SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

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4518 Metabolomic Identifiers Predictive of Adverse Events due to Acetaminophen Administration

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.337 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 110-110

Author(s):

Brandon Joseph Sonn ◽

Kennon Heard ◽

Andrew Monte

Keyword(s):

High Performance ◽

Adverse Reactions ◽

Demographic Variable ◽

Liquid Chromatography Mass Spectrometry ◽

Chi Square ◽

Toxic Response ◽

Therapy Initiation ◽

Study Population ◽

Therapeutic Doses ◽

Time Point

OBJECTIVES/GOALS: Acetaminophen (Tylenol, APAP) toxicity has been well documented and well explored over the last 50 years. However, there has been no investigation into identification of specific metabolites that can predict which patients will have adverse reactions to therapeutic doses of APAP. METHODS/STUDY POPULATION: 205 subjects recruited from the Denver, CO community received the highest recommended daily dosing of APAP, 4 grams, for 16 days. Subjects were grouped by 1) alanine aminotransferase (ALT) at any monitored time point above 60units/L (n = 20) vs 2) no increase in ALT at any time point (n = 185). Blood was collected at days 0, 4, 7, 16, and 31. Samples were run on ultra-high performance liquid chromatography mass spectrometry with 27 heavy-labeled standards for metabolites documented to be associated with APAP metabolism. Data will be analyzed to look for significant changes in metabolite and demographic variable expressions using t-tests, chi square and logistic regression, as appropriate. RESULTS/ANTICIPATED RESULTS: It is expected that there will be greater elevations of conjugated non-toxic APAP metabolites (APAP-glucuronide, APAP-sulfate) in subjects whose ALT did not elevate because of successful hepatoprotection. Conjugated APAP metabolites are expected to only be present in samples taken after APAP therapy initiation confirming exposure as compared to being predictive of toxic response. Increases in lactate and cysteine in pre-exposure samples would allow for prediction of APAP toxicity as they are expected to have increased expression in subjects whose ALT became elevated which is indicative of increased hepatic damage due to oxidative damage. DISCUSSION/SIGNIFICANCE OF IMPACT: Identification of metabolites and/or demographic factors associated with toxic response to APAP prior to administration could advise APAP recommendations. Quantification of post-APAP administration metabolites would identify extent of successful hepatoprotective mechanisms.

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Clinical Development of Biological Response Modifiers

Canadian Journal of Infectious Diseases ◽

10.1155/1994/583805 ◽

1994 ◽

Vol 5 (suppl a) ◽

pp. 5A-8A

Author(s):

Jay P Siegel

Keyword(s):

Adverse Reactions ◽

Biological Response ◽

Clinical Trial Design ◽

The United States ◽

Biological Response Modifier ◽

Clinical Development ◽

Response Modifier ◽

United States Food ◽

Study Population ◽

States Food

OBJECTIVE: To present perspectives on selected issues that frequently arise during the clinical development of biological response modifier (BRM) therapies.DATA SOURCES: The perspectives and opinions presented herein were developed over several years of reviewing and consulting on the clinical development of BRM therapies at the United States Food and Drug Administration.CONCLUSIONS: BRM therapies encompass a broad spectrum of products used to treat a wide variety of diseases. Due to this diversity. most principles of clinical trial design and conduct applicable to the majority of BRMS are those that are applicable to all therapies. Nevertheless, the clinical development of BRM therapies often raises specific issues and problems in the areas of selecting animal models, defining the study population, adverse reactions, dosing and defining end-points. Over 10 years’ experience in testing biotechnology derived BRMS in clinical trials has created a database from which we can draw valuable generalizations for guidance in future studies.

