ETIKA PENELITIAN: APA DAN BAGAIMANA?

ETIKA PENELITIAN: APA DAN BAGAIMANA

Implikasi Klinis Variasi Jumlah Copy Gen CYP2D6

Enzim CYP2D6 adalah salah satu varian sitokrom P450 (CYP450) yang berperan dalam metabolisme obat di hati. Isoform ini berperan dalam memetabolisme 25% obat yang saat ini beredar di pasaran. Aktivitas CYP450 dapat dipengaruhi oleh berbagai faktor seperti usia, jenis kelamin, fungsi organ pemetabolisme, jenis dan derajat penyakit, serta variasi genetik. Salah satu faktor penentu aktivitas CYP2D6 adalah sifat gene CYP2D6 yang sangat polimorfik. Faktor penentu polimorfisme gen CYP2D6 adalah mutasi pada nukleotida tunggal (single nucleotide polymorphisms (SNPs)) dan variasi jumlah copy (copy number variation (CNV)) gen CYP2D6. Kejadian mutasi gen dan variasi jumlah copy gen CYP2D6 dapat meningkatkan atau menurunkan aktivitas enzim CYP2D6 yang selanjutnya dapat menurunkan atau meningkatkan efikasi obat yang merupakan substrat CYP2D6 ataupun dapat menimbulkan toksisitas obat. Berbagai penelitian telah dilakukan untuk mengevaluasi hubungan mutase SNPs gen CYP2D6 dengan efek obat. Dalam tinjauan kali ini akan dibahas mengenai pengaruh variasi jumlah copy (copy number variation) gen CYP2D6 terhadap efek terapi ataupun efek samping obat

Opioid Use in Cancer Pain Management in Indonesia: a Call For Attention

Severe pain is a major problem for cancer patients, and pain management often requires the use of opioids. Indonesia is one of the countries where the use of opioids for cancer patients is extremely low, and this calls for attention, as many cancer patients in the country undergo unnecessary suffering as the consequence of this opioid underuse. The inability to assess pain correctly, failure to determine the correct dose, fear of addiction, overly tight regulation, all contribute to the failure to implement rational use of opioids for cancer patients. Breakthrough pain, a problem which requires special attention not only because it is commonly found but also requires proper knowledge to handle them. These hurdles are discussed in the present review, in order to bring a better understanding about the correct use of opioids in severe cancer pain. Some examples where opiods are used inappropriately in cancer pain management are also discussed.Key words: opioid, break through pain, cancer pain, morphine

Prothrombin Fragment 1.2 (F1.2) in Relation with Plasma Leakage Dan Thrombocytopenia in Dengue Infection

Latar belakang: Manifestasi klinis demam berdarah Dengue (DBD) adalah kebocoran plasma dan trombositopenia. Salah satu teori penyebab kedua hal tersebut adalah kadar trombin yang meningkat akibat aktivasi koagulasi. Kadar trombin dapat diwakili oleh kadar F1.2. Tujuan penelitian ini adalah untuk mengetahui hubungan antara kadar F1.2 dengan kebocoran plasma dan trombositopenia pada infeksi Dengue. Metode: Desain penelitian ini adalah potong lintang, mengggunakan plasma EDTA dari pasien terinfeksi virus Dengue. Subyek penelitian adalah 10 subyek dengan kebocoran plasma dan 10 subyek tanpa kebocoran plasma pada infeksi Dengue, 6 sampel berpasangan untuk perbandingan fase kritis dan fase konvalesen, 26 sampel untuk uji korelasi antara kadar F1.2 dengan jumlah trombosit. Hasil: Penelitian menunjukkan kadar F1.2 pada pasien terinfeksi virus Dengue dengan kebocoran plasma (rerata ± 2SD) 147,4 ± 105,82 pg/mL lebih tinggi secara bermakna dibanding tanpa kebocoran plasma 51,3 ±39,92 pg/mL. Kadar F1.2 pada fase kritis dengan median 186,3 (108,6-223,2) pg/mL lebih tinggi secara bermakna dibanding fase konvalesen 46,5 (27,4-51,9) pg/mL. Terdapat korelasi negatif yang bermakna dengan kekuatan sedang antara kadar F1.2 dengan jumlah trombosit, nilai r = - 0,609. Kesimpulan: Terdapat peningkatan aktivasi koagulasi yang ditunjukkan dengan peningkatan kadar F1.2 pada fase kritis, berkaitan dengan kebocoran plasma dan trombositopenia pada pasien terinfeksi virus Dengue. Kata kunci: infeksi Dengue, kebocoran plasma, trombin, fragmen protrombin (F1.2), trombositopenia Background: Clinical manifestations of Dengue hemorrhagic fever are plasma leakage and thrombocytopenia. Both manifestations are thought to be caused by an increased thrombin level due to activation of coagulation. The aim of this study is to look for any association between F1.2 level and plasma leakage and also between F1.2 level and thrombocytopenia in Dengue infected patients. Methods: This study used EDTA plasma from patients infected with Dengue virus. The study design was cross sectional. The thrombin level was represented by the prothrombin fragment 1.2 (F1.2) level. Twenty subjects were enrolled in this study, consisted of 10 subjects with plasma leakage and 10 without plasma leakage, 6 pairs of samples in critical phase and convalescent phase, 26 samples for correlation test between F1.2 level and platelet count. Results: In this study, it was found that the F1.2 level in patients with plasma leakage (mean ± 2 SD) 147.4 ± 105.82 pg/mL is significantly higher compared to patients without plasma leakage 51.3 ±39.92 pg/mL, and the F1.2 level in critical phase has a median of 186.3 (108.6-223.2) pg/mL which is significantly higher compared to convalescent phase 46.5(27.4-51.9) pg/mL. Also it was found that a medium negative correlation between F1.2 level and the thrombocyte count existed, r = - 0.609. Conclusion: The results of the study suggest that there was increased coagulation activation at critical phase in patients infected with Dengue virus associated with plasma leakage and thrombocytopenia

