Lack of association of CYP2B6 pharmacogenetics with cyclophosphamide toxicity in patients with cancer.

PURPOSE: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment. METHODS: Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity. RESULTS: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p > 0.05). CONCLUSION: The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer.

SLCO1B3 polymorphisms and clinical outcomes in kidney transplant recipients receiving mycophenolate.

Aim: Determine the influence of SLCO1B3 polymorphisms on outcomes in kidney transplant recipients. Materials & methods: We retrospectively evaluated 181 adult kidney transplant recipients receiving mycophenolate. Outcomes included treated biopsy-proven acute rejection (tBPAR), de novo donor-specific antibody (dnDSA) formation, graft survival, patient survival and mycophenolate-related adverse effects among SLCO1B3 genotypes. Results: The presence of SLCO1B3 variants was not associated with increased risk of tBPAR (HR: 1.45, 95% CI: 0.76-2.74), dnDSA (HR: 0.46, 95% CI: 0.16-1.36) or composite of tBPAR or dnDSA (HR: 1.14, 95% CI: 0.64-2.03). Graft and patient survival were reduced among variant carriers; however, inconsistent findings with the primary analysis suggest these associations were not due to genotype. Adverse effects were similar between groups. Conclusion: Presence of SLCO1B3 polymorphisms were not predictive of rejection or dnDSA in kidney transplant recipients.

Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy.

Aim: To evaluate toxicity risk in carriers of four DPYD variants using an institutional genetic repository. Materials & methods: Of over 65,000 patients in the repository, 582 were evaluated for the primary composite end point of grade 3 or higher toxicity or treatment modification due to toxicity. Results: The primary end point was more common in DPYD variant carriers (36.5 vs 18.1%, adjusted odds ratio 2.42, 95% CI: 1.05-5.55, p = 0.04), and in patients with decreased DPD activity (≤1 vs 2) (75.6 vs 17.0%, adjusted odds ratio 16.31, 95% CI: 2.64-100.68, p = 0.003). Conclusion: Patients carrying any of the four DPYD variants are at increased risk of severe toxicity or subsequent treatment modifications, suggesting such patients may benefit from genotype-informed treatment.

Improvement Initiative to Develop and Implement a Tool for Detecting Drug-Drug Interactions During Oncology Clinical Trial Enrollment Eligibility Screening.

OBJECTIVES: Screening subjects for drug-drug interactions (DDIs) before enrollment in oncology clinical trials is integral to ensuring safety, but standard procedures or tools are not readily available to screen DDI in this setting. Our objectives were to develop a DDI screening tool for use during oncology clinical trial enrollment and to test usability in single-center and multicenter pilot studies. METHODS: A multistage approach was used for this quality improvement intervention. Semistructured interviews with individuals responsible for DDI screening were conducted to develop a prototype tool. The tool was used for screening DDI in subjects enrolling in National Clinical Trials Network trials of commercially available agents during a single-center 3-month pilot. Improvements were made, and a 3-month multicenter pilot was conducted at volunteer SWOG Cancer Research Network sites. Participants were surveyed to determine tool usability and efficiency. RESULTS: A tool was developed from semistructured interviews. A critical feature was reporting which medications had specific pharmacokinetic and pharmacodynamic characteristics including transporter and cytochrome P450 substrates, inhibitors, or inducers and QT prolongation. In the 12-site study, average (SD) DDI screening time for each patient decreased by 15.7 (10.2) minutes (range, 3-35 minutes; P < 0.001). Users reported the tool highly usable, with >90% agreeing with all positive usability characterizations and disagreeing with all negative complexity characterizations. CONCLUSIONS: A DDI screening tool for oncology clinical trial enrollment was created and its usability confirmed. Further testing with more diverse investigator sites and study drugs during eligibility screening is warranted to improve safety and data accuracy within clinical trials.

Primary amenorrhea in females attending gynaecological outpatient of a tertiary care hospital at Peshawar.

OBJECTIVE: To determine the aetiological factors of amenorrhea. METHODS: The pilot cross-sectional study was conducted in Government Naserullah Khan Babar Memorial Hospital, Peshawar, Pakistan, from January 2015 to December 2017, and comprised amenorrhea cases. Cases were analysed according to their clinical profile, ultrasound findings and biochemical tests. Data was analysed using SPSS 20. RESULTS: There were 100 patients with a mean age of 22.17±5.52 years (range: 14-36 years). Anatomical defects were the most common cause in 60(60%) patients. Imperforate hymen and transverse vaginal septum were found in 7(7%), 7(7%) patients each, while mullerian abnormalities were found in 46(46%) patients. Hypergonadotropic hypogonadism and polycystic ovarian syndrome were found in 17(17%) patients each. CONCLUSIONS: Anatomical defects were found to be the most common cause among amenorrhea patients.

Comparison of eight screening tools to detect interactions between herbal supplements and oncology agents.

