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Clinical Impact of Supplementation of Vitamins B1 and C on Patients with Sepsis-Related Acute Respiratory Distress Syndrome.
Yoo, JW, Kim, RB, Ju, S, Lee, SJ, Cho, YJ, Jeong, YY, Lee, JD, Kim, HC
Tuberculosis and respiratory diseases. 2020;83(3):248-254
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Acute respiratory distress syndrome (ARDS) is a life-threatening condition that commonly develops in patients with sepsis. Patients with ARDS require admission to intensive care and invasive mechanical ventilation. Vitamin B1 and C deficiencies have been reported in critically ill patients with sepsis. Vitamin B1 is involved in aerobic metabolism, and vitamin C has anti-inflammatory and anti-oxidative effects. The aim of this Korean retrospective cohort study was to evaluate the clinical impact of vitamin B1 and C supplementation in patients with sepsis-related ARDS. Patients with ARDS requiring invasive mechanical ventilation, admitted to an intensive care unit (ICU) were included in this study. Clinical outcomes were compared between patients administered with vitamin B1 (200 mg/day) and C (2 g/day) between June 2018-May 2019 (the supplementation group) and those who did not receive vitamin B1 and C administration between June 2017-May 2018 (the control group). Seventy-nine patients were included. Thirty-three patients received vitamin B1 and C, and 46 patients did not. There were no significant differences in the number of deaths between the patients who received vitamin B1 and C and those who did not. The mean number of days not requiring ICU admission or ventilation was greater in patients supplemented with vitamin B1 and C than that in the control patients, but the difference was not statistically significant. Steroid administration was more frequent in patients receiving vitamin B1 and C supplementation than in those without it. The authors concluded that Vitamin B1 and C supplementation at the doses used in this study did not reduce the death rates in ARDS patients.
Abstract
BACKGROUND Although few studies have reported improved clinical outcomes with the administration of vitamin B1 and C in critically ill patients with septic shock or severe pneumonia, its clinical impact on patients with sepsis-related acute respiratory distress syndrome (ARDS) remains unclear. The purpose of this study was to evaluate the association with vitamin B and C supplementation and clinical outcomes in patients with ARDS. METHODS Patients with ARDS requiring invasive mechanical ventilation, admitted to the medical intensive care unit (ICU) were included in this study. Clinical outcomes were compared between patients administered with vitamin B1 (200 mg/day) and C (2 g/day) June 2018-May 2019 (the supplementation group) and those who did not receive vitamin B1 and C administration June 2017-May 2018 (the control group). RESULTS Seventy-nine patients were included. Thirty-three patients received vitamin B1 and C whereas 46 patients did not. Steroid administration was more frequent in patients receiving vitamin B1 and C supplementation than in those without it. There were no significant differences in the mortality between the patients who received vitamin B1 and C and those who did not. There were not significant differences in ventilator and ICU-free days between each of the 21 matched patients. CONCLUSION Vitamin B1 and C supplementation was not associated with reduced mortality rates, and ventilator and ICU-free days in patients with sepsis-related ARDS requiring invasive mechanical ventilation.
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Neonatal seizures and white matter injury: Role of rotavirus infection and probiotics.
Yeom, JS, Park, JS, Kim, YS, Kim, RB, Choi, DS, Chung, JY, Han, TH, Seo, JH, Park, ES, Lim, JY, et al
Brain & development. 2019;(1):19-28
Abstract
BACKGROUND Recent reports associate rotavirus infection with neonatal seizures of distinctive white matter injury (WMI) pattern, but evidence is lacking. We examined this association prospectively and analyzed factors related to occurrence of seizures and WMI pattern in neonates with rotavirus infection. METHODS We prospectively included 228 neonates (≥34 gestational weeks) who were admitted to a regional neonatal intensive care unit between February 2015 and April 2016 and underwent rotavirus antigen testing using stool samples. Patients with neonatal seizures of other etiologies were excluded. RESULTS Seventy-eight (34.2%) neonates were rotavirus-positive. Otherwise-unexplained seizures were more frequently observed among rotavirus-positive than among rotavirus-negative neonates (20.5% vs. 4.0%, p < 0.001). Rotavirus infection increased the risk of seizures (odds ratio [OR], 6.19; p < 0.001), even after adjustment for confounders (OR, 4.46; p = 0.007). After stratification according to probiotic administration immediately after birth, rotavirus infection remained a significant risk factor only in patients without probiotic medication (OR, 4.83; p = 0.01 vs. OR, 2.44; p = 0.49). The WMI pattern was observed in 9 of 22 neonates with seizures, and this subgroup was characterized by rotavirus infection (100% vs. 53.8%, p = 0.004) and seizure onset on days 4-6 of life (66.7% vs. 15.0%; p = 0.02). G9P[8] was the most common genotype in this subgroup but was also commonly detected in neonates without seizures. CONCLUSION Rotavirus infection is an independent risk factor for neonatal seizures, and associated with the WMI. Immediate administration of probiotics after birth may reduce rotavirus-associated neonatal seizures.
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Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.
Danese, E, Raimondi, S, Montagnana, M, Tagetti, A, Langaee, T, Borgiani, P, Ciccacci, C, Carcas, AJ, Borobia, AM, Tong, HY, et al
Clinical pharmacology and therapeutics. 2019;(6):1477-1491
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Abstract
The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.
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Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers.
Borrie, AE, Kim, RB
Expert opinion on drug metabolism & toxicology. 2017;(2):149-156
Abstract
Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms. Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia. Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.
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Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.
Kim, RB, Morse, BL, Djurdjev, O, Tang, M, Muirhead, N, Barrett, B, Holmes, DT, Madore, F, Clase, CM, Rigatto, C, et al
Kidney international. 2016;(5):1144-1152
Abstract
Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.
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Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.
Shaw, K, Amstutz, U, Kim, RB, Lesko, LJ, Turgeon, J, Michaud, V, Hwang, S, Ito, S, Ross, C, Carleton, BC, et al
Therapeutic drug monitoring. 2015;(4):428-36
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Abstract
OBJECTIVE To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. RESULTS Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. SIGNIFICANCE This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.
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Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption.
Goldberg, AS, Tirona, RG, Asher, LJ, Kim, RB, Van Uum, SH
Thyroid : official journal of the American Thyroid Association. 2013;(11):1374-8
Abstract
BACKGROUND Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. METHODS The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 μg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. RESULTS Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). CONCLUSION Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4.
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Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
DeGorter, MK, Tirona, RG, Schwarz, UI, Choi, YH, Dresser, GK, Suskin, N, Myers, K, Zou, G, Iwuchukwu, O, Wei, WQ, et al
Circulation. Cardiovascular genetics. 2013;(4):400-8
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Abstract
BACKGROUND A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. METHODS AND RESULTS In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (P<0.001) and ABCG2 c.421C>A (P<0.01) were important to rosuvastatin concentration (adjusted R(2)=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (P<0.01) and c.521T>C (P<0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R(2)=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. CONCLUSIONS Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy.
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Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.
Gong, IY, Kim, RB
The Canadian journal of cardiology. 2013;(7 Suppl):S24-33
Abstract
Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.
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Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy.
Gong, IY, Tirona, RG, Schwarz, UI, Crown, N, Dresser, GK, Larue, S, Langlois, N, Lazo-Langner, A, Zou, G, Roden, DM, et al
Blood. 2011;(11):3163-71
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Abstract
Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P = .52, P = .28) and risk of overanticoagulation (P = .64, P = .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.