Pharmacokinetics and bioavailability of ketoprofen when compounded with iron dextran for use in nursing piglets.

In Canada, piglets receive analgesia to control pain after surgical castration. There is interest in examining the potential to mix non-steroidal anti-inflammatory drugs with iron dextran prior to injection to minimize piglet handling and labor. The objective of this study was to compare pharmacokinetics and the relative bioavailability of ketoprofen given alone (3.0 mg/kg IM) versus the same dose of ketoprofen mixed with iron dextran (52.8 mg/kg IM) (ketoprofen + iron dextran) before injection in piglets. Piglets 8 to 11 d old were allocated into 2 treatment groups (n = 8/group). Plasma drug concentrations were measured using mass spectrometry at 13 time points after injection. No significant differences were detected between the 2 groups when examining pharmacokinetic parameters (e.g., Cmax, Tmax, AUC) or relative bioavailability for either S- or R-ketoprofen enantiomers (P > 0.05). However, pain control efficacy and food safety studies of these formulations are required to further examine this practice.

Pharmacocinétique et biodisponibilité du kétoprofène lorsque mélangé avec du fer dextran pour utilisation chez les porcelets allaitants. Au Canada, les porcelets reçoivent une analgésie pour diminuer la douleur après une castration chirurgicale. Il y a un intérêt à examiner la possibilité de mélanger des anti-inflammatoires non stéroïdiens avec du fer dextran avant l'injection afin de minimiser la manipulation des porcelets et le travail. L'objectif de cette étude était de comparer la pharmacocinétique et la biodisponibilité relative du kétoprofène administré seul (3,0 mg/kg IM) par rapport à la même dose de kétoprofène mélangé à du fer dextran (52,8 mg/kg IM) (kétoprofène + fer dextran) avant l'injection des porcelets. Des porcelets âgés de 8 à 11 jours ont été répartis en deux groupes de traitement (n = 8/groupe). Les concentrations plasmatiques de médicament ont été mesurées par spectrométrie de masse à 13 moments dans le temps après l'injection. Aucune différence significative n'a été détectée entre les deux groupes lors de l'examen des paramètres pharmacocinétiques (par ex., Cmax, Tmax, AUC) ou de la biodisponibilité relative pour les énantiomères S- ou R-kétoprofène (P > 0,05). Cependant, des études sur l'efficacité de la diminution de la douleur et la sécurité alimentaire de ces formulations sont nécessaires pour examiner de manière plus approfondie cette pratique.(Traduit par Dr Serge Messier).

Completeness of reporting of systematic reviews in the animal health literature: A meta-research study.

Systematic reviews are a valuable tool for evaluating the efficacy of interventions and for quantifying associations. To be properly assessed, reviews must be comprehensively reported. The primary objective of this study was to evaluate the completeness of reporting of systematic reviews and meta-analyses in animal health. The secondary objective was to further characterize methods for literature searches and risk of bias assessments and to document whether the risk of bias component represented an assessment of risk of bias, study quality, or levels of evidence based on the primary studies included. The dataset comprised 91 systematic reviews or meta-analyses of interventions or exposures with at least one health outcome measured at the animal or animal byproduct level, in any companion or food animal species and published between 2014 and 2018. Two reviewers independently collected information on whether each item in the PRISMA reporting guidelines was reported, with disagreements resolved by consensus. There was considerable variability in the completeness of reporting among reviews; some items, such as eligibility criteria for inclusion, were reported in most reviews (>65 %). Other items were not consistently reported; for instance, in 60 % (54) of the reviews there was no information provided on the sample size of individual studies, populations, interventions and comparators, outcomes, or follow up period. Although 89 % (81) of systematic reviews with meta-analysis included the effect size estimate and confidence intervals, it was not possible to determine which study designs were included for 30 % (14) of reviews. Results from individual PRISMA item questions were combined to determine whether all aspects of each recommended item were reported; 71 % of items were adequately reported in less than half the systematic reviews without a meta-analysis, 35 % of the items were adequately reported in less than half the systematic reviews with a meta-analysis, and 71 % of items were adequately reported in less than half of the meta-analyses without a systematic review component. An assessment of individual study level bias was included in 64 % of the reviews, although this component included an evaluation of risk of bias (35 reviews), study quality (25 reviews), or levels of evidence based on study design (12 reviews). Reporting guidelines or clinical guidelines were inappropriately used to assess risk of bias in 9 reviews. Overall, the results of this study reveal that reporting of systematic reviews in the animal health literature is suboptimal and improvements are needed to enhance utility of these reviews.