INTRODUCTION: Patients with cancer are increasingly using herbal supplements, unaware that supplements can interact with oncology treatment. Herb-drug interaction management is critical to ensure optimal treatment outcomes. Several screening tools exist to detect drug-drug interactions, but their performance to detect herb-drug interactions is not known. This study compared the performance of eight drug-drug interaction screening tools to detect herb-drug interaction with anti-cancer agents. METHODS: The herb-drug interaction detection performance of four subscription (Micromedex, Lexicomp, PEPID, Facts & Comparisons) and free (Drugs.com, Medscape, WebMD, RxList) drug-drug interaction tools was assessed. Clinical relevance of each herb-drug interaction was determined using Natural Medicine and each drug-drug interaction tool. Descriptive statistics were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Linear regression was used to compare performance between subscription and free tools. RESULTS: All tools had poor sensitivity (<0.20) for detecting herb-drug interaction. Lexicomp had the highest positive predictive value (0.98) and best overall performance score (0.54), while Medscape was the best performing free tool (0.52). The worst subscription tools were as good as or better than the best free tools, and as a group subscription tools outperformed free tools on all metrics. Using an average subscription tool would detect one additional herb-drug interaction for every 10 herb-drug interactions screened by a free tool. CONCLUSION: Lexicomp is the best available tool for screening herb-drug interaction, and Medscape is the best free alternative; however, the sensitivity and performance for detecting herb-drug interaction was far lower than for drug-drug interactions, and overall quite poor. Further research is needed to improve herb-drug interaction screening performance.

Epidemiology of potential drug-drug interactions in elderly population admitted to critical care units of Peshawar, Pakistan.

BACKGROUND: Aging population, is a reality in many countries because of improvement in the health care, patient safety and other supplemental factors. Pharmacotherapy in this population must be evaluated due to their higher susceptibility to adverse drug outcomes, like potential drug-drug interactions (PDDIs). Research in this regard is limited particularly in developing countries. The aim of the study was to evaluate the prevalence and associated factors in this population. METHODS: The multicentered study evaluated the prevalence of potential drug-drug interactions and associated factors in elderly population at critical care units in Peshawar, Pakistan. Potential drug-drug interactions were evaluated using Micromedex DrugReax, while statistical analysis was performed using SPSS. RESULTS: A total of 70.17% elderly patients were observed to have at least one PDDI. A significant association was observed between presence of PDDIs and number of prescribed drugs, duration of stay and age (p < 0.05). A total of 3019 PDDIs were observed, attributing to 225 drug pairs. Prevalent PDDIs were of moderate severity, good documentation and pharmacodynamic in nature. One-way ANOVA revealed a significant difference in the means of PDDIs between Northwest general hospital and the rest of the hospitals. Moreover, there was a significant difference in the means of PDDIs of CCU and SU with rest of the units. CONCLUSION: The prevalence of PDDIs was observed to be high in elderly population which can be managed by avoiding or managing a limited number of drug combinations. Such studies are necessary to evaluate the risks of these PDDIs in a population which is already physiologically compromised.

Risk of potential drug-drug interactions in the cardiac intensive care units. A comparative analysis between 2 tertiary care hospitals.

OBJECTIVES: To identify and compare the prevalence of drug-drug interactions (DDIs) in the intensive cardiac care units (CCUs) of 2 tertiary care hospitals and analyze their association with various predictors. Methods: This one-year prospective cross-sectional study was conducted in 2 tertiary care hospitals of Peshawar, Khyber Teaching Hospital (KTH) and Hayatabad Medical Complex (HMC), Peshawar, Pakistan, between January 2014 to Janury 2015. The patient medication profiles from the respective CCUs were evaluated for potential DDIs (PDDIs) using Micromedex DrugReax and Drug interaction facts. Results: The prevalence of PDDIs was 96.5% and  95.7% in the 2 hospitals, with over 1200 PDDIs in total. A significant association was found between the number of prescribed drugs and PDDIs in both  hospitals.  Conclusion: The knowledge of PDDIs is either lacking among the clinicians or is not taken into consideration. Monitoring PDDIs and timely interventions are required to minimize the adverse outcomes.

Drug utilization in neonatal setting of Pakistan: focus on unlicensed and off label drug prescribing.

