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Pharmacokinetics Interaction and Biodistribution of 5 Fluorouracil with Radiopharmaceuticals 99mTc Glutathione for Cancer Diagnostic in Mice Cancer Model
Full text linkRadiopharmaceutical 99mTc-Glutathione has been developed for cancer diagnostic in nuclear medicine. Interactions between chemotherapy drugs and radiopharmaceuticals can altered radiopharmaceuticals performance. Drug interaction 5-fluorouracil (5-FU) with a radiopharmaceutical 99mTc-Glutathione in mice cancer model has been proven in pharmacokinetics study. The biological half-life distribution of 99mTc-Glutathione for cancer model mice when administrated with 5-FU become longer to 0.340±0.121h if compared with 99mTc-Glutathione. Biological half-life elimination for cancer model mice given with 99mTc-Glutathione is 72.712±2.427h. Administration of 5-FU makes the biological half-life elimination of 99mTc-Glutathione shorter to 17.030±3.459h. Biodistribution study of 5-FU continued with 99mTc-Glutathione for cancer model mice showed higher physiological uptake in the kidney was observed (39.77±2.70%ID/g) for 99mTc-Glutathione has lower uptake on kidney (29.55.3.73 %ID/g) with p<0.05. Based on calculation on cancer model mice with colon cancer compared with muscle, shown target/non-target (T/NT) ratio 2.93 for 5-FU continued with 99mTc-Glutathione has ratio 0.42. Low ratio T/NT may affect to poor organ visualization for cancer diagnosis. Acute toxicity study has shown drugs safety for clinical purpose. The knowledge about chemotherapy drug interaction with a radiopharmaceutical is important to have a correct diagnosis of the patient on clinical application
In Vitro Study of the Combination of Doxorubicin, Curcuma xanthorrhiza, Brucea javanica, and Ficus septica as a Potential Novel Therapy for Metastatic Breast Cancer
Full text linkLess optimized therapeutic effects constrain the use of doxorubicin as the main agent of chemotherapy for metastatic breast cancer, resistance and side effects. Therefore we need a combination of more than one chemopreventive agent which has different molecular targets to solve that problem. The aims of this study is to prove the inhibitory effect of ethanolic extract of rhizome of Curcuma xanthorrhiza (ECx), fruit of Brucea javanica (EBj), leave of Ficus septica (EFs) and doxorubicin (Dox) alone and its combination on migration and invasion of a highly metastatic 4T1 breast cancer cell line. Cytotoxic activity of single and combination treatment was evaluated by MTT assay, followed by an experiment of apoptosis induction by using flow cytometry. The inhibitory effect on migration was observed by the scratch wound-healing assay. Furthermore, the observation of the activity of matrix metalloproteinase-9 (MMP-9) was analyzed by gelatin zymography. The results showed that ECx, EBj, EFs, and Dox has cytotoxic activity on 4T1 cells with the value of IC50 respectively 49.7±1.53mg/mL, 59.9±1.79mg/mL, 15.2±2.12mg/mL and 1.2±0.23mM. Furthermore, combination of ECx-EBj-Dox and ECx-EBj-EFs revealed synergistic effect on 4T1 cells and decrease cell viability through the induction of apoptosis and necrosis. Based on wound healing assay, 24 hours incubation of this combination inhibited 4T1 cells migration compared to single treatment. Gelatin zymography analysis showed that this combination also inhibited the activity of MMP-9 greater than a single use. Curcuma xanthorrhiza, Brucea javanica, and Ficus septica may have potential to be developed as a combination with or without doxorubicin for metastatic breast cancer treatment
The Effect of Thionamide to TRH, TSH, IL-4, T-REG, and Anti-TPO in Graves’ Disease
Full text linkThe most common cause of hyperthyroidism is Graves' disease. TRH and TSH are hormonal factors that modulate and control thyroid function in Graves' disease. In the immunological aspect, Graves' disease is played by the role of T-reg, IL-4, and anti-TPO. Graves' disease treatment goal is to inhibit thyroid hormone secretion by administering thionamide. The evaluation of this treatment is its hormonal and immunological aspects. To describe the effect of thionamide on serum TRH, TSH, IL-4, T-reg, and anti-TPO levels in Graves' disease. This study is a clinical trial study in 25 study participants. All study participants were given thionamide, namely PTU 300mg for three months and blood samples were taken for laboratory tests. Serum TRH, TSH, IL-4, T-reg FOXP3, and anti-TPO levels were examined by ELISA. The mean levels at the beginning and after three months of therapy are: serum TRH 92.589pg/mL and 115.944pg/mL; serum TSH 0.041mU/L and 0.223mU/L; serum IL-4 19.759pg/mL and 23.040pg/mL; T-reg FOXP3 gene polymorphism 0.621ng/mL and 0.518 ng/mL; serum anti-TPO 2697.539pg/mL and 2604.710pg/mL. Increased levels of serum TRH and TSH levels were statistically significant. The change in serum IL-4, T-reg FOXP3 gene polymorphism, and anti-TPO levels were not statistically significant. The administration of thionamide in Graves' disease for three months will significantly decrease Wayne index and serum FT4 levels, increase serum TRH and TSH levels
