Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant.

Toxicol Appl Pharmacol. 2020 Apr 07;:115000

Authors: Ibtissem H, Nadia BF, Zohra C, Najah BF, Haifa BR, Yvan T, Boughattas Naceur A, Amel C, Karim A

Abstract
The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients. The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2. We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences.

PMID: 32275916 [PubMed - as supplied by publisher]

Congenital diabetes mellitus.

Minerva Pediatr. 2020 Apr 09;:

Authors: Iafusco D, Zanfardino A, Bonfanti R, Rabbone I, Tinto N, Iafusco F, Meola S, Gicchino MF, Ozen G, Casaburo F, Piscopo A, Miraglia Del Giudice E, Barbetti F

Abstract
INTRODUCTION: Congenital diabetes mellitus is a rare disorder characterized by hyperglycaemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycaemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of Diabetes of Infancy: Transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent.
EVIDENCE ACQUISITION: Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology.
EVIDENCE SYNTHESIS: The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cels the switch from insulin to Glibenclamide per os has greatly improved the quality of life.
CONCLUSIONS: Congenital Diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (Type 1 Diabetes) is the possibility of treatment with hypoglycaemic agents and the apparent lower frequency of chronic complications.

PMID: 32274916 [PubMed - as supplied by publisher]

Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin.

J Thromb Thrombolysis. 2020 Apr 10;:

Authors: Elewa H, Qurishi I, Abouelhassan R, Abou Safrah S, Alhamoud E, Bader L

Abstract
There is no strong evidence on pharmacogenetics role on the quality of INR control after the initiation phase and on the maintenance of stable INR on the long term as measured by the time in therapeutic range (TTR). The benefit of a score such as SAMe-TT2R2 is that it can preemptively guide clinicians on whether to start the patient on warfarin or direct oral anticoagulant. To determine the association between genetic variants in CYP2C9, VKORC1, and CYP4F2 and TTR. To validate SAMe-TT2R2 score predictive ability on the quality of anticoagulation in Qatari patients. This is an observational nested case-control study that was conducted on a cohort of Qatari patients treated with warfarin with previously identified genotype for the CYP2C9, VKORC1, and CYP2F4. The sample size of this cohort was 148 patients. Mean TTR was 62.7 ± 21%. TTR was not significantly different among carriers of the CYP2C9*2 &*3, VKORC1(-1639G>A) or CYP4F2*3 compared to their non-carriers alleles. None of the factors in the SAMe-TT2R2 score had a significant effect on the TTR except for the female gender where TTR was significantly lower in females (n = 89) compared to males (n = 59) (59.6 ± 21% vs. 67.2 ± 20%, p = 0.03). Furthermore, patients with SAMe-TT2R2 score of zero had significantly better TTR compared to those with higher scores (76.5 ± 17% vs. 61.8 ± 21%, p = 0.04). Logistic regression analysis showed that high SAMe-TT2R2 score was the only statistically significant predicting factor of poor INR control (odds ratio (OR) 5.7, 95% confidence interval (CI) 1.1-28.3, p = 0.034). Genetic variants have no contribution to the quality of INR control. SAMe-TT2R2 score was predictive for the poor quality of anticoagulation in a cohort of Qatari patients.

PMID: 32274641 [PubMed - as supplied by publisher]

Exhaled breath condensate biomarkers for lung cancer.

J Breath Res. 2019 08 20;13(4):044002

Authors: Campanella A, De Summa S, Tommasi S

Abstract
Lung cancer is the main cause of cancer incidence and mortality worldwide and the identification of clinically useful biomarkers for lung cancer detection at both early and metastatic stage is a pressing medical need. Although many improvements have been made in the treatment and in the early screening of this cancer, most diagnosis are made at a late stage, when a lot of genetic and epigenetic changes have occurred. A promising source of biomarkers reflective of the pathogenesis of lung cancer is exhaled breath condensate (EBC), a biological fluid and a natural matrix of the respiratory tract. Molecules such as DNAs, RNAs, proteins, metabolites and volatile compounds are present in EBC, and their presence/absence or their variation in concentrations can be used as biomarkers. The aims of this review are to briefly describe exhaled breath composition, firstly, and then to document some of the EBC candidate biomarkers for lung cancer by dividing them according to their origin (genome, transcriptome, epigenome, metabolome, proteome and microbiota) in order to demonstrate the potential use of EBC as a helpful tool in cancer diagnostics, molecular profiling, therapy monitoring and screening of high risk individuals.

PMID: 31282387 [PubMed - indexed for MEDLINE]

Impact of CYP2C9-Interacting Drugs on Warfarin Pharmacogenomics.

Clin Transl Sci. 2020 Apr 09;:

Authors: Agrawal S, Heiss MS, Fenter RB, Abramova TV, Perera MA, Pacheco JA, Smith ME, Rasmussen-Torvik LJ, George AL

Abstract
Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug-drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based on CYP2C9 and VKORC1 genotypes, had significantly greater international normalized ratio (INR) variability over time. Participants who were concurrently taking CYP2C9-interacting drugs were found to have greater INR variability and lesser time in therapeutic range. The associations of INR variability with genotype were driven by the subgroup not exposed to interacting drugs, whereas the effect of interacting drug exposure was driven by the subgroup categorized as normal responders. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies.

