Oxcarbazepine-Induced Cutaneous Reaction in a Female of Mexican Ancestry.

Objectives: To report an oxcarbazepine (OXC)-induced cutaneous reaction in a female of Mexican ancestry. Case Summary: A 60-year-old female of Mexican ancestry presented to clinic with a diffuse morbilliform rash, with erythema and eruptions of papules/pustules concentrated on her neck and torso. The rash appeared 1 week following the initiation of OXC for trigeminal neuralgia. Initially, the correlation between the reaction and initiation of OXC was not recognized by the provider. OXC was continued for a total of 4 weeks and several medical encounters transpired in the interim. Supportive therapy, in the form of oral antihistamines and oral/topical corticosteroids, failed to resolve the rash. A clinical pharmacist prompted the discontinuation of OXC due to suspicion that it incited the adverse reaction. Oral corticosteroid therapy was initiated and tapered over 2 weeks, with rash dissipation occurring in 1 month. Discussion: The association of OXC with the cutaneous eruption was classified as "probable" based on the Naranjo Scale. While financial resources were not available to perform genetic testing, it may be possible that the genetic status of this patient lent itself to greater potential for cutaneous reactions with OXC. Further research is needed to determine whether pharmacogenetic variables affiliated with pre-Columbian lineage may predispose individuals to specific adverse drug reactions. Conclusion: As regional genotypes disperse globally, it is imperative that clinicians are cognizant of risks regarding genetically implicated adverse drug reactions. While information is limited for certain ethnicities, it is essential that providers diligently monitor all populations for reactions characteristic to specific medications.

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance.

BACKGROUND: Glucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene. METHODS: Adult male rats of SHR-Lx.PD5PD-Zbtb16 (n = 9) and SHR-Lx.PD5SHR-Zbtb16 (n = 8) were fed standard diet (STD) and subsequently treated with DEX in drinking water (2.6 µg/ml) for 3 days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols (TGs), free fatty acids, insulin, and C-reactive protein levels were assessed before and after the DEX treatment. Insulin sensitivity of skeletal muscle and visceral adipose tissue was determined by incorporation of radioactively labeled glucose. RESULTS: The differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563 kb and contains six genes: Htr3a, Htr3b, Usp28, Zw10, Tmprss5, and part of Drd2. The SHR-Lx.PD5PD-Zbtb16 minimal congenic strain contains only Zbtb16 gene on SHR genomic background and its differential segment spans 254 kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared with SHR-Lx.PD5SHR-Zbtb16 , however, no differences in the weights of adipose tissue depots were observed. While STD-fed rats of both strains did not show major differences in their metabolic profiles, after DEX treatment the SHR-Lx.PD5PD-Zbtb16 congenic strain showed increased levels of TGs, glucose, and blunted inhibition of lipolysis by insulin. Both basal and insulin-stimulated incorporation of radioactively labeled glucose into skeletal muscle glycogen were significantly reduced in SHR-Lx.PD5PD-Zbtb16 strain, but the insulin sensitivity of adipose tissue was comparable between the two strains. CONCLUSION: The metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR-Lx.PD5PD-Zbtb16 reveal the Zbtb16 locus as a possible sensitizing factor for side effects of GC therapy.

Pharmacist-Provided Pharmacogenetic Point-of-Care Testing Consultation Service: A Time and Motion Study.

Background: With recent advances in pharmacogenomics (PGx) comes the potential to customize medication use based on genetic data. Support for PGx has found practical limitations in terms of workflow and turnaround time of a test. However, with the expansion of point-of-care testing (POCT) in pharmacy practice models comes opportunity for PGx testing in the pharmacy setting. Objective: The purpose of this study is to quantify the amount of time spent during each step of a PGx POCT encounter in a community pharmacy setting. Methods: A time and motion study was conducted using a mock community pharmacy space for a simulated PGx-focused encounter to manage antiplatelet therapy following hospital discharge. PGx POCT was conducted using the Spartan RX instrument. Simulated patient encounters were divided into 7 categories. Time spent in each step, as well as total time spent, was tracked. Results: A total of 54 simulated PGx POCT encounters took place with an average time of 9.49 minutes (SD ± 1.38 minutes). Instrument run time adds 60 minutes to the total time required to obtain a result. Duties that could be performed by an appropriately trained pharmacy technician totaled 6.86 minutes. Conclusions: PGx POCT would require 9.49 minutes of pharmacy staff hands-on time for the encounter, which could be reduced to 2.64 minutes of pharmacist time with appropriate pharmacy technician involvement. Time requirements for PGx POCT are similar to that of community pharmacy-based immunizations. Future studies could explore how practice could change if PGx testing were routinely performed in the pharmacy.