Effect of Platelet-rich Plasma on Caspase-3 and IGF-1 mRNA expression in the diabetic rat testis
Full text linkTesticular damage is a serious complication of diabetes mellitus resulting in male infertility, which is associated with caspase-3 and IGF-1 mRNA expression. Platelet-rich plasma (PRP), with its rich growth factor composition, has proven beneficial in regenerative therapy. It is believed that PRP has not been studied in testes for diabetes mellitus and there are no studies in the literature concerning the influence of PRP on expressions of growth factors in testes.The aim of this study was to investigate the efficacy of adjunctive PRP in insulin treatment for repair of testicular damage in a diabetic rat model. Diabetes was induced by administering single dose 60 mg/kg streptozotocin. Twenty Wistar male rats were divided into four groups: group 1, control group; group 2, diabetes without treatment; group 3, diabetes with treated insulin; and group 4, diabetes with treated insulin and PRP. Rats were euthanized after two weeks of treatment, and testes were taken for caspase-3 and IGF-1 mRNA expression measurements.Diabetes mellitus induction caused a significant increase in caspase-3 mRNA expression with p=0.049 and significant decrease in IGF-1 mRNA expression with p=0.004. There was no difference in caspase-3 and IGF-1 mRNA expression of the diabetic rat testis given insulin and PRP compared to without PRP
Cost Effectiveness Analysis of Rivaroxaban Compared to Warfarin and Aspirin for Stroke Prevention Atrial Fibrillation (SPAF) in the Indonesian healthcare setting
Full text linkMain drugs used in the prevention of stroke among atrial fibrillation (AF) patients are antiplatelets (aspirin) and oral anticoagulants (OAC). OAC therapy can be difficult to administer due to drug and food interactions, adds the burden of required blood monitoring, narrow therapeutic window, and requirements for dose titration. Rivaroxaban is a single-dose oral anticoagulant which does not require blood monitoring, dose titration or has dietary interactions. Phase III clinical data from the ROCKET trial have recently been reported the non-inferiority of rivaroxaban over warfarin for the prevention of strokes in AF patients. To develop an economic model evaluating the clinical and cost-effectiveness of rivaroxaban for the prevention of stroke in non-valvular AF patients in the Indonesian health care settings. We conducted cost effectiveness analysis from the perspective of payer (national health insurance). Effectiveness data used the international data from previous RCT and network metaanalysis studies. Costs data used local data of Indonesia from national health insurance’s reimbursement tariffs. Markov model was used, comprised of health and treatment states describing the management and consequences of AF. The main analysis was based on data from the phase III trials. Three months was used as cycle length. The time horizon was set at patients’ lifetime (20 years). Costs and outcomes were discounted at a 3% annual rate. Subgroup analysis and extensive sensitivity analysis was conducted. Willingness to pay (WTP) threshold in Indonesia was set as 3 times GDP of Indonesia in 2015, equal about IDR 133,375,000 per quality-adjusted life year (QALY). Base case rivaroxaban vs warfarin has ICER of IDR 141,835,063per QALY at the current cost of rivaroxaban IDR 23,500 and ICER of 130,214,687 per QALY at the proposed cost of rivaroxaban IDR 22,000. One-way sensitivity analysis showed that the key drivers of cost-effectiveness were the utility decrement applied to stable warfarin patients, discontinuation/subsequent discontinuation rates for rivaroxaban, and discontinuation/subsequent discontinuation rates for warfarin. The probabilistic sensitivity analysis suggested that rivaroxaban was cost-effective compared to warfarin in about 45% of cases at the WTP per QALY. Rivaroxaban with the proposed price of IDR 22,000 was considered to be more cost-effective when compared to warfarin