DEVELOPMENT AND VALIDATION OF CARBAMAZEPINE PLASMA CONCENTRATIONS MEASUREMENT AND ITS APPLICATION ON EPILEPSY PATIENTS

Objective: To develop and validate high-performance liquid chromatography with photodiode array (HPLC-PDA) detector as a method for measuring carbamazepine plasma concentrations in epilepsy patients treated with monotherapy or polytherapy.Methods: Carbamazepine was extracted from epilepsy patients' plasma through liquid-liquid extraction, using protein precipitation with chloroform. Analysis was performed using HPLC with Inertsil DS-4 C18 (4.6x150 mm), 5 μm particle size column. The optimal condition for separation was established in a mobile phase consisting of acetonitrile: water (50:50) at a flow rate of 1.0 ml/min, detected by PDA detector at 220 nm. Propylparaben was used as the internal standard. The retention time was 3.5 min.Results: Linearity was obtained over a concentration range of 0.5-16 μg/ml with r = 0.999. The method showed good intra-and inter-day precision and accuracy of more than 90% difference (% diff) and 95% relative standard deviation (RSD). Lower limit of quantification (LOQ) was 0.5 μg/ml and lower limit of detection (LOD) was 0.2 μg/ml with 100% accuracy and more than 90% precision. Recovery test was nearly 100%. Stability of carbamazepine plasma concentration in 3 epilepsy patients was measured on the first and third month of treatment, ranging between 83.5 to 98.7%. When used to compare carbamazepine as a monotherapy versus polytherapy, the method showed good selectivity.Conclusion: The present HPLC method was valid for measuring carbamazepine plasma concentrations in epilepsy patients treated with monotherapy or polytherapy. This method meets the standard in the EMEA guideline in terms of linearity, precision, and accuracy, also selectivity in epilepsy patients treated with polytherapy

New Insight into the Molecular Drug Target of Diabetic Nephropathy

Diabetic nephropathy (DN) lowered quality of life and shortened life expectancy amongst those affected. Evidence indicates interaction between advanced glycation end products (AGEs), activated protein kinase C (PKC) and angiotensin II exacerbate the progression of DN. Inhibitors of angiotensin-converting enzyme (ACEIs), renin angiotensin aldosterone system (RAAS), AGEs, and PKC have been tested for slowing down the progression of DN. The exact molecular drug targets that lead to the amelioration of renal injury in DN are not well understood. This review summarizes the potential therapeutic targets, based on putative mechanism in the progression of the disease

DETERMINATION OF IRBESARTAN AND SINENSETIN SIMULTANEOUSLY BY LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY AND THEIR APPLICATION TO DRUG INTERACTION STUDY IN RAT PLASMA