Association of Presenting Symptoms With Abnormal Laboratory Values for Vector-Borne Illness - Experience in an Urban Gastroenterology Practice.

PURPOSE: In the clinical setting, it is not common practice to consider a vector bite, such as from a tick or flea, to be a contributing factor to chronic digestive symptoms. This article investigates associations we have observed among symptomatic patients and positive blood tests for vector-borne illness (VBI). METHODS: Patients who visited an urban gastroenterology clinic over a 3-year period were retrospectively reviewed. A total of 270 patients presenting with a constellation of digestive symptoms - and who had no apparent digestive pathology and reported no prior diagnosis or treatments for VBI - were analyzed. Before the initial visit, all patients completed a review of systems medical history form, which comprised 19 gastrointestinal (GI) symptoms and 73 non-GI-related symptoms and conditions. Patients were tested for small intestinal bacterial overgrowth (SIBO) by lactulose breath test. VBI (babesiosis, ehrlichiosis, anaplasmosis, bartonellosis, borreliosis) was established using 1 or more of several blood tests. Odds ratio (OR) analysis determined associations between exposure to VBI, SIBO, and presenting symptoms/conditions. Two age groups (≤35 years and ≥36 years) were studied using Cochran-Mantel-Haenszel stratum-based test. RESULTS: A higher OR (2.03, 95% CI: 1.5-3.6) was found between patients with ≥3 digestive symptoms and positive blood tests for ≥1 VBI. Five of the 19 GI symptoms were independently associated with VBI-positive samples: food intolerance, indigestion, nausea/vomiting, constipation, and heartburn. A similar association in patients with ≥3 non-GI symptoms (OR: 2.83, 95% CI: 1.3-6.4) was observed. Five of the 73 non-GI symptoms/conditions were independently associated with VBI-positive samples: chest pain, shortness of breath, extremity or joint pain, anxiety, and night sweats. Having ≥3 of any digestive or nondigestive symptoms generated significant relative risk of being VBI-positive. Presence of SIBO alone did not identify significant relative risk for a VBI, and age was not a confounder. CONCLUSIONS: Findings revealed an association between positive blood tests for vector-borne illness and chronically symptomatic patients regardless of whether symptoms were digestive or nondigestive. The manifestation of 3 or more gastrointestinal and/or extraintestinal symptoms should raise suspicion for a VBI.

Assessing Pain Control Efficacy of Meloxicam and Ketoprofen When Compounded with Iron Dextran in Nursing Piglets Using A Navigation Chute.

The efficacy of analgesics such as meloxicam and ketoprofen to control pain in piglets when mixed with iron dextran (ID) before injection is unknown. The purpose of this study was to compare perceived pain in castrated piglets treated 1 h before castration with either of these drugs alone, or when mixed with ID, by observing the time it takes for piglets to navigate a chute. Piglets were divided into seven treatment groups (n = 25 piglets per treatment group) including castration with analgesia (meloxicam or ketoprofen), castration with analgesic plus ID, castration without analgesic or ID, sham handled and given ID, and sham handled alone. Piglets were placed in a short chute and their time to navigate the chute was recorded at four timepoints following castration. Piglets given meloxicam or ketoprofen, with or without ID did not differ from each other in their chute navigation times. Additionally, these piglets did not differ from treatment groups that were not castrated. Piglets castrated without analgesia had significantly longer navigation times. These results indicate that meloxicam or ketoprofen, whether mixed with ID prior to injection or not, provide similar analgesic efficacy.

Avoidable drug-gene conflicts and polypharmacy interactions in patients participating in a personalized medicine program.