PMID: 32270628 [PubMed - as supplied by publisher]

Pharmacogenetics of statin intolerance.

Intern Med J. 2020 Apr;50(4):506-507

Authors: Suthers G, Somogyi AA

PMID: 32270606 [PubMed - in process]

Pharmacogenomics of breast cancer: highlighting CYP2D6 and tamoxifen.

J Cancer Res Clin Oncol. 2020 Apr 08;:

Authors: Chan CWH, Law BMH, So WKW, Chow KM, Waye MMY

Abstract
PURPOSE: To review recent pharmacogenomics studies on breast cancer patients undergoing tamoxifen therapy, highlighting how our knowledge on cytochrome P450 2D6 (CYP2D6) can help to guide the development of adjuvant therapies for these patients.
METHODS: A comprehensive literature search was conducted. Articles reporting findings pertaining to the effect of CYP2D6 on the therapeutic efficacy of tamoxifen, those reporting how targeting CYP2D6 could inform tamoxifen-based therapy development, and those on the tamoxifen effects on cell lines and animal models were included in the review.
RESULTS: With CYP2D6 being the primary enzyme for tamoxifen metabolism, single-nucleotide polymorphisms (SNPs) in this gene were one of the determinants in the rate of tamoxifen metabolism, thereby potentially having an effect on the efficacy of tamoxifen-based therapies. Our review indicates the potential effectiveness of targeting these SNPs, including those for the CYP2D6*10 allele (c. 100C > T), in modifying the level of tamoxifen metabolism. These findings suggest the importance of pharmacogenomics research in our understanding of the efficacy of adjuvant therapies. However, the involvement of multiple enzymes in tamoxifen metabolism, dietary factors, ethnic differences in gene frequencies, and patients' compliance to tamoxifen therapies in studies do present challenges in pharmacogenomics research.
CONCLUSIONS: Pharmacogenomics could play important roles in mediating the advancement of tamoxifen-based adjuvant therapies. Research efforts should be directed towards the exploration of further SNPs of CYP2D6 that affect tamoxifen metabolism, as well as epigenetic changes in CYP2D6, enabling the design of precision medicine and confirming clinical validity in the use of pharmacogenomics for tamoxifen.

PMID: 32270286 [PubMed - as supplied by publisher]

Exploring Biologic Predictors Response Disparities to Atypical Antipsychotics among Blacks: A Quasi-Systematic Review.

Ethn Dis. 2020;30(Suppl 1):229-240

Authors: Jerome RN, Pulley JM, Sathe NA, Krishnaswami S, Dickerson AB, Worley KJ, Wilkins CH

Abstract
Purpose: Management of schizophrenia among Blacks in the United States is affected by persistent disparities. This review explored response to atypical antipsychotics among Blacks compared with other groups to assess systematic variation that may contribute to disparities.
Methods: We conducted a quasi-systematic review of studies reporting response to atypical antipsychotics among Blacks compared with other groups, including effects of genetic variation.
Results: Of 48 identified research articles, 29 assessed differences in outcomes without inclusion of genetic variation and 20 explored effects of genetic variation; of note: one article included both types of data. Analysis of the 29 papers with clinical outcomes only suggests that while data on efficacy and risk of movement disorders were heterogeneous, findings indicate increased risk of metabolic effects and neutropenia among Blacks. Of the 20 articles exploring effects of genetic variation, allelic or genotypic variations involving several genes were associated with altered efficacy or safety among Blacks but not Whites, including risk of decreased response involving variation in DRD4 and DRD1, and improved efficacy associated with variants in DRD2, COMT, and RGS4. Others showed significant improvement in treatment response only among Whites, including variation in DTNBP1, DRD4, and GNB3.
Conclusions: The current analysis can help tailor management among Blacks using an atypical antipsychotic. Heterogeneity in genetic variation effects and response allele frequency suggests that pharmacogenetics approaches for atypical antipsychotics will need to explicitly incorporate race and ethnicity.

PMID: 32269465 [PubMed - in process]

Participatory Genomic Testing Can Effectively Disseminate Cardiovascular Pharmacogenomics Concepts within Federally Qualified Health Centers: A Feasibility Study.

