The determination of epigenetic target specificity and identification of epigenetics-related in vivo adverse drug reactions

BACKGROUND The Naranjo criteria are frequently used for determination of causality for suspected adverse drug reactions (ADRs); however, the psychometric properties have not been studied in the critically ill. OBJECTIVE To evaluate the reliability and validity of the Naranjo criteria for ADR determination in the intensive care unit (ICU). METHODS All patients admitted to a surgical ICU during a 3-month period were enrolled. Four raters independently reviewed 142 suspected ADRs using the Naranjo criteria (review 1). Raters evaluated the 142 suspected ADRs 3–4 weeks later, again using the Naranjo criteria (review 2). Inter-rater reliability was tested using the kappa statistic. The weighted kappa statistic was calculated between reviews 1 and 2 for the intra-rater reliability of each rater. Cronbach alpha was computed to assess the inter-item consistency correlation. The Naranjo criteria were compared with expert opinion for criterion validity for each rater and reported as a Spearman rank (rs) coefficient. RESULTS The kappa statistic ranged from 0.14 to 0.33, reflecting poor inter-rater agreement. The weighted kappa within raters was 0.5402–0.9371. The Cronbach alpha ranged from 0.443 to 0.660, which is considered moderate to good. The rs coefficient range was 0.385–0.545; all rs coefficients were statistically significant (p < 0.05). CONCLUSIONS Inter-rater reliability is marginal; however, within-rater evaluation appears to be consistent. The inter-item correlation is expected to be higher since all questions pertain to ADRs. Overall, the Naranjo criteria need modification for use in the ICU to improve reliability, validity, and clinical usefulness.

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In Vitro and In Vivo Tests in Cutaneous Adverse Drug Reactions

Advances in Diagnosis and Management of Cutaneous Adverse Drug Reactions ◽

10.1007/978-981-13-1489-6_18 ◽

2018 ◽

pp. 247-263

Author(s):

Annick Barbaud

Keyword(s):

Adverse Drug Reactions ◽

Drug Reactions ◽

In Vivo Tests

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Polymyxins Nebulization over Intravenous Injection: Pharmacokinetics and Pharmacodynamics-Based Therapeutic Evaluation

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2018/v25i430104 ◽

2019 ◽

pp. 1-10

Author(s):

Md. Jahidul Hasan

Keyword(s):

Respiratory Tract ◽

Adverse Drug Reactions ◽

Intravenous Administration ◽

Polymyxin B ◽

Multidrug Resistant ◽

Drug Reactions ◽

Pharmacokinetics And Pharmacodynamics ◽

Gram Negative ◽

Tract Infections

Polymyxins are the last line potential antibiotics against multi-drug resistant gram-negative bacteria and consist of two sister antibiotics: Polymyxin B and colistin (polymyxin E). Intravenous use of polymyxins was started from a long ago in the treatment of serious gram-negative infections and once their uses were restricted due to potential adverse drug reactions, such as nephrotoxicity and neurotoxicity. Lack of in vivo clinical studies on polymyxins mostly, in human body makes the pharmacokinetics and pharmacodynamics of polymyxin B and colistin unclear in many aspects, such as the distribution of polymyxins in different compartments of lung. The nebulization of polymyxins is practicing very limitedly and lack of clinical evidence has not justified this administration technique yet properly to date. The main objective of this review study was to evaluate the pharmacokinetic and pharmacodynamic properties of intravenous and nebulized polymyxins and the related therapeutic potentialities. Aerosolized polymyxins directly administered to the respiratory tract was found with higher drug concentration in different subcompartments of lungs than the intravenous administration and sustainably meets the minimum inhibitory concentration locally with superior bactericidal properties in respiratory tract infections. In contrast, intravenous administration of polymyxins shows similar anti-infective superiority in other organs, such as blood, urinary tract etc. So, during this alarming situation of rapidly emerging multidrug-resistant organisms in human communities, therapeutic administration techniques of last resort polymyxins should be clinically evidence-based for achieving optimum therapeutic outcomes with minimum chance of adverse drug reactions.

