Improving the use of antibiotics in primary health centres through a problem-based pharmacotherapy training approach

ABSTRACT Iwan Dwiprahasto & Erna Kristin - Improving the use of antibiotics in primary health centres through a problem-based pharmacotherapy training approach Background: Inappropriate use of antibiotics in the treatment of common diseases such as acute respiratory infection (ARI) and diarrhoea has been the major health problems in primary health centres (PHCs). Beside increasing the risk of adverse event, excessive use of antibiotics has also led to bacterial resistance worldwide. Objective: To improve the quality of prescribing of Primary Health Centers\u27 (PHCs) physicians and paramedics particularly in the treatment of ARI and diarrhoea. Design: Prospective intervention study with control group involving 113 PHCs\u27 physicians in both arms. Thirteen districts were randomly selected for study area, in which intervention was carried out in 8 districts while 5 other districts as control group. A systematic problem-based approach of 3 days training were carried out in the intervention group using 3 sets of modules, followed by self monitoring & regular visit & feedback by a Training Team. Evaluation on prescribing was carried out 3 times, i.e at the 6th , 12th, &18th month after intervention. Results: More than 17 thousands and 8600 prescriptions for ARI and diarrhoea were collected during the study. There was a significant reduction in the use of antibiotics for ARI in the intervention group from 92.3 before the study, to 67.4, 52.8 and 39.5%, 6, 12, & 18 month after the study (p0.05). There has been significant antibiotics prescribing shift toward more rational choice in the intervention group 18 months after the study. Conclusions: A systematic problem-based pharmacotherapy training followed by self monitoring & regular visit & feedback significantly improved antibiotic prescribing for ARI and diarrhoea. Key words: antibiotics - prescribing - problem-based pharmacotherapy training - acute respiratory infection - diarrhoe

Pengaruh pemberian rifampisin terhadap profil farmakokinetika glipizid pada orang sehat

Luciana Kuswibawati, Iwan Dwiprahasto, Erna Kristin - The effect of rifampicin administration on the pharmacokinetic profile of glipizid in normal subjects Background: The use of antituberculosis drugs among diabetic patients is not infrequent. Among these, glipizide is one of the widely used antidiabetic drugs. The use of this second generation sulfonylurea in combination with rifampicin is common.Rifampicin is known as enzyme inductor that can influence other drugs metabolism used in combination. Objective: To investigate the effect of rifampicin pretreatment on the pharmacokinetic parameters of glipizide among 12 Indonesian healthy volunteers. Methods: Using randomized crossover design, volunteers were divided into two groups, i.e control and rifampicin pretreatment groups. Before starting the experiment, the pretreatment group was given 450 mg of rifampicin orally which should be taken daily for 7 days. Subsequently, a single dose of 5 mg glipizide was ingested to control and the pretreatment group as well. After oral administration of single dose of 5 mg glipizide, the samples were collected serially at 00.50.7511.522.534579 and 12 hours to analyze blood glipizide level. High Pert ormace Liquid Chromatography (HPLC) method was used to analyze glipizide pharmacokinetic profile. From the data obtained, the pharmacokinetic parameters were calculated using noncompartment model. Results: The results showed that there were no significant change in the value of Tmax, Cmax, Ka, significant increases clearence (CI) 101.8% and elimination rate constant (Kel) 116.7% of the rifampicin pretreatment group. The elimination half life (T1/2) were shortened 39.5% from 3.8 to 2.3 hours (

EFFECTIVENESS OF TICAGRELOR COMPARED TO CLOPIDOGREL IN REDUCING THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CORONARY HEART DISEASE AFTER PERCUTANEOUS CORONARY INTERVENTION

Objective: Antiplatelet therapy is recommended in patients with coronary heart disease (CHD) who had the percutaneous coronary intervention (PCI) procedure to reduce major adverse cardiovascular events (MACE). There has been a lack of population-based studies that showed the superior effectiveness of ticagrelor over clopidogrel and similar studies have not been conducted in Indonesia yet. The aim of the study was to investigate the effectiveness of ticagrelor compared to clopidogrel in reducing the risk of MACE in patients with CHD after PCI. Methods: A retrospective cohort study with 1-year follow-up was conducted. 361 patients consisted of 111 patients with ticagrelor exposure and 250 patients with clopidogrel exposure. The primary outcome was MACE, defined as a composite of repeat revascularization, myocardial infarction, or all-cause death. The association between antiplatelet exposure and the MACE was analyzed with Cox proportional hazard regression, adjusted for sex, age, comorbid, PCI procedures and concomitant therapy. Results: MACE occurred in 22.7% of the subjects. Clopidogrel had a significantly higher risk of MACE compared with ticagrelor (28.8%, vs 9.0%, hazard ratio (HR): 1.96 (95% CI 1.01 to 3.81, p=0.047). There were no significant differences in risk of repeat revascularization (20.40% vs 5.40%, HR: 2.32, 95% CI 0.99 to 5.42, p = 0.05), myocardial infarction (11.60% vs 3.60%, HR: 2.08, 95% CI, 0.73 to 5.93, p = 0.17), and death (1.60% vs 1.80%, HR: 0.77, 95% CI, 0.14 to 4.25, p = 0.77). Conclusion: Clopidogrel had a higher risk of MACE compared to clopidogrel in patients with CHD after PCI, but there were no significant differences in the risk of repeat revascularization, myocardial infarction, and all-cause death.Â&nbsp