Evaluation of Pain Scale Decrease and Adverse Effects of Ketorolac Injections: An Observational Study in Patients with Postoperative Pain
Full text linkThe use of ketorolac injections in Indonesia is restricted with the provision of 2-3 ampoules per day with a maximum of two days even though the literature states that ketorolac could be used for no more than five days. This study aimed to determine the decrease in pain scale as well as gastrointestinal and renal adverse effects of ketorolac injections in two days of use. This study was an observational study with one-group pre-test post-test design conducted prospectively. The group was a group of patients with postoperative pain who received ketorolac injections and were treated during January till April 2018 in an academic hospital in Yogyakarta. The results showed that ketorolac injections did not provide a statistically significant decrease in pain scale in two days of use compared to before surgery (median [range] = 2.0[0.0-9.33] vs 1.33[0.0-8.33]; p=0.32). Ketorolac injections decreased the kidney function of subjects in two days of use compared to before surgery based on creatinine values (0.76mg/dL vs 0.80mg/dL; p=0.024) and GFR (96.13mL/min/m2 vs 87.52mL/min/m2; p=0.023), and as many as 31 subjects (43.06%) experienced complaints that were suspected to be the gastrointestinal adverse effects of ketorolac injections with the three most complaints were bloating (18.06%), nausea (16.67%), and heartburn (15.28%). Those three results support the use of ketorolac injections following what has been regulated in the Indonesian National Formulary
Formulation, Characterization and Stability of Ibuprofen-Loaded Self-Nano Emulsifying Drug Delivery System (SNEDDS)
Full text linkIbuprofen is a poorly water-soluble drug with analgesic, antipyretic and anti-inflammatory effects. Self-Nano Emulsifying Drug Delivery System (SNEDDS) formulation is a solution to improve the solubility and bioavailability of ibuprofen. This research purposed to perform a formulation, characterization, and stability studies of ibuprofen-loaded Self-Nano Emulsifying Drug Delivery System (SNEDDS). Screening of ibuprofen SNEDDS was prepared by ternary diagrams for the chosen co-surfactants, surfactants, and oil. The following was characterizations of droplet size, zeta potential, and clarity. The solubility test for the determination of co-surfactant, surfactant, and oil obtained Propylene glycol monocaprylate (Capryol-90), Polysorbate 20 (Tween 20) and PEG 400. The screening of SNEDDS showed nine formulas (compositions) in the range concentration of Propylene glycol monocaprylate (1-3 mL), Polysorbate 20 (4-8 mL), and PEG 400 (1-3 mL). The composition of Propylene glycol monocaprylate (1-2 mL), Polysorbate 20 (5-8 mL) and PEG 400 (1-3 mL) passed the thermodynamic stability test. The test of robustness to dilution and stability study indicated that the formula with Propylene glycol monocaprylate, Polysorbate 20 and PEG 400 with the ratio of 1: 8: 1 and 1: 7: 2 was more stable. In conclusion, the stable ibuprofen SNEDDS could be prepared with Propylene glycol monocaprylate, Polysorbate 20, and PEG 400
The Application of Multiplate Resazurin Reduction Assay in The Screening for Anti-Mycobacterial Activity from Indonesian Medicinal Plants
Full text linkTuberculosis (TB) is an airborne illness generated by Mycobacterium tuberculosis (Mtb), also one of the prominent infectious killers of adults worldwide. There is a pressing need to expand novel anti-mycobacterial drugs because of the increasing resistance of pathogenic mycobacteria to existing antibiotics. Native compounds acquired from microbial resources and medicinal cultivars have played an essential part as the origin of TB medications. The microplate resazurin reduction assay (MRRA) is generally utilized to assess natural and synthetic compounds for anti-mycobacterial activity. In our work, the MRRA method was employed to evaluate the anti-mycobacterial activity of extracts from curative plants using Mycobacterium smegmatis and Mycobacterium bovis BCG and to compare them to rifampicin as an anti-mycobacterial drug. The optimized MRRA utilized 2% aqueous DMSO and 62.5 μg/mL resazurin as an indicator compound in 5% aqueous Tween 80. The optimal incubation time for M. smegmatis was 24 hours, and for M. bovis BCG was 48 hours. The methanolic plant extracts were acquired from various Indonesian medicinal plants known to have anti-mycobacterial activity. The MRRA method using M. smegmatis or M. bovis BCG as anti-mycobacterial targets offers a distinct advantage such as low-cost, rapid, and safe screening for anti-mycobacterial activity in a middle to high-through-put-format