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AN OVERVIEW OF VARIOUS SCALES USED IN CAUSALITY ASSESSMENT OF ADVERSE DRUG REACTIONS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2020v12i5.37209 ◽

2020 ◽

pp. 1-5

Author(s):

ADUSUMILLI PRAMOD KUMAR ◽

DHARINI BHOOPATHI ◽

HARIPRIYA SUNKARA ◽

SRI HARSHA CHALASANI

Keyword(s):

Adverse Drug Reactions ◽

Causality Assessment ◽

Individual Variability ◽

Drug Reactions ◽

Root Cause ◽

Advantages And Disadvantages ◽

Single Scale ◽

Relationship Of ◽

High Possibility

Establishing a relationship of causality between the medications received and the events occurred utilizing causality assessment scale is much needed to reduce the occurrence of Adverse Drug Reactions (ADRs) and to prevent exposure of patients towards additional drug hazards. Causality assessment can be defined as the determination of chance, whether a selected intervention is the root cause of the adverse event observed. The causality assessment is the responsibility of either a single expert or an established committee. As it is a common phenomenon of variable perception of knowledge and experience by each expert, there is a high possibility of disagreement and inter-individual variability on assessment. Many of the causality assessment methods have their advantages and disadvantages. However, no single scale has been adopted as standardized and considered for uniform acceptance.

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PGI3 Determination of Efficacy, Adverse Drug Reactions and Cost Effectiveness of Three Triple Drug Regimens for the Treatment of H. Pylori Infected Acid Peptic Disease Patients

Value in Health ◽

10.1016/j.jval.2012.08.2086 ◽

2012 ◽

Vol 15 (7) ◽

pp. A635

Author(s):

A.D. Kandhare ◽

P. Ghosh ◽

D. Gauba ◽

K.S. Raygude ◽

S.L. Bodhankar

Keyword(s):

Cost Effectiveness ◽

Adverse Drug Reactions ◽

Drug Reactions ◽

Peptic Disease ◽

Drug Regimens ◽

H Pylori

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Fuzzy Comprehensive Evaluation Assistant 3D-QSAR of Environmentally Friendly FQs to Reduce ADRs

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16173161 ◽

2019 ◽

Vol 16 (17) ◽

pp. 3161 ◽

Cited By ~ 7

Author(s):

Ren ◽

Wang ◽

Xu ◽

Li ◽

Han

Keyword(s):

Adverse Drug Reactions ◽

Comprehensive Evaluation ◽

Metabolic Activation ◽

Fuzzy Comprehensive Evaluation ◽

3D Qsar ◽

New Drugs ◽

Drug Reactions ◽

Improved Method ◽

Biological Studies

Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure–activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety.

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Abstract 229: Correlation of in vitro Studies and Human Drug Interaction Studies with Gemcabene

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.229 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Margaret McShane ◽

Louis Radulovic ◽

Charles L Bisgaier

Keyword(s):

Drug Interaction ◽

Drug Interactions ◽

Adverse Drug Reactions ◽

Multiple Dose ◽

Drug Reactions ◽

Open Label ◽

Transport Pathways ◽

Dose Study

Background: Gemcabene is a novel lipid-regulating compound being developed as an adjunct to diet and statin therapy for dyslipidemia treatment. Patients with dyslipidemia typically take many medications often including statins and it is essential to understand potential risk of drug-drug interactions (DDI) to minimize the risk of adverse drug reactions. In the best circumstances, drugs entering the market will provide metabolic or transport pathways that do not interfere with commonly co-administered drugs. The current studies provide the analysis of potential drug interactions with gemcabene both in vitro and in vivo . Methods: Caco-2 cells were used to assess the potential P-gp substrate and inhibitor interaction and the major drug-metabolizing CYP450 isozymes and FMO-3 were used to assess the potential CYP450 and FM0-3 metabolism interaction. The results from the in vitro P-gp and CYP450 studies was correlated with the results of three DDI clinical studies with digoxin, atorvastatin and simvastatin. Results: In an open-label, multiple-dose study in 12 healthy subjects, gemcabene (900 mg) did not significantly affect the exposure (Cmax and AUC 0-24 ) of digoxin (0.25 mg). Specifically, the 90% confidence interval for digoxin AUC (0-24) ratios were within the 80% to 125% range, thus confirming the in vitro results of no DDI with a P-gp substrate. In two open-label, multiple-dose studies in healthy volunteers, gemcabene (900 mg) did not significantly affect the exposure (Cmax and AUC 0-24 ) of atorvastatin (80 mg) or simvastatin (80 mg) thus confirming the in vitro results of no DDI with CYP450 (see Figure below). Conclusion: These results suggest gemcabene is unlikely to elicit a metabolic (i.e., CYP450 or FMO3) or P-gp-mediated drug interaction. Gemcabene (900 mg) was well-tolerated in combination with highest dose of atorvastatin and simvastatin. Clinical Implications: Understanding potential for drug interactions minimizes the risk of adverse drug reactions.

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