Cost-Effectiveness of Ibrutinib as First-line Treatment for Older Patients With Chronic Lymphocytic Leukemia in Iran.

OBJECTIVES: We aimed to evaluate the cost-effectiveness of ibrutinib versus chemoimmunotherapy for frontline treatment of elderly patients with chronic lymphocytic leukemia in Iran. METHODS: We developed a partitioned survival model with 3 health states (progression-free survival, post-progression survival, and death) and a lifetime horizon. State memberships were determined by parametric survival analysis of the ALLIANCE (A041202) randomized controlled trial's results, comparing first-line ibrutinib with bendamustine plus rituximab. Direct medical costs were calculated from an Iranian health system perspective. Utility values were extracted from the literature to calculate the incremental costs and quality-adjusted life-years (QALYs) associated with each strategy. To address parameter uncertainties, deterministic and probabilistic sensitivity analyses were also performed. RESULTS: In the base-case analysis, ibrutinib and bendamustine plus rituximab were associated with $3739.72 and $3991.20 costs per patient as the first-line treatment strategy, respectively. They resulted in an average of 2.86 and 2.66 QALYs per patient. Thus, first-line ibrutinib was associated with 0.20 incremental QALY and $251.48 cost-saving per patient and was therefore the "dominant" strategy. In deterministic sensitivity analysis, drug prices were the key drivers of model outputs. However, none of the resulting incremental cost-effectiveness ratios exceeded the currently accepted threshold by the Iranian Food and Drug Administration ($1550 per QALY). In probabilistic sensitivity analysis, 63.3% of iterations were cost-saving and 77.4% were cost-effective. CONCLUSIONS: Our findings suggest that ibrutinib as a first-line treatment appears to be the dominant strategy, compared with the standard of care, for unselected older adults with chronic lymphocytic leukemia in Iran.

Precision medicine journey through omics approach.

It has been well established that understanding the underlying heterogeneity of numerous complex disease process needs new strategies that present in precision medicine for prediction, prevention and personalized treatment strategies. This approach must be tailored for each individual's unique omics that lead to personalized management of disease. The correlation between different omics data should be considered in precision medicine approach. The interaction provides a hypothesis which is called domino effect in the present minireview. Here we review the various potentials of omics data including genomics, transcriptomics, proteomics, metabolomics, pharmacogenomics. We comprehensively summarize the impact of omics data and its major role in precision medicine and provide a description about the domino effect on the pathophysiology of diseases. Each constituent of the omics data typically provides different information in associated with disease. Current research, although inadequate, clearly indicate that the information of omics data can be applicable in the concept of precision medicine. Integration of different omics data type in domino effect hypothesis can explain the causative changes of disease as it is discussed in the system biology too. While most existing studies investigate the omics data separately, data integration is needed on the horizon of precision medicine by using machine learning.

Pharmacogenomics Implementation and Hurdles to Overcome; In the Context of a Developing Country.

Having multiple dimensions, uncertainties and several stakeholders, the costly pharmacogenomics (PGx) is associated with dynamic implementation complexities. Identification of these challenges is critical to harness its full potential, especially in developing countries with fragile healthcare systems and scarce resources. This is the first study aimed to identify most salient challenges related to PGx implementation, with respect to the experiences of early-adopters and local experts' prospects, in the context of a developing country in the Middle East. To perform a comprehensive reconnaissance on PGx adoption challenges a scoping literature review was conducted based on national drug policy components: efficacy/safety, access, affordability and rational use of medicine (RUM). Strategic option development and analysis workshop method with cognitive mapping as the technique was used to evaluate challenges in the context of Iran. The cognitive maps were face-validated and analyzed via Decision Explorer XML. The findings indicated a complex network of issues relative to PGx adoption, categorized in national drug policy indicators. In the rational use of medicine category, ethics, education, bench -to- bedside strategies, guidelines, compliance, and health system issues were found. Clinical trial issues, test's utility, and biomarker validation were identified in the efficacy group. Affordability included pricing, reimbursement, and value assessment issues. Finally, access category included regulation, availability, and stakeholder management challenges. The current study identified the most significant challenges ahead of clinical implementation of PGx in a developing country. This could be the basis of a policy-note development in future work, which may consolidate vital communication among stakeholders and accelerate the efficient implementation in developing new-comer countries.

Cost-utility analysis of Macitentan Vs. Bosentan in pulmonary atrial hypertension.