The effect of Phyllanthus niruri L extracts on human leukemic cell proliferation and apoptosis induction
Full text linkObjective: To investigate the effect of Phyllanthus niruri Linn (Euphorbiaceae) in the proliferation of human leukemic cells (MOLT-4 and K562).Methods: Phyllanthus niruri L (P.niruri) was macerated by using various solvents to obtain the crude extracts. Cytotoxicity of the extracts against MOLT-4 and K562 cells was tested using MTT assay to find the IC50 value. To analyse cell cycle progression, cellular DNA was measured using propidium iodide (PI) staining. Apoptosis induction was evaluated using Annexin V-FITC and PI staining and analysed using FACSVerse flow cytometry. Finally, the expression of p53 on MOLT-4 and K562 cell lysate was measured by western blotting, to identify the possible mode of action of the anticancer activity.Results: P. niruri crude extracts demonstrated a potential anti-cancer effect towards MOLT-4 cells (IC50 range was 42.21 ± 4.98 to 97.06 ± 18.29 µg/ml). However, against K562 cells, P.niruri extracts exhibited a lower inhibitory potency (the IC50 was 120.19 ± 8.48 to 256.55 ± 26.22 µg/ml). The results showed the selectivity of the toxic effect of the extracts against MOLT-4 and K562. To evaluate the possible mechanism of action the anticancer effect, we evaluated P. niruri extract action in apoptosis induction and p53 expression. The results showed that methanol and hexane extract inhibited MOLT-4 cell progression from G1 to S-phase, indicating G1 cell arrest. Moreover, apoptotic cell population following treatment of MOLT-4 and K562 cells with methanol extract was markedly increased, showing morphological signs of apoptosis including membrane degradation and chromatin condensation. Furthermore, we found that there was an increase in p53 expression following MOLT-4 treatment with methanol extract, suggesting that p53 induction may be involved in cell apoptosis.Conclusions: The results indicated the involvement of p53 pathway in the mechanism of anti-cancer activity exerted by P. niruri extract on MOLT-4 cells. However, for cancer cells lacking P53 expression, such as K562 cells, apoptosis might take place via other pathways
The capability of Several Population-based Approach Software to Analyze Sparse Drug Plasma Concentration Data after Intra-Venous Bolus Injection
Full text linkMonolix, NONMEM, and WinBUGS-PKBUGS are among available software package for population-based modeling. The sparse condition of drug plasma concentration versus time (Cp-time) data is prevalent in clinically based studies involving patients. It is not ethical in this case, to collect a many and large volumes of blood samples. This study was aimed to simulate the capability of Monolix, NONMEM, and WinBUGS-PKBUGS to analyze very sparse Cp-time data after an intravenous bolus drug administration and to estimate the minimum number of Cp-time data required for an adequate analysis. Data of Cp-time were obtained based on simulation using the pharmacokinetic one-compartment open model following an intravenous bolus administration of 50 mg of a hypothetical drug. In this respect, six random values of k (rate constant of elimination) and Vd (volume of distribution) with mean and standard deviation values of 0.3 ±0.1 per hour and 30 ± 10 L, respectively, were used to create simulated Cp-time data of 6 subjects. Simulated Cp-time data in each subject were randomly ranked to choose data based on the intended number of samples in each subject. Several sparse Cp-time data scenarios, starting from a very limited state, i.e., with a total of 6 Cp-time data (1 datum per subject) to a rich situation with 48 Cp data (8 data per subject), were examined.The goodness of fit evaluations, as well as the similarity of individual values of k and Vd to the respective real values (p>0.05), indicate that nonlinear-mixed-effect-model using Monolix, NONMEM and WinBUGS-PKBUGS can appropriately describe sparse Cp-time data even with only 2 data per subject. This fact is an important finding to support the demand of analytical tool for a limited number of Cp-time data such as obtained in therapeutic drug monitoring event