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Prediction of Cardiovascular Disease in suburban population of 3 municipalities in Nepal

Nepalese Heart Journal ◽

10.3126/njh.v8i1.8328 ◽

2013 ◽

Vol 8 (1) ◽

pp. 3-7 ◽

Cited By ~ 2

Author(s):

R Koju ◽

R Gurung ◽

P Pant ◽

S Humagain ◽

CM Yogol ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Smoking Status ◽

Morbidity And Mortality ◽

World Health ◽

South East Asia ◽

Male Population ◽

Cardiovascular Morbidity And Mortality ◽

Study Population ◽

Health Organization

Background Cardiovascular disease (CVD) is a major cause of morbidity and mortality throughout the world including Nepal. The assessment of risk factors responsible for CVD can predict 10 year risk of CVD. World Health Organization (WHO) risk assessment chart, specially designed for South East Asia Sub-region D can predict the risk of CVD in Nepal. Method and Materials A total 532 study population from Panauti, Banepa and Dhulikhel were calculated their 10 year risk of CVD using WHO/ISH risk prediction chart on the basis of risk factors: age, gender, smoking status, diabetes, systolic blood pressure and total cholesterol. Result Ten year risk of developing cardiovascular disease is less than 10% among the population less than 50 years, irrespective of gender. 5% of male population had more than 10% chance of developing cardiovascular events in next ten years. One third of 60 – 69 years people had more than 10% chance of developing cardiovascular disease whereas it increased to 50% among 70 years and older group. Conclusion The assessment of risk factors is quite easy and cheap tool to predict the cardiovascular event, which support to practice the good clinical management to prevent the cardiovascular morbidity and mortality. DOI: http://dx.doi.org/10.3126/njh.v8i1.8328 Nepalese Heart Journal Vol.8(1) 2011 pp.3-7

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COMPARATIVE STUDY ON RAMIPRIL AND TELMISARTAN-ASSOCIATED HYPONATREMIA

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i12.39848 ◽

2020 ◽

pp. 162-164

Author(s):

BHUVANESHWARI S ◽

VIJAYA D

Keyword(s):

Serum Sodium ◽

Adverse Reactions ◽

Serum Sodium Level ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Drug Dosage ◽

Care Hospital ◽

Age Group ◽

Study Population ◽

Pro Forma

Objectives: This study was planned to study the association of ramipril and telmisartan with hyponatremia and to compare the hyponatremia effect of ramipril and telmisartan. Methods: The study was conducted in a tertiary care hospital. Serum sodium levels were assayed in patients taking ramipril and telmisartan. Fifty-one patients were recruited. The patient’s age, gender, drug dosage, and frequency of drug administration were collected using a pro forma. Statistical analysis of data was performed using SPSS version 23.0. Results: About 35.3% (28 out of 51) of the study population administered with ramipril and telmisartan developed hyponatremia. Predisposition to develop hyponatremia was high in males compared to females. Incidence of hyponatremia was 43.8% (7 out of 16) in the age group of 50–60 years. Although, incidence of hyponatremia was 56.5% (13 out of 23) in ramipril group compared to 17.9% (5 out of 28) in telmisartan group, it was not statistically significant. Conclusion: The current study laid emphasis on the requisite for monitoring of serum sodium level in patients on ramipril and telmisartan administration to avoid morbidity and mortality due to unexpected adverse reactions.

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Metabolic syndrome – a risky combination

ARS Medica Tomitana ◽

10.2478/v10307-012-0036-4 ◽

2012 ◽

Vol 18 (4) ◽

pp. 188-192

Author(s):

R. S. Şuţa ◽

Cristina Şuţa

Keyword(s):

