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  1. Wan Puteh SE, Mohamad Selamat E, Aizuddin AN, Tumian NR, Sathar J
    Asian Pac J Cancer Prev, 2022 Dec 01;23(12):4253-4260.
    PMID: 36580008 DOI: 10.31557/APJCP.2022.23.12.4253
    BACKGROUND: The burden of chronic myeloid leukaemia (CML) is increasing due to longer patient survival, better life expectancy of the general population, and increasing drug prices. Funding is one of the main concerns in the choice of CML medication used worldwide; thus, patient assistance programmes were introduced to ensure accessibility to affordable treatment. In this study, we evaluated CML drug distribution inequality in Malaysia through patient assistance programmes, using pharmaco-economics methods to evaluate CML treatment from the care provider's perspective.

    METHODS: Patients with CML were recruited from outpatient haematological clinics at the national centre of intervention and referral for haematological conditions and a public teaching hospital. The health-related quality of life or utility scores were derived using the EuroQol EQ-5D-5L questionnaire. Costing data were obtained from the Ministry of Health Malaysia Casemix MalaysianDRG. Imatinib and nilotinib drug costs were obtained from the administration of the participating hospitals and pharmaceutical company.

    RESULTS: Of the 221 respondents in this study, 68.8% were imatinib users. The total care provider cost for CML treatment was USD23,014.40 for imatinib and USD43,442.69 for nilotinib. The governmental financial assistance programme reduced the total care provider cost to USD13,693.51 for imatinib and USD19,193.45 for nilotinib. The quality-adjusted life years (QALYs) were 17.87 and 20.91 per imatinib and nilotinib user, respectively. Nilotinib had a higher drug cost than imatinib, yet its users had better life expectancy, utility score, and QALYs. Imatinib yielded the lowest cost per QALYs at USD766.29.

    CONCLUSION: Overall, imatinib is more cost-effective than nilotinib for treating CML in Malaysia from the care provider's perspective. The findings demonstrate the importance of cancer drug funding assistance for ensuring that the appropriate treatments are accessible and affordable and that patients with cancer use and benefit from such patient assistance programmes. To establish effective health expenditure, drug distribution inequality should be addressed.