AIM: Determine the ability of a pharmacogenetic service, PRIMER, to identify drug-gene (DGI) and drug-drug interactions (DDI) in patients across multiple conditions. PRIMER consists of patient selection criteria, a gene panel and actionable guidance for DGIs and DDIs. RESULTS: The average patient was prescribed 12 medications. PRIMER identified significant DGIs in 73% of patients tested, with 43% having more than one DGI. DDIs were found in 87% of patients. The most common actionable DGIs were for opioid, psychotropic and cardiovascular medications. CONCLUSION: The pairing of patient selection criteria, a multigene panel with evidence-based interpretation and review of DDIs maximizes the patients tested who have actionable benefit and alerts physicians to potentially critical adjustments needed for the patient's medication regimen.

Pharmacogenomics in Psychiatric Practice.

Pharmacogenomic testing in psychiatry is becoming an established clinical procedure. Several vendors provide clinical interpretation of combinatorial pharmacogenomic testing of gene variants that have documented predictive implications regarding either pharmacologic response or adverse effects in depression and other psychiatric conditions. Such gene profiles have demonstrated improvements in outcome in depression, and reduction of cost of care of patients with inadequate clinical response. Additionally, several new gene variants are being studied to predict specific response in individuals. Many of these genes have demonstrated a role in the pathophysiology of depression or specific depressive symptoms. This article reviews the current state-of-the-art application of psychiatric pharmacogenomics.

Clinical Utility and Economic Impact of CYP2D6 Genotyping.

Pharmacogenetics examines an individual's genetic makeup to help predict the safety and efficacy of medications. Practical application optimizes treatment selection to decrease the failure rate of medications and improve clinical outcomes. Lack of efficacy is costly due to adverse drug reactions and increased hospital stays. Cytochrome P450 2D6 (CYP2D6) metabolizes roughly 25% of all drugs. Detecting variants that cause altered CYP2D6 enzymatic activity identifies patients at risk of adverse drug reactions or therapeutic failure with standard dosages of medications metabolized by CYP2D6. This article discusses the clinical application of pharmacogenetics to improve care and decrease costs.

The Pharmacist's Perspective on Pharmacogenetics Implementation.

The future for pharmacogenetics will continue to expand. Pharmacists can apply and incorporate drug knowledge in collaboration with other health providers using pharmacogenetics. Patients benefit with enhanced therapeutic outcomes that could lead to more streamlined drug approaches, fewer follow-up visits, cost savings, and shorter times to achieve therapeutic outcomes. As more drug-gene pathways are discovered and use of this knowledge increases, the potential for algorithm development for medication use will occur, resulting in better patient outcomes, higher standard of care, and reflect evidence-based medicine.

Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy.

Tamoxifen, a widely prescribed drug for the treatment and prevention of breast cancer, is metabolized to more potent metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme. Variants in the CYP2D6 gene can cause patients to be either intermediate or poor metabolizers, thereby rendering tamoxifen treatment less effective. Testing for CYP2D6 gene variants is available in Clinical Laboratory Improvement Amendments-certified clinical laboratories; however, the biological complexity of the variants makes result interpretation and phenotype prediction challenging. This article describes the clinical significance of variants as well as important analytical, interpretative, and reporting issues. It is designed to be a guideline for clinical laboratory professionals in performing tests and interpreting results with respect to CYP2D6 genetic variants.

Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation.

We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient's genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management.

Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy.

BACKGROUND: The application of pharmacogenetic results requires demonstrable correlations between a test result and an indicated specific course of action. We developed a computational decision-support tool that combines patient-specific genotype and phenotype information to provide strategic dosage guidance. This tool, through estimating quantitative and temporal parameters associated with the metabolism- and concentration-dependent response to warfarin, provides the necessary patient-specific context for interpreting international normalized ratio (INR) measurements. METHODS: We analyzed clinical information, plasma S-warfarin concentration, and CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genotypes for 137 patients with stable INRs. Plasma S-warfarin concentrations were evaluated by VKORC1 genotype (-1639G>A). The steady-state plasma S-warfarin concentration was calculated with CYP2C9 genotype-based clearance rates and compared with actual measurements. RESULTS: The plasma S-warfarin concentration required to yield the target INR response is significantly (P < 0.05) associated with VKORC1 -1639G>A genotype (GG, 0.68 mg/L; AG, 0.48 mg/L; AA, 0.27 mg/L). Modeling of the plasma S-warfarin concentration according to CYP2C9 genotype predicted 58% of the variation in measured S-warfarin concentration: Measured [S-warfarin] = 0.67(Estimated [S-warfarin]) + 0.16 mg/L. CONCLUSIONS: The target interval of plasma S-warfarin concentration required to yield a therapeutic INR can be predicted from the VKORC1 genotype (pharmacodynamics), and the progressive changes in S-warfarin concentration after repeated daily dosing can be predicted from the CYP2C9 genotype (pharmacokinetics). Combining the application of multivariate equations for estimating the maintenance dose with genotype-guided pharmacokinetics/pharmacodynamics modeling provides a powerful tool for maximizing the value of CYP2C9 and VKORC1 test results for ongoing application to patient care.