OBJECTIVE: Endothelin (ET) receptor antagonists (ERAs) have considerable improvements in pulmonary arterial hypertension (PAH) patients' symptoms. Macitentan, a novel ERA, has more significant positive effects like reduction of morbidity and mortality in PAH patients by 45% and decreases PAH hospitalization. Besides, macitentan was able to improve both the physical and mental aspects of patients' lives. This study aimed to evaluate an incremental cost-utility analysis of macitentan compared with bosentan in PAH patients in the Iranian health care system. METHODS: We developed a hybrid model consisting of a decision tree in which PAH patients would take and continue either macitentan or bosentan with different probabilities. Subsequently, each patient would enter one of the 4 Markov's, each consisting of 5 states, PAH fraction I, PAH fraction II, PAH fraction III, PAH fraction IV, and death. The cycles and time horizon were considered 3 months and lifetime, respectively. We assessed the impact of each medicine on patients' quality-adjusted life-years (QALYs) and costs, consequently calculated the ICER (Incremental Cost-Effectiveness Ratio). The costs were measured in the dollar (1 dollar is equal to 42000 rials) with the perspective of the payer. The discount rates were assumed 3% for utility and 5% for costs. In addition, a sensitivity analysis was conducted. RESULTS: The costs are about 14163 dollars for bosentan and 13876 dollars for macitentan for each patient in a lifetime. The QALY produced per patient by macitentan was 0.81 more than that of bosentan. The calculated ICER was -357.47 which means that for each incremental QALY, the payer is charged less. CONCLUSION: Macitentan is preferable to and dominant over bosentan in both effectiveness and expenditure. Thus, the therapeutic regimen containing macitentan is introduced as a favorable treatment strategy.

Providing a framework for assessment of the access to medicine.

OBJECTIVE: Improving access to effective and safe medicines is one of the major goals of all health systems. To achieve this goal, assessment is a fundamental phase of national medicine programs for access improvement. Collecting and compiling applicable indicators and impart a comprehensive framework for assessing access to medicine, are the aims of this study. METHODS: To investigate the published materials on access to medicines framework or indicators, a literature review with a systematic search was conducted using PubMed/ Medline, Scopus, and Google Scholar databases. The results were completed with a general search of documents in Iran Food and Drug Administration (IRFDA). Two independent researchers reviewed all the articles and documents. Thereafter the related indicators were extracted. In focused group discussion of academics and IRFDA experts, duplicate entries or ineffectual concepts were cleaned from the preliminary indicators. In the next step, Delphi questionnaire was sent to the 17 experts that work in academia, Social Security Insurance, IRFDA, Ministry of Health and Iran Pharmacist Association. The results of Delphi technique were finalized in an expert panel. RESULTS: One hundred and thirty one indicators were found in systematic search. After primary extraction of related indicators, 77 indicators were sent to the 17 experts in a Delphi form. The results of Delphi were finalized in a specialized-working group and 67 indicators were accepted in 5 categories including physical availability and geographical accessibility (19 indicators), affordability (23 indicators), human resources (4 indicators), quality and safety (5 indicators), information and rational use (16 indicators). CONCLUSION: The indicators that inclusively assess the full access to medicine in the concept of rational use have been categorized into five categories in this study. To determine the access to medicine status in each country further local surveys are necessary for all several indicators in each category. Graphical abstract The graphical abstract of accomplished steps.

Investigation of simvastatin-induced apoptosis and cell cycle arrest in cancer stem cells of MCF-7.

CONTEXT: Recent studies have shown the association between statins use and cancer risk reduction. Furthermore the importance of cancer stem cells (CSCs) in tumor initiation, progression and migration has been firmly established in a variety of solid tumors. Hence, the effective targeting of breast CSCs has a potential to improve cancer treatment outcome significantly. AIMS: This study has been designed to investigation the anticancer effects of simvastatin on breast CSCs. SETTINGS AND DESIGN: In this study, MCF-7 CSCs were isolated from parent cells and cytotoxic effects of simvastatin were evaluated and compared in both cells. SUBJECTS AND METHODS: Stem cell isolation was done by flow cytometry technique and the effects of simvastatin on the stem cell viability, apoptosis and cell cycle were evaluated and compared with parent cells. STATISTICAL ANALYSIS USED: The results were analyzed using one.way ANOVA, followed by Tukey.Kramer posttest. The P < 0.05 was considered as significant. RESULTS: Based on the result, simvastatin shows dose-dependent cytotoxic effects on both CSCs and parent MCF-7 cells, whereas the apoptosis induction and the elimination of nonapoptotic programmed death were increased in CSC compared with parent cells. In addition, simvastatin showed the reduction in DNA synthesis and induced cell cycle arrest in the G1 phase in MCF-7 CSCs. CONCLUSIONS: This finding indicates that simvastatin with specific apoptotic effect on MCF-7 CSC may provide supporting reasons for future in vivo and in vitro statin trials.