    Matched MeSH terms: Pyrimidines/adverse effects
  2. Boo YL, Liam CCK, Lim SY, Look ML
    Hong Kong Med J, 2019 Feb;25(1):74-5.
    PMID: 30713145 DOI: 10.12809/hkmj176972
    Matched MeSH terms: Pyrimidines/adverse effects*
  3. Bee PC, Gan GG, Teh A, Haris AR
    Med J Malaysia, 2006 Dec;61(5):547-52.
    PMID: 17623954 MyJurnal
    This study was done to assess the overall response rate of imatinib mesylate in local patients with chronic myeloid leukaemia. A total of 69 patients were recruited with male/female ratio of 7:3. Of the 69 patients; 35% were in the chronic phase, 41% were in the accelerated phase, 17% were in blast crisis and the remaining 7% were after stem cell transplantation. Complete haematological response rates of patients in chronic phase, accelerated phase and blast crisis were 95.8%, 96.4% and 41.7% respectively. Thirty-eight percent of patients achieved complete cytogenetic response and 10% achieved partial cytogenetic response. The cytogenetic response rates were 80%, 41.7% and 18.2% in chronic, accelerated and blast crisis phase respectively (p < 0.005). Twenty-six percent of patients developed anaemia, 13% had neutropenia and 12% had thrombocytopenia after starting on treatment. In addition, 14% of patients developed peripheral oedema, 13% complained of musculoskeletal pain, 12% had gastrointestinal side effects which include nausea, vomiting and diarrhoea, 9% had grade 1 hepatotoxicity, 7% developed skin rashes and one patient had an abnormal renal function test. Patients taking 600mg or higher dosage of imatinib had more gastrointestinal side effects. Patients who weighed less than 60kg had a much higher risk of developing anaemia. Anaemia was a negative predictor of cytogenetic response. Presenting high white blood cell counts and absence of cytogenetic response were also negative predictors of survival. Overall survival was 87%. This was affected by the different phases of disease (chronic phase was better than accelerated and blast crisis) (p < 0.001). In conclusion, our local CML patients did well on treatment with imatinib.
    Matched MeSH terms: Pyrimidines/adverse effects
  4. Chng WJ, Tan LH
    Leuk. Res., 2005 Jun;29(6):719-20.
    PMID: 15863215
    Matched MeSH terms: Pyrimidines/adverse effects*
  5. Hall DA, Ray J, Watson J, Sharman A, Hutchison J, Harris P, et al.
    Hear Res, 2019 06;377:153-166.
    PMID: 30939361 DOI: 10.1016/j.heares.2019.03.018
    AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.
    Matched MeSH terms: Pyrimidines/adverse effects
  6. Hughes TP, Munhoz E, Aurelio Salvino M, Ong TC, Elhaddad A, Shortt J, et al.
    Br J Haematol, 2017 10;179(2):219-228.
    PMID: 28699641 DOI: 10.1111/bjh.14829
    The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).
    Matched MeSH terms: Pyrimidines/adverse effects
  7. Somchit N, Chung JH, Yaacob A, Ahmad Z, Zakaria ZA, Kadir AA
    Drug Chem Toxicol, 2012 Jul;35(3):304-9.
    PMID: 22288423 DOI: 10.3109/01480545.2011.614619
    Voriconazole is a new, potent broad-spectrum triazole systemic antifungal drug, a second-generation azole antifungal that is increasing in popularity, especially for the treatment of invasive aspergillosis and fluconazole-resistant invasive Candida infections. However, it is also known to induce hepatotoxicity clinically. The aim of this study was to investigate the hepatotoxicity and nephrotoxicity potential of voriconazole in vivo in rats. Forty rats were treated intraperitoneally with voriconazole as single (0, 10, l00, and 200 mg/kg) or repeated (0, 10, 50, and l00 mg/kg per day for 14 days) doses. Venous blood was collected for the repeated-dose group on days 1 and 14. Rats were sacrificed 24 hours after the last dose. Body weight, liver weight, and kidney weight of rats were recorded. Livers and kidneys samples were taken for histological and transmission electron microscopy (TEM) analysis. Results revealed that voriconazole had no effects on serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphotase, gamma glutamyl transpeptidase, blood urea nitrogen, and creatinine for both the single- and repeated-dose groups. However, histologically, in the repeated 50- and 100-mg/kg voriconazole-treated rats, mild focal inflammation was observed. Under TEM, only small changes in the 100 mg/kg/day group were revealed. These results collectively demonstrated that voriconazole did not induce significant hepatotoxicity and nephrotoxicity, even at very high doses.
    Matched MeSH terms: Pyrimidines/adverse effects*
  8. Wahiduzzaman M, Pubalan M
    Dermatol. Online J., 2008;14(12):14.
    PMID: 19265627
    Imatinib mesylate--Gleevec (US), Glivec (worldwide), STI571--is an oral cancer drug that selectively inhibits several protein tyrosine kinases associated with human malignancy. The drug is used for the treatment of chronic myeloid leukemia, malignant gastrointestinal stromal tumors, and some other conditions. Treatment with imatinib is generally well tolerated but not without the risk of adverse effects. The risk of severe adverse events is low. Cutaneous side effects of this drug are common but muco-cutaneous lichenoid eruption with nail changes is very rare. We report a case of lichenoid eruption during imatinib therapy involving the skin, mucous membranes, and nails that cleared in spite of ongoing imatinib therapy.
    Matched MeSH terms: Pyrimidines/adverse effects*
  9. Zhu JR, Tomlinson B, Ro YM, Sim KH, Lee YT, Sriratanasathavorn C
    Curr Med Res Opin, 2007 Dec;23(12):3055-68.
    PMID: 18196620
    BACKGROUND: Most studies investigating the benefits of statins have focused on North American and European populations. This study focuses on evaluating the lipid-lowering effects of rosuvastatin and atorvastatin in Asian patients.

    OBJECTIVES: The DIrect Statin COmparison of LDL-C Values: an Evaluation of Rosuvastatin therapY (DISCOVERY)-Asia study is one of nine independently powered studies assessing the efficacy of starting doses of statins in achieving target lipid levels in different countries worldwide. DISCOVERY-Asia was a 12-week, randomised, open-label, parallel-group study conducted in China, Hong Kong, Korea, Malaysia, Taiwan, and Thailand.

