memiliki pola raslo 'swelling' yang mengecil dengan meningkatnya suhu. Adanya variasi dosis teofilin clan pH media disolusi dapat mempengaruhi profil penglepasannya, yang pada suhu 37°C mengikutl model difusi non- Fickian orde satu clan menunjukkan suatu sistem matriks 'swelling'terkendali (kombinasi difusi-disolusi). Dari hasil penelitian liii dapat dikembangkan suatu sistem penyampahan obat yang memanfaatkan hidrogel PVA-ko- NIPAAm sebagai matniks sediaan dengan penglepasan terkendali. ...... Controlled release dosage form is a dosage form which , releases its contents in a controlled manner. Copolymerization of poly(vinyl alcohol) (PVA) 10% with N-isopropylacrylamide (NIPAAm) 5% by irradiated by C060 gamma-ray from with a dose of 30 kGy (dose rate 8 kGy/h) has been carried out, in order to obtain a hydrogel. Hydrogels PVA-co-NIPAAm have produced elastic properties and thermoresponsive properties. The swelling ratio of the PVA-co-NIPAAm hydrogels were measured in various temperatures. Immobilization of theophylline with doses of 50, 100, and 150 mg were loaded into hydrogel dosage form (weight 1000 mg, diameter 30.67 mm at 28°C) by absorption and simultaneous methods. The release of theophylline from hydrogels was tested using dissolution tester apparatus in pH 1.2; 6.8; 7.4; and 10.0. The results showed that hydrogels with increasing temperature will decrease their swelling ratio . The release profile of theophylline at 37 °C from hydrogel matrix was influenced by theophylline doses and the pH of dissolution media. The release profile followed first order non-Fickian diffusion model and represented as a swelling-controlled matrix system (combination by diffusion-dissolution). From those results, it is possible to develope drug delivery system that used PVA-co-NIPAAm hydrogel as a matrix for the controlled release dosage form. 'V

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Penyakit coronavirus 2019 (COVID-19) merupakan penyakit yang disebabkan oleh severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Penyakit ini dapat menular melalui cairan yang berasal dari hidung atau mulut penderita. Simulasi penambatan molekul dengan PyRx memprediksi senyawa Teofilin dan Dexamethason dapat berinteraksi baik dengan spike glikoprotein S2 SARS-CoV 2, dengan ΔGbinding yang diperoleh adalah berturut-turut sebesar -6,3; -7,8; -8,1 kcal/mol melalui nteraksi pada residu Ala348, Arg357 dan Val341. Sehingga dapat disimpulkan bahwa Teofilin dan Dexamethason memiliki potensi untuk dijadikan agen pengenal SARS-CoV 2. Namun simulasi dengan penambatan molekul juga menunjukan bahwa hemagglutinin (HA) H1N1 berpotensi menganggu pengukuran spike glikoprotein SARS-CoV 2. Hasil studi komputasi ini menjadi acuan untuk pengujian potensi Teofilin dan Dexamethason sebagai agen pengenal SARS-CoV 2 dengan HA H1N1 sebagai uji interferensi. Selanjutnya Studi elektrokimia dengan teknik voltametri siklik menggunakan elektroda boron-doped diamond (BDD) pada Teofilin menunjukkan puncak arus oksidasi pada potensial +0,506 V dan puncak arus reduksi pada potensial -0,5 V. Arus yang dihasilkan linear pada rentang konsentrasi 10 μM sampai 100 μM. Deteksi spike glikoprotein S2 SARS-CoV 2 dilakukan dengan melihat penurunan arus oksidasi Teofilin dengan kehadiran spike glikoprotein S2 SARS-CoV 2 dan virus kultur SARS- CoV 2 pada waktu optimum 10 menit. Penurunan arus linier pada rentang konsentrasi 1 ng/mL sampai 200 ng/mL. Sedangkan Dexamethason tidak elektroaktif namun pengukuran dengan spektrofotometri UV-Vis menunjukkan puncak absorbansi pada bilangan gelombang 241 nm. ......Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease can be transmitted through droplets from the nose or mouth of the patient. Molecular docking simulation with PyRx predicts Theophylline and Dexamethason compounds can interact well with the spike glycoprotein S2 SARS-CoV 2, with G_bindings obtained are -6.3, respectively; -7.8; -8.1 kcal/mol via interaction with residues Ala348, Arg357 and Val341. So that theophylline and dexamethason have the potential to be used as SARS-CoV 2 identification agents. However, simulations with molecular docking also show that hemagglutinin (HA) H1N1 has the potential to interfere with the measurement of the SARS-CoV 2 spike glycoprotein with bioactive compounds. The results of this computational study serve as a reference for testing potential Theophylline and Dexamethasone as identification agents for SARS-CoV 2 and HA H1N1 as an interference compound. Furthermore, electrochemical studies using cyclic voltammetry techniques using boron-doped diamond (BDD) electrodes on theophylline showed peak oxidation currents at +0.548  V potential and peak reduction currents at -0.5 V potentials. The resulting currents were linear in the concentration range of 10 M to 100 M. Detection of spike glycoprotein S2 SARS-CoV 2 was carried out by observing a decrease in the oxidation current of Theophylline in the presence of spike glycoprotein S2 SARS-CoV 2 and cultured virus SARS-CoV 2 at the optimum time of 10 minutes. Linearity current decrease in the concentration range of 1 ng/mL to 200 ng/mL. Meanwhile, Dexamethasone is not electroactive, but measurements using UV-Vis spectrophotometry show the absorbance peak at a wave number of 241 nm. This absorbance is linear in the concentration range of 10 M to 200 M. Detection of spike glycoprotein S2 SARS-CoV 2 with Dexamethasone was carried out by decreasing absorbance in the presence of spike glycoprotein S2 SARS-CoV 2. at the optimum time of 10 minutes. Linearity current decrease in the concentration range of 1 ng/mL to 200 ng/mL. Furthermore, the interference test performed with HA-H1N1 and spike glycoprotein S2 SARS-CoV 2 showed that neither the current in theophylline nor the peak absorption of Dexamethasone changed significantly. These results indicate Theophylline and Dexamethasone are selective against the SARS-CoV 2 spike glycoprotein S2 and can be applied as identification agents on the SARS-CoV 2 spike glycoprotein S2 sensor.

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Penggunaan teofilin sebagai salah satu obat penyakit paru obstruktif kronik (PPOK) yang digunakan secara massal di seluruh dunia menjadi perhatian khusus bagi tenaga medis dalam memantau konsentrasinya dalam tubuh pasien. Dalam meningkatkan efisiensi dan efektifitas monitoring atau deteksi teofilin, telah dilakukan pembuatan atau modifikasi elektroda dengan penyangga karbon yang dideposisi dengan bubuk borondoped diamond (BDD) dan film TiO2 NT. Pada penelitian ini dilakukan sintesis TiO2 nanotube (NT) berfasa anatase melalui metode anodisasi. Film TiO2 NT dideposisikan pada BDD yang telah terdeposisi diatas elektroda karbon (karbon-BDD/TiO2 NT). Modifikasi ini dilakukan untuk mendapatkan keuntungan dari luas permukaan TiO2 NT yang besar dan BDD yang memiliki konduktivitas serta potential-window yang lebar, sehingga dapat meningkatkan performa dari kinerja sensor. Pada penelitian ini dilakukan berbagai pengujian terhadap elektroda karbon-BDD/TiO2 NT, yaitu penentuan luas permukaan elektroaktif, penentuan rasio arus signal-to-background (S/B), optimasi pH, penentuan linearitas dan LoD sebelum dikemas diatas SPCE. Elektroda karbon- BDD/TiO2 NT memiliki nilai S/B sebesar 1,1454 dengan pH optimum pada pH 3, serta nilai LoD dan LoQ sebesar 137,41 μM dan 458,05 μM dengan linearitas konsentrasi 80- 200 μM. Sementara itu sensitivitas, %recovery, dan %RSD karbon-BDD/TiO2 NT dalam mendeteksi teofilin, baik secara linearitas dan di dalam