Association of IL10, IL4, IFNG, and CTLA4 Gene Polymorphisms with Efavirenz Hypersensitivity Reaction in Patients Infected with Human Immunodeficiency Virus.

We evaluated interleukin-10 (IL10) －592 C/A, IL4－589 C/T, interferon gamma (IFNG)＋874 A/T, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)＋49 A/G gene polymorphisms associated with efavirenz hypersensitivity reaction. A total of 63 human immunodeficiency virus-positive patients under treatment at a public hospital were included in the study, of whom 21 presented with efavirenz hypersensitivity. Patients who presented with efavirenz hypersensitivity reaction showed a higher frequency of the IL10 －592A allele than the controls (p＝0.028). The allele A was associated with increased risk of efavirenz hypersensitivity (odds ratio＝2.40). In case of IL4, a significant difference in the frequency of the IL4 －589 (C/T) polymorphism was not observed between patients and controls. A significant inverse correlation was observed when comparing the CTLA4＋49A/G and IL4 －589 C/T polymorphisms (r＝－0.650, p＝0.001); that is, the CTLA4 +49GG genotype, involved with the lowest capacity of inhibition, was inversely correlated IL4－589TT genotype, which induces high production of IL-4. With respect to the CTLA4＋49A/G and IFNG＋874T/A gene polymorphisms, significant differences in allele and genotype frequencies were not observed between the groups. Therefore, our data suggest that polymorphisms in regulatory regions of cytokine genes could modulate an individual's susceptibility to efavirenz hypersensitivity reaction.

Benefits, Potential Harms, and Optimal Use of Nutritional Supplementation for Preventing Progression of Age-Related Macular Degeneration.

OBJECTIVE: To briefly review age-related macular degeneration (AMD), the main findings from the Age Related Eye Disease Study (AREDS) report number 8 on the use of nutritional supplements for AMD, and to focus on data suggesting that supplement use should be guided using genetic testing of AMD risk genes. DATA SOURCES: A literature search (January 2001 through October 26, 2016) was conducted using MEDLINE and the following MeSH terms: Antioxidants/therapeutic use, Genotype, Macular Degeneration/drug therapy, Macular degeneration/genetics, Dietary Supplements, Proteins/genetics, and Zinc Compounds/therapeutic use. Bibliographies of publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing AREDS supplement response in patients with AMD in relation to complement factor H gene ( CFH) and age-related maculopathy susceptibility 2 gene ( ARMS2) risk alleles were evaluated. DATA SYNTHESIS: Three of the 4 studies demonstrated a treatment interaction between ARMS2 and CFH genotypes and a differential response to supplements. The fourth study documented an interaction for the CFH genotype only. Reported response interactions included attenuated response, no response, and good response, whereas a subset showed increased progression of AMD. Conversely, one study reported no interactions between CFH and ARMS2 risk alleles and response to supplements. CONCLUSIONS: The weight of the evidence supports using genetic testing to guide selection of ocular vitamin use. This approach will avoid using supplements that could speed the progression of AMD in vulnerable patients, avoid using supplements that will have little to no effect in others, and result in appropriately using supplements in those that are likely to derive meaningful benefits.

Population pharmacokinetics of cyclosporine in hematopoietic stem cell transplant patients: consideration of genetic polymorphisms.

BACKGROUND: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce. OBJECTIVE: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data. METHODS: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program. RESULTS: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA. CONCLUSIONS: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.

Is abeta a sufficient biomarker for monitoring anti-abeta clinical studies? A critical review.

Amyloid-beta (Aß) in Alzheimer's disease (AD) appeared to be a promising target for disease-modifying therapeutic strategies like passive immunotherapy with anti-Aß monoclonal antibodies (mAbs). Biochemical markers in cerebrospinal fluid (CSF) include alterations of Aß that allow the diagnosis of AD. Biomarker strategies, such as the levels of Aß in CSF and plasma, currently play an important role in early clinical trials for AD. Indeed, these strategies have a relevant impact on the outcome of such studies, since the biomarkers are used to monitor the bioactivity of anti-Aß mAbs. The clinical trials of Solanezumab were mainly based on the readout of Aß levels in CSF and plasma, whereas those of Bapineuzumab were based on cognition; however, little is known about the mechanisms altering these biomarker levels, and no biomarker has yet been proven to be a successful predictor for AD therapy. In addition, the Aß biomarkers allow for the determination of free and bound anti-Aß mAb in order to monitor the available amount of bioactive drug and could give hints to the mechanism of action. In this review, we discuss clinical Aß biomarker data and the latest regulatory strategies.