BACKGROUND: Unlicensed and off label drug use is an issue recognized worldwide in pediatric pharmacotherapy. The study was designed to assess the prevalence and predictors of unlicensed and off label drug use in neonatal population of Pakistan. METHOD: A prospective, observation study was conducted in nursery units at pediatric department of four tertiary care hospitals during the 1 year. Micromedex DRUGDEX was used to evaluate the case notes of 1300 patients. Logistic regression was employed to calculate the odds ratio for the predictors of unlicensed and off label drug use. RESULTS: A total of 1300 patients were included in this study who were treated with 52 different drugs. The prevalence of off label drug use was higher (52.14%) as compared to unlicensed drug use (33.35%). Dose (61.29%) and indication (13.68%) were the most frequent reasons for off label prescribing. In comparison to the corresponding reference categories, females and preterm infants were less likely to receive unlicensed prescriptions. While patients staying at hospital more than 5 days and infants receiving 3 or more medications were significantly more likely to receive unlicensed prescriptions. Moreover, in comparison to the corresponding reference categories, females were less likely to receive off label prescriptions while infants receiving 3 or more medications were 7 times more likely to receive off label prescriptions. CONCLUSION: The significant prevalence of unlicensed and off label drug prescriptions was found in neonatal population of Pakistan. The findings imply that more data on prevalence of unlicensed and off label prescriptions are required to provide a better picture of pediatric therapy in developing countries. Furthermore, advance formulations with new dosing in pediatrics is also necessary to minimize the risk of adverse drug events.

Unlicensed and off-label use of drugs in pediatric surgical units at tertiary care hospitals of Pakistan.

Background Unlicensed and off-label prescribing practice is global dilemma around the world. This pioneering study was designed to determine unlicensed and off-label use of drug in surgical wards of tertiary care hospitals of Pakistan. Objective To assess unlicensed and off-label use of drugs in pediatric surgical unit at three tertiary care hospitals in Peshawar, Pakistan. Setting Two government and one private tertiary care hospitals in Pakistan. Method Drug profiles of 895 patients from three different clinical settings were evaluated for unlicensed and off-label use of drugs using Micromedex DRUGDEX. Main outcome measure Characteristics of the unlicensed and off-label drug prescriptions. Result Total of 3168 prescribed drugs were analyzed in this study. Indication (38.7%) and dose (34.8%) were the most frequent off-label categories. In comparison with the corresponding reference categories, infants and children, male patients and having less than five prescribed drugs were significant predictors of unlicensed prescriptions. In comparison with the corresponding reference categories, significant predictors of off-label drug prescribing were children younger than two year, children between 2-12 years, patient staying at hospital less than 5 days and patients having less than five prescribed drugs. Conclusion The prevalence of unlicensed and off-label drug prescriptions are high at pediatric surgical ward of tertiary care hospitals. More awareness of the efficacy and safety of drugs are required in pediatrics. In addition, new formulations with advanced dosing for children are also required to minimize the risk of adverse outcomes.

Pharmacological screening of Monotheca buxifolia (Falc.) A. DC. for antinociceptive, anti-inflammatory and antipyretic activities.

BACKGROUND: Medicinal plants have proven their importance as a valuable source of molecules with therapeutic potential. Monotheca buxifolia (Falc.) A. DC. (family: Sapotaceae) is traditionally used as a hematinic, laxative, digestive, anthelmintic, antipyretic, and in the treatment of gastro-urinary disorders. To provide scientific evidence for its folkloric use, the present study investigated Monotheca buxifolia fruit hydro-ethanolic extract (MBHE) for its prospective antinociceptive, anti-inflammatory and antipyretic activities. MBHE was eluted through column chromatography to isolate the bioactive secondary metabolites which may probably involve in its beneficial properties. METHODS: The phytochemical constituents in MBHE was elucidated using UV, IR, (1)H-NMR, (13)C NMR, 2D-NMR spectra in combination with EIMS and FAB-MS spectrometric techniques and comparison with literature data of related compounds. The antinociceptive activity of MBHE was evaluated in the acetic acid induced abdominal constriction assay; the anti-inflammatory potential was assessed in the carrageenan induced paw edema, while the antipyretic effect was tested against brewer's yeast induced pyrexia in BALB/c mice at doses of 50, 100 and 150 mg/kg. RESULTS: Elution of MBHE along with various characterization techniques led to the isolation of oleanolic acid and isoquercetin. Significant attenuation of chemical induced nociception was observed with MBHE at tested doses of 50 mg/kg (P < 0.01, 68.87 %), 100 mg/kg (P < 0.01, 68.87 %) and 150 mg/kg (P < 0.001, 83.02 %). During a duration of 1-5 h in the carrageenan induced paw edema assay, significant ameliorative effect (P < 0.01, P < 0.001) was demonstrated by MBHE at 50 mg/kg (22.94-20 %), 100 mg/kg (33.23-21.13 %) and 150 mg/kg (38.23-25 %). MBHE also significantly alleviated the brewer's yeast induced pyrexic response when tested at doses of 50 mg/kg (P < 0.05 in 2nd h), 100 mg/kg (P < 0.05, P < 0.01 and P < 0.001 in 1-5 h) and 150 mg/kg (P < 0.01 and P < 0.001 in 1-5 h). CONCLUSION: These findings suggest that Monotheca buxifolia possess pain, inflammation and pyrexia ameliorating properties, probably mediated by the presence of oleanolic acid and isoquercetin contents, though the involvement of other important phytochemicals constituents cannot be ignored.