Controlling type 2 diabetes mellitus with herbal medicines: A triple-blind randomized clinical trial of efficacy and safety.

BACKGROUND: The use of alternative medicines is common in patients with diabetes mellitus. The primary aim of the present study was to determine the effects of cinnamon and Caucasian whortleberry (Vaccinium arctostaphylos L.) on blood glucose control, lipid profile and body mass index (BMI) in patients with type 2 diabetes (T2DM). METHODS: In all, 105 T2DM patients were recruited to the present randomized triple-blinded clinical trial. Patients were randomly divided into three groups and administered either placebo, cinnamon or whortleberry supplements (1 g/day) for 90 days. Fasting blood glucose (FBG), serum insulin, lipid profiles, and HbA1c were measured before and after the study. RESULTS: There were no significant differences in baseline characteristics among the three groups. After treatment, FBG, 2-h blood postprandial glucose and homeostasis model assessment of insulin resistance (HOMA-IR) scores were significantly reduced in patients in the whortleberry group, but not in the placebo group. After treatment, there was a significant difference in BMI between the cinnamon and control groups (P = 0.02). There were no significant differences in any variables between the cinnamon and whortleberry groups (P>0.05 for all). In addition, there was a significant decrease in all indices of glucose control in all the cinnamon and whortleberry groups (P < 0.05). CONCLUSIONS: There were no significant differences in blood glucose levels, insulin sensitivity or lipid profile among the three groups. However, the use of cinnamon and whortleberry in addition to conventional medical treatment is recommended to adjust weight and blood glucose levels in patients with T2DM, respectively.

Non-addictive opium alkaloids selectively induce apoptosis in cancer cells compared to normal cells.

BACKGROUND: Cytotoxic effects of some of the members of papaveraceae family have been reported in Iranian folk medicine. Recent reports has indicated that alkaloids fraction of opium may be responsible for its cytotoxic effect; however, the mechanism of this effect is not fully understood. This study has been designed to investigate the selective cytotoxic, genotoxic and also apoptosis induction effects of noscapine, papaverine and narceine, three non-addictable opium alkaloids, on HT29, T47D and HT1080 cancer cell lines. Mouse NIH3T3 cell line was chosen to present non-cancerous cells and Doxorubicin was selected as the positive control. METHODS: Cells were treated by different concentrations of Noscapine, Papaverine, Narceine and doxorubicin; viability was assessed by MTT assay. The genotoxicity and apoptosis induction were tested with comet assay and Annexin-V affinity when the concentration of each these drugs is less than its IC50. In addition, the DNA damage and caspase activity of the T47D cells were examined and the results were compared. RESULTS: This study noted the cytotoxicity and genotoxicity of noscapine and papaverine, specifically on cancerous cell lines. Furthermore, papaverine induces apoptosis in all studied cancer cell lines and noscapine showed this effect in T47D and HT29 cells but not in NIH-3 T3 cells as noncancerous cell line. narceine also showed genototoxicity in the studied cell lines at its IC50 concentration. CONCLUSIONS: This experiment suggests that noscapine and papaverine may be of use in cancer treatment due to their specific cytotoxicity and genotoxicity. However, further in vivo studies are needed to confirm its usefulness in cancer treatment.

Evaluation of the expression of P-glycoprotein in propoxur-resistant Caco-2 cells.

UNLABELLED: There is a great concern about the effect of propoxur, as one of the more common N-methyl carbamate pesticides, on human health due to its extensive use in agricultural and non-agricultural applications. Caco-2 cells became resistant to propoxur, and the resistance was confirmed through MTT assay. Then the cell membrane integrity and P-glycoprotein expression were measured by LDH assay and western blot analysis, respectively and compared to the parent cells.  Contrary to what was expected, the expression of P-glycoprotein in propoxur resistant cells was lower than parent cells. CONCLUSION: This study indicates that the resistance to propoxur may not be related to P-glycoprotein expression directly, since P-glycoprotein expression has decreased in these cells.