METHODS: The pharmacy supply database and the medical records of patients with non-valvular atrial fibrillation (NVAF) receiving warfarin, dabigatran or rivaroxaban at two tertiary hospitals were reviewed. Patients who experienced an OAC-associated major or CRB event within 12 months of follow-up, or who have received OAC therapy for at least 1 year, were identified. The BRSs were fitted separately into patient data. The discrimination and the calibration of these BRSs as well as the factors associated with bleeding events were then assessed.
RESULTS: A total of 1017 patients with at least 1-year follow-up period, or those who developed a bleeding event within 1 year of OAC use, were recruited. Of which, 23 patients experienced a first major bleeding event, whereas 76 patients, a first CRB event. Multivariate logistic regression results show that age of 75 or older, prior bleeding and male gender are associated with major bleeding events. On the other hand, prior gastrointestinal bleeding, a haematocrit value of less than 30% and renal impairment are independent predictors of CRB events. All the BRSs show a satisfactory calibration for major and CRB events. Among these BRSs, only HEMORR2 HAGES (C-statistic = 0.71, 95% CI 0.60-0.82, P oral anticoagulant users. These BRSs show poor to acceptable predictive performance on OAC-induced major or CRB events. An improvement in the existing BRSs for OAC users is warranted.
METHODS: In assessing the safety of DC resin methanol extract, acute and sub-acute oral toxicity tests performed following OECD guidelines 423 and 407, respectively, with slight modifications. In acute oral toxicity test, DC resin methanol extract administered to female Sprague Dawley rats by oral gavage at a single dose of 300 and 2000 mg/kg body weight. Rats observed for toxic signs for 14 days. In sub-acute oral toxicity test, DC resin methanol extract administered to the rats by oral gavage at 500, 1000, and 1500 mg/kg body weight daily up to 28 days to male and female Spradgue Dawley rats. The control and high dose in satellite groups were also maintained and handled as the previous groups to determine the late onset toxicity of DC resin methanol extract. At the end of each test, hematological and biochemical analysis of the collected blood were performed as well as gross and microscopic pathology.
RESULTS: In acute oral toxicity, no treatment-related death or toxic signs were observed. It revealed that the DC resin methanol extract could be well tolerated up to the dose 2000 mg/kg body weight and could be classified as Category 5. The sub-acute test observations indicated that there are no treatment-related changes up to the high dose level compared to the control. Food consumption, body weight, organ weight, hematological parameters, biochemical parameters and histopathological examination (liver, kidney, heart, spleen and lung) revealed no abnormalities. Water intake was significantly higher in the DC resin methanol extract treated groups compared to the control.
CONCLUSION: This study demonstrates tolerability of DC resin methanol extract administered daily for 28 days up to 1500 mg/kg dose.
Objective: To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy.
Design, Setting, and Participants: The Vitamin E in Neuroprotection Study (VENUS) was a parallel, double-blind, placebo-controlled trial that recruited participants from January 30, 2011, to December 7, 2014, with 12 months of follow-up. This trial screened 14 289 patients with diabetes from 6 health clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of 391 patients who reported neuropathic symptoms were further assessed with Total Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.
Interventions: Patients were randomized to receive 200 mg of mixed tocotrienols twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia (homocysteine level ≥2.03 mg/L) received oral folic acid, 5 mg once daily, and methylcobalamin, 500 μg thrice daily, in both groups.
Main Outcomes and Measures: The primary outcome was patient-reported neuropathy TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at 12 months. The secondary outcomes were NIS and sensory nerve conduction test result.
Results: Of 391 eligible patients, 300 were recruited (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and 229 (76.3%) completed the trial. The TSS changes between the tocotrienols and placebo groups at 12 months (-0.30; 95% CI, -1.16 to 0.56; P = .49) were similar. No significant differences in NIS (0.60; 95% CI, -1.37 to 2.65; P = .53) and sensory nerve conduction test assessments were found between both groups. In post hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with hemoglobin A1C levels greater than 8% (P = .03) and normohomocysteinemia (homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in both groups were similar, except more infections were observed in the tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified intention-to-treat analyses.
Conclusions and Relevance: Supplementation of oral mixed tocotrienols, 400 mg/d for 1 year, did not improve overall neuropathic symptoms. The preliminary observations on lancinating pain among subsets of patients require further exploration.
Trial Registration: National Medical Research Registry Identifier: NMRR-10-948-7327 and clinicaltrials.gov Identifier: NCT01973400.
MATERIALS AND METHODS: We reviewed the clinical notes of all patients prescribed with oral capecitabine chemotherapy for any tumour sites in University Malaya Medical Centre (UMMC) from 1st January 2009 till 31st June 2010. Information collected included patient demographics, histopathological features, treatment received including the different chemotherapy regimens and intent of treatment whether the chemotherapy was given for neoadjuvant, concurrent with radiation, adjuvant or palliative intent. The aim of this study is to establish the pattern of usage, FN and TRD rates with capecitabine in clinical practice outside of clinical trial setting. FN is defined as an oral temperature >38.5°or two consecutive readings of >38.0° for 2 hours and an absolute neutrophil count <0.5 x 109/L, or expected to fall below 0.5 x 109/L (de Naurois et al., 2010). Treatment related death was defined as death occurring during or within 30 days of last chemotherapy treatment.
RESULTS: Between 1st January 2009 and 30th June 2010, 274 patients were treated with capecitabine chemotherapy in UMMC. The mean age was 58 years (range 22 to 82 years). Capecitabine was used in 14 different tumour sites with the colorectal site predominating with a total of 128 cases (46.7%), followed by breast cancer (35.8%). Capecitabine was most commonly used in the palliative setting accounting for 63.9% of the cases, followed by the adjuvant setting (19.7%). The most common regimen was single agent capecitabine with 129 cases (47.1%). The other common regimens were XELOX (21.5%) and ECX (10.2%). The main result of this study showed an overall FN rate of 2.2% (6/274). The overall TRD rate was 5.1% (14/274). The FN rate for the single agent capecitabine regimen was 1.6% (2/129) and the TRD rate was 5.4% (7/129). All the TRDs were with single agent capecitabine regimen were used for palliative intent.
CONCLUSIONS: Oral capecitabine is used widely in clinical practice in a myriad of tumour sites and bears a low risk of febrile neutropaenia. However, capecitabine like any other intravenous chemotherapeutic agent carries a significant risk of treatment related death.