The influence of acetylation status of tuberculosis patients on the isoniazid serum concentrations and sputum conversion after intensive phase therapy

Isoniazid (INH), one of the major antituberculosis drugs, is metabolized by acetylation. Previously study proved the significant differences of serum INH concentration between subject with fast and slow acetylation status. However, the correlation of acetylation status with treatment outcome after fixed-dose combination antituberculosis therapy (FDC-ATT) was not explained. The aim of this study was to evaluate the influence of acetylation status on the treatment outcome and the serum INH concentrations in the adult tuberculosis patients underwent FDC-ATT. A cross sectional study was carried out on 31 tuberculosis patients. Acetylation status was measured by spectrophotometer and serum INH concentration was measured by high performance liquid chromatography (HPLC). Sputum conversion assay was conducted by Ziehl Nelsen method. t-Test, chi square, Mann-Whitney, and Fisherman were used to analyze the data. The proportion of the fast acetylator was 61.3%, whereas the slow acetylator was 38.7%. The proportion of success and failure sputum conversion were 83.9% and 16.1%, respectively. The mean serum INH concentration in the fast acetylator groups (1.52 ± 0.15 μg/mL) was significantly lower than that in the slow acetylator groups (3.84 ± 0.35 μg/mL). The failure conversion risk of the fast acetylator group was about two folds higher than the slow acetylator group, although it was not significantly different (RR=2.53; 95% CI=0.32-20.00; p>0.05). Moreover, the mean serum INH concentration in success (2.46 ± 0.31 μg/mL) and failure (1.89 ± 0.20 μg/mL) sputum conversion was not significantly different (p>0.05). In conclusion, the acetylation status does not influence the sputum conversion in adult tuberculosis patients after FDC-ATT although the serum INH concentration on slow acetylation status is higher than that fast acetylation status.

CYP3A4*1G gene Polymorphism on Javanese People

Most of drugs are metabolized by cytochrome P 450 (CYP) enzyme. Cytochrome P450 3A4 is the cytochrome that is involved in metabolizing more than 60% of all medicine used in human. The variation of this CYP3A4 gene will affect the catalytic activity of this enzyme. Recently, CYP3A4*1G in intron 10 was found in Chinese and Japanese population. There is a substitution of G to A at position 82266 in intron 10. The purpose of this research was to investigate the frequency of allele and genotype CYP3A4*1G. Samples were taken from bloods of the subjects of the research. The examination of CYP3A4*1G was conducted by RTLP-PCR method.As the results of this research, the frequency of CYP3A4*1G in Javanese people is CYP3A4*1/*1 0.25, CYP3A4*1/*1G 0.55 and CYP3A4*1G/*1G 0.20. Frequency of allele G: 0.53, allele A: 0.47. The Fisher’s exact- test shows that the allele and genotype frequencyis p. 1.000. The allele and genotype frequency of Javanese people isstill in Hardy-Weinberg equilibrium

Cost Effectiveness Analysis of Rivaroxaban Compared to Warfarin and Aspirin for Stroke Prevention Atrial Fibrillation (SPAF) in the Indonesian healthcare setting

Main 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

Increasing Serum Transaminase and The Relation with The Serum Concentration of Isoniazid and Rifampicin of Tuberculosis Patients which Given Antituberculosis Fixed Dose Combination in Yogyakarta

ABSTRACT Tuberculosis is still a major health problem in Indonesia. Isoniazid and rifampicin are major antituberculosis drugs. These two drugs have been known to cause hepatotoxicity which is characterized by an increase of serum transaminase concentration. Previous study proved the increase of hepatotoxicity due to isoniazid and rifampicin but did not explain about the correlation with the drugs concentration. The aim of this study is to know the relation between increasing serum transaminase and the serum concentration of  isoniazid and rifampicin of tuberculosis patients which given antituberculosis fixed dose combination in Yogyakarta. We carried out a cross sectional study involving 31 TB patients who received antituberculosis fixed dose combination containing isoniazid and rifampicin. Serum transaminase was measured with an automatic chemical analyzer. Isoniazid and rifampicin concentration was measured by using HPLC. We used t- test, Mann Whitney, Fisher and Spearman to analyze the data. There is no correlation between mean isoniazid concentration with high (7,07±6,24mg/ml) and normal ALT (2,42±0,26mg/ml)  (p>0,05). There is no correlation between mean isoniazid concentration with high (5,03+4,14 mg/ml) and normal AST (p>0,05). There is no correlation between mean rifampicin concentration with high (10,67+3,76 mg/ml) and normal ALT (3,66+0,30 mg/ml) (p>0,05). There is no correlation between mean rifampicin concentration with high (8,52+3,06 mg/ml) and normal AST (3,64+0,32 mg/ml) (p>0,05). Mean of rifampicin concentration in this study are low (4, 12+0,46 mg/ml). So the conclusion that there are no correlation between isoniazid serum concentration with an increase of serum transaminase and no correlation between rifampicin serum concentration with an increase of serum transaminase