    RESULTS: A total of 1482 adults with primary hypercholesterolaemia and high cardiovascular risk (> 20%/10 years, type 2 diabetes, or a history of coronary heart disease) were randomised in a 2 : 1 ratio to receive rosuvastatin 10 mg once daily (o.d.) or atorvastatin 10 mg o.d. The percentage of patients achieving the 1998 European Joint Task Force low-density lipoprotein cholesterol (LDL-C) goal of < 3.0 mmol/L at 12 weeks was significantly higher in the rosuvastatin group (n = 950) compared with the atorvastatin group (n = 471) (79.5 vs. 69.4%, respectively; p < 0.0001). Similar results were observed for 1998 European goals for total cholesterol (TC), and the 2003 European goals for LDL-C and TC. LDL-C and TC levels were reduced significantly more with rosuvastatin compared with atorvastatin. Both drugs were well-tolerated and the incidence and type of adverse events were similar in each group.

    TRIALS REGISTRATION: The trial registry summary is available at http://www.clinicaltrials.gov/; ClinicalTrials.gov Identifier: NCT00241488

    CONCLUSIONS: This 12-week study showed that the starting dose of rosuvastatin 10 mg o.d. was significantly more effective than the starting dose of natorvastatin 10 mg o.d. at enabling patients with primary hypercholesterolaemia to achieve European goals for LDL-C and TC in a largely Asian population in real-life clinical practice. The safety profile of rosuvastatin 10 mg is similar to that of atorvastatin 10 mg in the Asian population studied here, and is consistent with the known safety profile of rosuvastatin in the white population.

    Matched MeSH terms: Pyrimidines/adverse effects
  10. Tan SY, Kan E, Lim WY, Chay G, Law JH, Soo GW, et al.
    J Pharm Pharmacol, 2011 Jul;63(7):918-25.
    PMID: 21635257 DOI: 10.1111/j.2042-7158.2011.01296.x
    The pharmacokinetic interaction between metronidazole, an antibiotic-antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.
    Matched MeSH terms: Pyrimidines/adverse effects
  11. Erman M, Biswas B, Danchaivijitr P, Chen L, Wong YF, Hashem T, et al.
    BMC Cancer, 2021 Sep 14;21(1):1021.
    PMID: 34521387 DOI: 10.1186/s12885-021-08738-z
    BACKGROUND: Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking.

    METHODS: PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI).

    RESULTS: Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving  10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%).

    CONCLUSIONS: Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies.

    Matched MeSH terms: Pyrimidines/adverse effects
  12. Lee HC, Hamzah H, Leong MP, Md Yusof H, Habib O, Zainal Abidin S, et al.
    Sci Rep, 2021 Feb 15;11(1):3847.
    PMID: 33589712 DOI: 10.1038/s41598-021-83222-z
    Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. In the study, we assessed the effect of non-maternal toxic dosages of ruxolitinib (0-30 mg/kg/day between E7.5-E20.5) on the brain of the developing mouse embryos. While the pregnant mice did not show any apparent adverse effects, the Gfap protein marker for glial cells and S100β mRNA marker for astrocytes were reduced in the postnatal day (P) 1.5 pups' brains. Gfap expression and Gfap+ cells were also suppressed in the differentiating neurospheres culture treated with ruxolitinib. Compared to the control group, adult mice treated with ruxolitinib prenatally showed no changes in motor coordination, locomotor function, and recognition memory. However, increased explorative behaviour within an open field and improved spatial learning and long-term memory retention were observed in the treated group. We demonstrated transplacental effects of ruxolitinib on astrogenesis, suggesting the potential use of ruxolitinib to revert pathological conditions caused by gliogenic-shift in early brain development such as Down and Noonan syndromes.
    Matched MeSH terms: Pyrimidines/adverse effects
  13. Au A, Aziz Baba A, Goh AS, Wahid Fadilah SA, Teh A, Rosline H, et al.
    Biomed Pharmacother, 2014 Apr;68(3):343-9.
    PMID: 24581936 DOI: 10.1016/j.biopha.2014.01.009
    The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
    Matched MeSH terms: Pyrimidines/adverse effects
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