Dynamic pharmacogenetic models in anticoagulation therapy.

This article demonstrates how a dynamic clinical-support tool can guide individualized drug therapy. We use the drug warfarin as a model to demonstrate how pharmacogenetics when combined with fundamental principles of pharmacokinetic and pharmacodynamics can provide a powerful decision-support tool to optimize personalized therapeutics.

The value of CYP2D6 and OPRM1 pharmacogenetic testing for opioid therapy.

In managing pain, clinicians working with the more than 80 million people in the United States who suffer annually from serious pain face decisions about choosing the most appropriate pharmacologic agent, to contemplating nonpharmacologic modalities. This article focuses on opioid use for pain management, their risks of toxicity and addiction, adverse reactions, undertreatment for fear of addiction, and integration of novel diagnostics, such as the pharmacogenetic biomarkers CYP2D6 and OPRM1 as holding promise for assessing a patient's risk of adverse events or likelihood of efficacy. Incorporation of such biomarkers is emerging on the forefront of personalized medicine, and has the potential to dramatically improve the utility and efficacy of both current and future pain management strategies.

Pharmacogenetic testing in schizophrenia and posttraumatic stress disorder.

Genotyping patients prior to beginning psychiatric pharmacological therapy can serve to inform practitioners as to each patient's likelihood of therapeutic response and their relative risk of experiencing toxicity and other adverse side effects from certain drugs. Such information could arm physicians with the knowledge they need to make appropriate drug and dosing decisions and avoid the lengthy trial-and-error process with which they are faced today. This article describes the current state of pharmacogenetic testing in schizophrenia and posttraumatic stress disorder.

Pharmacogenetic testing of CYP2D6 in patients with aripiprazole-related extrapyramidal symptoms: a case-control study.

Aripiprazole is primarily metabolized by the polymorphic CYP2D6. We genotyped four children (aged 6-15 years) who had developed extrapyramidal symptoms within 1 week of aripiprazole initiation or dose titration, and four matched children without extrapyramidal symptoms. All of the four children who developed extrapyramidal symptoms with aripiprazole had a dysfunctional CYP2D6 enzyme, based on genotype, and were categorized as either intermediate metabolizers (n = 2) or poor metabolizers (n = 2). By contrast, only two children from the control group had either of these phenotypes, and both were intermediate metabolizers. Children with CYP2D6 abnormalities may be at higher risk of aripiprazole-induced adverse drug reactions.

Identification of a synonymous polymorphism within the cytochrome P4502C9 gene that interferes with identification of the CYP2C9*2 allele.