Objective: To determine and validate of irbesartan and sinensetin simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and application of this method to study a pharmacokinetic interaction of irbesartan and ethanol extract of Orthosiphon stamineus herba in rat plasma.Methods: The irbesartan and sinensetin were simultaneously extracted from plasma by protein precipitation with acetonitrile. Samples containing irbesartan and sinensetin were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with C18 column Acquity® (100 mm × 2.1 mm), 1.7 μm particle size column at 40 °C. The gradient system of mobile phase composition was a mixture of acetonitrile and 0.1% formic acid (40:60 v/v), which was pumped at a flow rate of 0.3 ml/min. Mass detection was performed on Waters Xevo Triple Quadrupole equipped with an electro spray ionization (ESI) source at positive ion mode in the multiple reaction monitoring (MRM) mode. Irbesartan was detected at m/z 429.1>205.9, sinensetin was detected at m/z 373>342.9 and losartan as an internal standard was detected at m/z 423.05>404.9.Results: The method was validated according to EMEA guidelines which showed good reproducibility and linearity of 0.99, the lower limit of quantification (LLOQ) were 25 ng/ml and 250 ng/ml for irbesartan and sinensatin, respectively. The precision (% CV) values of within-run and between-run analysis is 9.3-5.25% and 1.52–5.47% (for irbesartan), 1.52–5.09% and 2.47–9.14% (for sinensetin) whereas the accuracy (% diff) of both irbesartan and sinensetin were less than 20%. Stability studies revealed that irbesartan and sinensetin have been stable for 24 h at room temperature, 24 h in the autosampler, 3 freeze-thaw cycles, and at least 30 d at-20 oC. The validated method was applied to evaluate pharmacokinetic interactions of irbesartan and ethanol extract of Orthosiphon stamineus herba in rat plasma.Conclusion: The developed LC/MS-MS method is valid to evaluate irbesartan and sinensetin simultaneous in vitro and showed good selectivity, linearity, accuracy, precision, matrix effect, and stability. The method was successfully applied to study the pharmacokinetics interaction of irbesartan and Orthosiphon stamineus herba in rat plasma.Â

KIDNEY INJURY MOLECULE-1 AS AN EARLY AMIKACIN-INDUCED NEPHROTOXICITY MARKER IN PATIENTS WITH SEPSIS HOSPITALIZED IN THE INTENSIVE CARE UNIT

Objective: This study sought to determine the correlation between trough plasma amikacin concentrations and urinary normalized kidney injurymolecule-1 (KIM-1) concentrations as an early biomarker of nephrotoxicity in patients with sepsis who are hospitalized in an intensive care unit.Methods: In this pilot study, 12 patients with sepsis were treated with amikacin 1000 mg/day between May 2015 and September 2015. The correlationbetween trough plasma amikacin concentrations measured after the third dose and the elevation of urinary normalized KIM-1 concentrations afterthe third amikacin dose relative to the first/second dose was evaluated.Results: In total, three patients had trough plasma amikacin concentrations exceeding the safe level (>10 μg/ml). Furthermore, eight patientsdisplayed higher normalized KIM-1 concentrations after third dose than after the first/second dose; however, there was no correlation betweentrough amikacin concentrations and the elevation of urinary normalized KIM-1 concentrations (r=0.3, p=0.3).Conclusion: The study results illustrated that short-term treatment with an amikacin dose of 1000 mg/day was generally safe in patients with sepsis

A Double-blind, Randomized Controlled Trial of Ciplukan (Physalis angulata Linn) Extract on Skin Fibrosis, Inflammatory, Immunology, and Fibrosis Biomarkers in Scleroderma Patients

Background: scleroderma is an autoimmune disease characterized by organ fibrosis, resistant to standard treatment. It is suspected the addition of Physalis angulata Linn. (Ciplukan) extract as adjuvant therapy can improve the scleroderma skin fibrosis. The aim at this study is to evaluate the effect of ciplukan extract as adjuvant on scleroderma skin fibrosis in standard therapy, based on modified Rodnan skin scale (MRSS), inflammatory biomarkers, immunology and serum fibrosis. Methods: double-blind, randomized clinical trial was performed in scleroderma patients with stable disease at Cipto Mangunkusumo hospital and Hasan Sadikin hospital during November 2015−March 2017 who met the selection criteria and continued to receive standard therapy. The subjects were randomly allocated into two groups: the study group received the ciplukan  extract 3 x 250 mg / day for 12 weeks and the placebo group. Examination of MRSS, ESR, P1NP, BAFF and sCD40L was performed every 4 weeks until the end of the study. Results: fifty-nine subjects completed the study. They consisted of 29 subjects of the treatment group and 30 of the placebo group, with an average age of 41 (SD 9) years, the proportion of women: male = 9 : 1. There was a significant improvement of skin fibrosis in the study group with a highly significant decrease in MRSS (35.9% VS 6.3%, p <0.001) and a relative decrease in P1NP levels (17.8% VS 0.7%, p = 0.002). No decrease in ESR, BAFF and sCD40L levels in both groups. There was a weak but significant positive correlation between MRSS with P1NP levels (r = 0.236, p = 0.036). Conclusion: Ciplukan extract with dose 3 x 250 mg for 12 weeks as adjuvant on scleroderma standard therapy alleviates skin fibrosis significantly based on MRSS and P1NP levels