CYP3A4*1G gene Polymorphism on Javanese People

AbtractMost of drugs are metabolized by cytochrome P 450 (CYP) enzyme. Cytochrome P450 3A4 is the cytochrome that is involved in metabolizing more than 60% of all medicine used in human. The variation of this CYP3A4 gene will affect the catalytic activity of this enzyme. Recently, CYP3A4*1G in intron 10 was found in Chinese and Japanese population. There is a substitution of G to A at position 82266 in intron 10. The purpose of this research was to investigate the frequency of allele and genotype CYP3A4*1G. Samples were taken from bloods of the subjects of the research. The examination of CYP3A4*1G was conducted by RTLP-PCR method.As the results of this research, the frequency of CYP3A4*1G in Javanese people is CYP3A4*1/*1 0.25, CYP3A4*1/*1G 0.55 and CYP3A4*1G/*1G 0.20. Frequency of allele G: 0.53, allele A: 0.47. The Fisher’s exact- test shows that the allele and genotype frequencyis p. 1.000. The allele and genotype frequency of Javanese people isstill in Hardy-Weinberg equilibrium.Keywords : CYP3A4*1G gene, polymorphism, Javanese peopl

Development of multi-criteria decision analysis (MCDA) framework for off-patent pharmaceuticals – an application on improving tender decision making in Indonesia

Abstract Background Off-patent pharmaceuticals (OPPs) hold vital importance in meeting public health objectives, especially in developing countries where resources are limited. OPPs are comprised of off-patent originals, branded generics and unbranded generics; nonetheless, these products are not identical and often there are differences in their equivalence, manufacturing quality standards and reliability of supply. This necessitates reconsideration of the lowest price policy objective in pharmaceutical decision making. The aim of this study was to develop a Multi-Criteria Decision Analysis (MCDA) framework through a pilot workshop to inform the national procurement of OPPs in Indonesia. Methods An initial list of potentially relevant criteria was identified based on previous work and a literature review. In a 2-day pilot policy workshop, twenty local experts representing different stakeholder groups and decision-making bodies selected the final criteria, approved the scoring function for each criterion, and assigned weights to each criterion. Results An MCDA framework was proposed for OPP drug decision making in developing countries, which included price and 8 non-price criteria. Based on the pilot policy workshop 6 + 1 criteria were considered relevant for Indonesia: pharmaceutical price (40% weight), manufacturing quality (18.8%), equivalence with the reference product (12.2%), product stability and drug formulation (12.2%), reliability of drug supply (8.4%), real world clinical or economic outcomes, such as adherence or non-drug costs (4.2%) and pharmacovigilance (3.6%). Conclusions According to the pilot policy workshop, other criteria apart from price need to be strengthened in the tendering process. The introduction of additional criteria for OPP procurement in an MCDA framework creates incentives for manufacturers to invest into improved manufacturing standards, equivalence proof, product quality, reliability of supply or even additional real-world data collection, which ultimately may result in more health gain for the society

Development of multi-criteria decision analysis (MCDA) framework for off-patent pharmaceuticals - an application on improving tender decision making in Indonesia

BackgroundOff-patent pharmaceuticals (OPPs) hold vital importance in meeting public health objectives, especially in developing countries where resources are limited. OPPs are comprised of off-patent originals, branded generics and unbranded generics; nonetheless, these products are not identical and often there are differences in their equivalence, manufacturing quality standards and reliability of supply. This necessitates reconsideration of the lowest price policy objective in pharmaceutical decision making. The aim of this study was to develop a Multi-Criteria Decision Analysis (MCDA) framework through a pilot workshop to inform the national procurement of OPPs in Indonesia.MethodsAn initial list of potentially relevant criteria was identified based on previous work and a literature review. In a 2-day pilot policy workshop, twenty local experts representing different stakeholder groups and decision-making bodies selected the final criteria, approved the scoring function for each criterion, and assigned weights to each criterion.ResultsAn MCDA framework was proposed for OPP drug decision making in developing countries, which included price and 8 non-price criteria. Based on the pilot policy workshop 6+1 criteria were considered relevant for Indonesia: pharmaceutical price (40% weight), manufacturing quality (18.8%), equivalence with the reference product (12.2%), product stability and drug formulation (12.2%), reliability of drug supply (8.4%), real world clinical or economic outcomes, such as adherence or non-drug costs (4.2%) and pharmacovigilance (3.6%).ConclusionsAccording to the pilot policy workshop, other criteria apart from price need to be strengthened in the tendering process. The introduction of additional criteria for OPP procurement in an MCDA framework creates incentives for manufacturers to invest into improved manufacturing standards, equivalence proof, product quality, reliability of supply or even additional real-world data collection, which ultimately may result in more health gain for the society