Metabolic Syndrome ◽

Cardiovascular Risk ◽

Arterial Hypertension ◽

Central Obesity ◽

International Diabetes Federation ◽

Hard Core ◽

Common Finding ◽

The Metabolic Syndrome ◽

Cardiovascular Morbidity And Mortality ◽

Study Population

Abstract The metabolic syndrome is characterized by a cluster of related clinical, anthropometric and biochemical features such as central obesity, dysglycaemia, dyslipidaemia and hypertension. It is highly prevalent in the general population (approximately 22%), with differences in relation to race, gender, and age. It carries an increased cardiovascular morbidity and mortality, which makes an early and correct assessment mandatory. The prevalence of the metabolic syndrome is very high in type 2 diabetes patients, in whom it influences the risk of chronic complications. The aim of the present report is to explore the characteristics and the combination types of the metabolic syndrome and to assess the cardiovascular risk in patients presenting this clinical entity. 329 patients consecutively diagnosed with metabolic syndrome were included in the study, both men and women, no limit regarding age. Patient selection was made during the periodic medical visits in the outpatient clinics of Diabetes, Cardiology and Internal Medicine. Metabolic syndrome (MetS) was diagnosed according to 2005 International Diabetes Federation (IDF) Criteria. Women were more frequent than men, mean age was 59.08±888 and they all had central obesity (it is the major criteria of 2005 IDF definition for MetS) .The diagnosis of the metabolic syndrome was fulfilled with only 3 criteria, most of the times. The complete metabolic syndrome was the rarest, less than 25% of the patients presenting all 5 definition criteria and it was more frequent among men (men 39.2% vs women 15.9%: p < 0.0001). Apart from central obesity, which is mandatory for diagnosing MetS and thus present in all patients, arterial hypertension is the most common finding in our study population, with impaired glycaemia and increased triglycerides occupying the second and third place, respectively. Central obesity, arterial hypertension and impaired glycaemia represent the most frequent combination, a real „hard core” of MetS. As expected, the cardiovascular risk was high in the study population. The cardiovascular „score” of our patients increased significantly with the number of components used for the diagnosis of MetS (MetS with 3 elements vs MetS with 4 elements vs MetS with 5 elements: SCORE - 5.36 ± 7.07 vs 7.66 ± 8.63 vs 8.52 ± 8.34, p < 0.01).

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Burden of diabetes and hypertension among people attending health camps in an urban area of Kancheepuram district

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20175771 ◽

2017 ◽

Vol 5 (1) ◽

pp. 140 ◽

Cited By ~ 1

Author(s):

S. Hariharan ◽

R. Umadevi ◽

T. Stephen ◽

S. Pradeep

Keyword(s):

Blood Pressure ◽

Blood Sugar ◽

Urban Area ◽

Blood Pressure Level ◽

Pressure Level ◽

Cross Sectional ◽

Total Study Population ◽

Random Blood Sugar ◽

Cardiovascular Morbidity And Mortality ◽

Study Population

Background: Diabetes and hypertension are among the most common non-communicable diseases affecting our population. They are the important risk factors for cardiovascular morbidity and mortality. The aims and objectives of the study were to determine the burden of diabetes and hypertension among people attending health camps in an urban area of Kancheepuram district. Formulation of suitable preventive measures based on the inferences from the study.Methods: A cross- sectional record based study was done on 825 people attending medical camps conducted by Sree Balaji Medical College & Hospital, in Anakaputhur area of Kancheepuram district. The data regarding Random Blood Sugar (RBS) level, blood pressure level, age, and gender were collected from the camp register (January and February, 2017). A random blood sugar (RBS) value of >200 mg/dl in a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis was defined as having diabetes. Blood pressure level equal to or greater than 140/90mm Hg was defined as having hypertension. Descriptive analysis and Chi square test was done to see the statistical association between various parameters. Results: Of the total study population of 825 people, 215 were males and 610 were females. The overall burden of diabetes and hypertension among the study population was 10.7% and 6.4% respectively. Co-existence of both diabetes and hypertension was seen in 5.7% of people. Conclusions: To reduce the disease burden due to diabetes and hypertension, primary prevention measures such as health education regarding adoption of healthy lifestyle should be instituted. Interventions such as screening and early initiation of treatment should also be made for controlling the diseases and preventing its complications.