Cytochrome P450 2C9 (CYP4502C9) genotyping is useful in dosage adjustments for several critical drug therapies, including warfarin. Potential interference compromising these genotyping results could lead to inappropriate dose adjustments that may result in adverse drug reactions. During routine clinical CYP4502C9 genotyping using multiplex allele-specific primer extension, an ambiguous result was obtained for determination of the CYP2C9 430C>T substitution, which defines the CYP2C9*2 allele. In this one patient sample submitted for CYP2C9 genotyping, the ratio for the variant 430T allele signal to the total signal (C+T alleles) was 0.29. This is above the expected ratio to be classified as wild-type (<0.15) and below the minimum expected ratio (>0.3) when the genotype is heterozygous at the 430 position. The mean fluorescence intensity for the 430C allele was consistent with that observed in subjects who are heterozygous at this nucleotide position. However, the corresponding signal for the 430T allele indicated the absence of the CYP2C9*2 allele. This suggests the assay was not able to determine the correct nucleotide at position 430 for one of the two alleles in this patient. Subsequent sequencing to investigate the allele-specific primer extension failure revealed the presence of a rare C>T nucleotide substitution at position 429. We tested this subject's CYP2C9 genotype using AvaII restriction endonuclease digestion and found that this rare substitution causes false-positive identification of the CYP2C9*2 allele when using this method. We developed a DpnII endonuclease digestion assay to specifically detect the CYP2C9 429C>T substitution and tested 100 randomly selected samples obtained from unrelated individuals. The 429C>T polymorphism was not identified in this sample set, which indicates an allele frequency of less than 2.0% (95% confidence interval, 0.0-1.8%) in the general population. Despite the rarity of this polymorphism, it has important implications for the accuracy of assays using allele-specific primers and the Ava II restriction endonuclease, when it occurs, which are two common methods currently applied for detecting the presence of the CYP2C9*2 allele.

Metal determines efficiency and substrate specificity of the nuclear NUDIX decapping proteins X29 and H29K (Nudt16).

The Xenopus X29 protein was identified by its high affinity binding to U8 small nucleolar RNA, a small nucleolar RNA required for ribosome biogenesis. X29 and its human homologue H29K (Nudt16) are nuclear nucleoside diphosphatase proteins localized within foci in the nucleolus and nucleoplasm. These proteins can remove m(7)G and m(227)G caps from RNAs, rendering them substrates for 5'-3' exonucleases for degradation in vivo. Here, a more complete characterization of these metal-dependent decapping proteins demonstrates that the metal identity determines both the efficiency of decapping and the RNA substrate specificity. In Mg(+2) the proteins hydrolyze the 5' cap from only one RNA substrate: U8 small nucleolar RNA. However, in the presence of Mn(+2) or Co(+2) all RNAs are substrates and the decapping efficiency is higher. The x-ray crystal structure of X29 facilitated structure-based mutagenesis. Mutation of single amino acids coordinating metal in the active site yielded mutant proteins confirming essential residues. In vitro assays with purified components are consistent with a lack of protein turnover, apparently due to an inability of the protein to release the decapped RNA, implicating critical in vivo interacting factors. Collectively, these studies indicate that the metal that binds the X29/H29K proteins in vivo may determine whether these decapping proteins function solely as a negative regulator of ribosome biogenesis or can decap a wider variety of nuclear-limited RNAs. With the potential broader RNA substrate specificity, X29/H29K may be the nuclear counterparts of the cytoplasmic decapping machinery, localized in specialized bodies involved in RNA decay.

Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes.

BACKGROUND: CYP2C9 polymorphisms are associated with decreased S-warfarin clearance and lower maintenance dosage. Decreased expression of VKORC1 resulting from the -1639G>A substitution has also been implicated in lower warfarin dose requirements. We investigated the additional contribution of this polymorphism to the variance in warfarin dose. METHODS: Sixty-five patients with stable anticoagulation were genotyped for CYP2C9 and VKORC1 with Tag-It allele-specific primer extension technology. Plasma S-warfarin concentrations and warfarin maintenance dose were compared among patients on the basis of the VKORC1 -1639G>A genotype. RESULTS: Eighty percent of CYP2C9*1/*1 patients stabilized on <4.0 mg/day warfarin had at least 1 VKORC1 -1639A allele. Mean warfarin doses (SD) were 6.7 (3.3), 4.3 (2.2), and 2.7 (1.2) mg/day for patients with the VKORC1 -1639GG, GA, and AA genotypes, respectively. Steady-state plasma concentrations of S-warfarin were lowest in patients with the VKORC1 -1639AA genotype and demonstrated a positive association with the VKORC1 -1639G allele copy number (trend P = 0.012). A model including VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose. CONCLUSIONS: The VKORC1 -1639A allele accounts for low dosage requirements of most patients without a CYP2C9 variant. Higher plasma S-warfarin concentrations corresponding to increased warfarin maintenance dosages support a hypothesis for increased expression of the VKORC1 -1639G allele. VKORC1 and CYP2C9 genotypes, age, sex, and body weight account for the majority of variance in warfarin dose among our study population.