artificial urine adalah 0,0218; 113,37% ; dan 2,15%. ......The use of theophylline as one of the widely used drug for chronic obstructive pulmonary disease (COPD) worldwide has become a concern for healthcare professionals in monitoring its concentration in the patient's body. To increase the efficiency and effectiveness of theophylline monitoring or detection, electrodes have been made or modified with carbon supports deposited with boron-doped diamond (BDD) powder and TiO2 NT film. In this research, TiO2 nanotubes (NT) in the anatase phase were synthesized using the anodization method. TiO2 NT film is deposited on BDD which has been deposited on a carbon electrode (carbon-BDD/TiO2 NT). This modification was carried out to take advantage of the large surface area of TiO2 NT and BDD which has wide conductivity and potential-window, to improve the performance of the sensor. In this research, various tests were carried out on carbon-BDD/TiO2 NT electrodes such as determining the electroactive surface area, determining signal-to-background current ratio (S/B), optimizing pH, and determining linearity and LoD before being further modified on SPCE. The carbon-BDD/TiO2 NT electrode has an S/B value of 1.1454 with an optimum pH of pH 3. The LoD and LoQ values are 137.41 μM and 458.05 μM with a concentration linearity of 80-200 μM. Meanwhile the sensitivity, %recovery, and %RSD of carbon-BDD/TiO2 NT in detecting theophylline, both linearly and in artificial urine was 0.0218; 113.37% ; and 2.15%, respectively.

Abstrak :
Telah dilakukan penelitian tentang profile teofilin dalam plasma dan urine setelah pemberian.peroral ka psul teofilin yang berisi 300 my teofilin.. Penelitian tersebut dilakukan terhada p 12 orang sukarelawan yang sehat, berat badan berkisar antara 47 sampal 58 kg. umur berkisar antara 17 sam pai 28 tahun. Pengambilan darah dilakukan sebelum obat diberikan, 60, 120, 180, 240, 360, 480 menit setelah ohat diminum. Urine dikump ulkan pada interval waktu tertentu selama 48 jam. Konsentrasi teofilin daiarn plasma dan urine ditetapkan secara spektr ofotometri. Dari hasil penelitian didapatkan kadar terapi teofilin dalam plasma dapat dicapal dengan pembenian 300 my teofilin. Ada hubungan antara profil teofilin dalam plasma dan urine dimana waktu untuk mencapai ekskresi puncak.teofilin dalam urine sama dengan waktu untuk mencapai kadar puncak teofilin dalam plasma pada t mid. Juga diperoleh parameter-parameter farmakokinetik seperti waktu oaruh teofilin (1 1/2), tetapan kece patan eliminasi (Ke), tetapankecepatan abbsorpsi (Ka) dan ekskresi teofilin dalam urine kumulatif. ......The studies of theophylline profile in plasma and urine after given theophylline orally capsule which contain 300 mg theophylline - has been carried out. The studies involved twelve healthy male volunteers, the range of body weight are beetwen 47 to 58 kg and the ages are between 17 to 28 years old. Blood samples were taken right before the drug was administered and 60, 120, 180, 240, 360, 480 minutes after that. Urine samples were collected at regular intervals over 48 hour periods. The concentration of theophylline in plasma and urine samples were determined by spectrophotometric method. From the data obtained, we observed that the therapeutic concentration of theophylline was reached after given 300 mg theophylline. There was relationship between theophylline profile in plasma and urine, in which the time needed to reach the maximum theophylline excreation in urine was same as the time needed to reach the maximum theophylline plasma concentration at t mid. From the data we also observed the pharmacokinetic parameters as the half ii:fe- (T1/2) elimination rate constant ( Ke ), absorption rate constant ( Ke ) and cumulative urinary excretion.