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Prevalence of overweight and obesity among patients with congenital and acquired heart disease in Kocaeli, Turkey

Cardiology in the Young ◽

10.1017/s1047951114000377 ◽

2014 ◽

Vol 25 (3) ◽

pp. 533-538 ◽

Cited By ~ 2

Author(s):

Kadir Babaoğlu ◽

Murat Deveci ◽

Özlem Kayabey ◽

Gürkan Altun ◽

Köksal Binnetoğlu

Keyword(s):

Heart Disease ◽

Overweight And Obesity ◽

Control Group ◽

Additional Risk Factor ◽

Catheter Intervention ◽

Control Subjects ◽

Cardiovascular Morbidity And Mortality ◽

Acquired Heart Disease ◽

Healthy Control ◽

Study Population

AbstractBackground:Childhood obesity has increased in the last half of the century. The aim of this study was to evaluate the frequency of obesity in the children with congenital or acquired heart disease.Methods:A total of 1410 children were assessed in this study. The study population was composed of 518 children (289 boys, 229 girls) as control group and 892 children (477 boys, 415 girls) as heart disease group. Patients were grouped into four categories: (I) “Clinic control subjects”; (II) “mild heart disease” that has not been treated with either surgical or catheter intervention; (III) congenital heart disease treated with surgical and/or catheter intervention; and (IV) “arrhythmias”. A body mass index ⩾85th percentile was defined as overweight, ⩾95th percentile as obese, and <5th percentile was defined as underweight.Results:We did not detect any association between heart disease and obesity. There was no difference in the rates of overweight, obesity, and underweight between the healthy control subjects and patients with heart disease (8.1%, 13.3%, and 5.0%; 9.0%, 10.7%, and 4.7%, respectively, p=0.145). All subgroups had a similar prevalence of underweight, overweight, and obesity as the healthy control population. Within the heart disease population, the overall prevalence rates for overweight, obesity, and underweight were similar between the boys and girls.Conclusion:Obesity is a common problem in children with heart disease, at least in general population. It is an important additional risk factor for long-term cardiovascular morbidity and mortality in children with heart disease. Precautions to prevent obesity should be a part of paediatric cardiologist’s examination.

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Subcutaneous administration of triamcinolone as part of the management of feline eosinophilic keratoconjunctivitis

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x20968660 ◽

2020 ◽

pp. 1098612X2096866

Author(s):

Danica R Lucyshyn ◽

Kathryn L Good ◽

Kelly E Knickelbein ◽

Maggie W Chang ◽

Ann R Strøm ◽

...

Keyword(s):

Adverse Reactions ◽

Antiviral Treatment ◽

Subcutaneous Administration ◽

Reference Population ◽

Retrospective Case ◽

Corneal Ulcers ◽

Triamcinolone Injection ◽

Study Population ◽

Immunomodulatory Therapies ◽

Control Study

Objectives The aim of this retrospective case-control study was to report the efficacy of subcutaneous triamcinolone as part of a regimen for feline eosinophilic keratoconjunctivitis (FEK). Methods Records and clinical photographs were reviewed and lesions semi-quantitatively graded for cats with cytologically confirmed FEK. Clinical data were compared between a study population of nine cats (11 eyes) treated with, and a reference population of seven cats (eight eyes) treated without, a median 0.11 mg/kg (range 0.10–0.20 mg/kg) of triamcinolone acetonide subcutaneously. Results Breed, sex, age and prevalence of corneal ulceration at presentation; corneal disease severity before and at the initiation of immunomodulation; and duration of antiviral treatment before immunomodulation did not differ significantly between populations ( P ⩾0.059). Corneal plaques resolved in five cats each from the study and reference populations ( P = 0.366). Median (range) time from immunomodulation to corneal plaque resolution did not significantly differ ( P = 0.246) between the study (median 14 days; range 8–38 days) and reference (median 28 days, range 14–46 days) populations. No adverse reactions were attributed to triamcinolone administration, and all corneal ulcers in the study population re-epithelialized within 14 days (range 8–38 days) following triamcinolone injection. Time to corneal ulcer re-epithelialization following triamcinolone injection varied minimally in those receiving antivirals prior to (8 or 30 days until re-epithelialization), simultaneously with (38 days) or after (14 or 24 days) triamcinolone. Conclusions and relevance In otherwise healthy cats with FEK, subcutaneous administration of triamcinolone appears to be well tolerated and as efficacious as conventional topical immunomodulatory therapies. It may be especially useful in ulcerated eyes where topical immunomodulation is contraindicated.

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