Ethn Dis. 2020;30(Suppl 1):167-176

Authors: Johnson A, Broughton S, Aponte-Soto L, Watson K, Pinto CDG, Empey P, Reis S, Winn R, Massart M

Abstract
Objective: We assessed feasibility of an educational program designed to enhance stakeholder knowledge and perceptions of pharmacogenomics at a federally qualified health center (FQHC).
Design: FQHCs have a rich history of providing care to the underserved, but often are not represented by studies evaluating cutting-edge concepts. We used a novel educational platform to provide participatory genomic testing and classroom education. We assessed participant knowledge and perceptions using questionnaires between May and July 2018.
Setting: We partnered with a FQHC affiliated with an academic medical center in Chicago.
Participants: Using convenience sampling, we recruited 20 providers and 10 community members for a feasibility study. Providers included physicians, physician extenders, community health workers, and patient health navigators. Community members were patients, supporters, and/or FQHC advisory board members.
Intervention: Participants had the option to undergo personal genomic testing. Online educational modules included basic genetics, cardiovascular pharmacogenomics, and personalized medicine. Education concluded in a 2-hour live course with case-based discussions.
Main Outcome Measures: Our main outcome was testing pilot feasibility. Baseline knowledge and perceptions were compared with post-intervention assessments using descriptive statistics, t tests (or Wilcoxon rank-sum) for continuous variables and chi-squared (or Fisher's exact) for categorical variables.
Results: We found that attitudes toward the intervention were positive and remained so after intervention. Our intervention was both feasible and acceptable. Genomics knowledge increased for nearly all participants.
Conclusions: We have determined that a pharmacogenomics educational program tailored for an underrepresented community is feasible and acceptable. Outcomes will advise methodology for larger implementation studies.

PMID: 32269458 [PubMed - in process]

Why African Americans say "No": A Study of Pharmacogenomic Research Participation.

Ethn Dis. 2020;30(Suppl 1):159-166

Authors: Nooruddin M, Scherr C, Friedman P, Subrahmanyam R, Banagan J, Moreno D, Sathyanarayanan M, Nutescu E, Jeyaram T, Harris M, Zhang H, Rodriguez A, Shaazuddin M, Perera M, Tuck M, ACCOuNT Investigators

Abstract
Objective: To identify reasons for nonparticipation by African Americans in cardiovascular pharmacogenomic research.
Design: Prospective, open-ended, qualitative survey.
Setting: Research staff approached patients eligible for the Discovery Project of The African American Cardiovascular pharmacogenomics CONsorTium in the inpatient or outpatient setting at four different institutions during September and October 2018.
Participants: Potential Discovery Project participants self-identified as African American, aged >18 years, were on one of five cardiovascular drugs of interest, and declined enrollment in the Discovery Project.
Main Outcome Measures: Reasons for nonparticipation.
Methods: After declining participation in the Discovery Project, patients were asked, "What are your reasons for not participating?" We analyzed their responses using a directed content analytic approach. Ultimately, responses were coded into one of nine categories and analyzed using descriptive statistics.
Results: Of the 194 people approached for the Discovery Project during an eight-week period, 82 declined participation and provided information for this study. The most common reason for refusal was concern about the amount of blood drawn (19.5%). The next most common reasons for refusal to participate included concerns about genetic testing (14.6%) and mistrust of research (12.2%). Across study sites, significantly more patients enrolled in the inpatient than outpatient setting (P<.001). Significantly more women and younger individuals declined participation due to concerns about genetic testing and too little compensation (P<.05).
Conclusions: Collection of blood samples and concerns about genetic testing are obstacles for the recruitment of African Americans to pharmacogenomics studies. Efforts to overcome these barriers to participation are needed to improve representation of minorities in pharmacogenomic research. Enrolling participants from inpatient populations may be a solution to bolster recruitment efforts.

PMID: 32269457 [PubMed - in process]

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Pharmacogenetics of antiemetics for chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis.

Crit Rev Oncol Hematol. 2020 Apr 04;149:102939

Authors: Eliasen A, Dalhoff K, Mathiasen R, Schmiegelow K, Rechnitzer C, Schelde AB, Perwitasari DA, Tsuji D, Brok J

Abstract
A substantial proportion of cancer patients experience chemotherapy-induced nausea and vomiting (CINV) despite the use of antiemetic drugs. Prevalent genetic polymorphisms involved in antiemetic drug metabolism, drug transport and receptor pathways likely affect the effectiveness of antiemetics. Knowledge on which polymorphisms to integrate into individualised clinical care is needed. We did a systematic review evaluating the association between polymorphisms and effectiveness of antiemetics in cancer patients receiving moderately to highly emetogenic chemotherapy. Twenty studies n = 2331 evaluated eight polymorphisms in five candidate genes involved in 5-HT3 antagonist pathways. HTR3C C1214G increased the risk of acute chemotherapy-induced vomiting in the dominant model (odds ratio (OR) = 2.67, 95 % confidence interval (CI): 1.08-6.63). ABCB1 C3435T reduced the risk of acute CINV in the recessive model (OR = 0.60, 95 % CI: 0.44-0.81). Future studies should evaluate candidate genes that affect pharmacogenetics of other antiemetics beside 5-HT3 antagonists.

PMID: 32259776 [PubMed - as supplied by publisher]

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis.

Front Oncol. 2019;9:1573

Authors: Liu W, Wang Y, Luo J, Yuan H, Luo Z

Abstract
Background: Platinum-based agents, including cisplatin, carboplatin, and oxaliplatin, are indispensable for the treatment of lung cancer. The development of toxicity frequently necessitates dose reduction or discontinuation of therapy, despite the clinical response. Pharmacogenomics studies were reviewed to identify the possible genetic variants that underlie individual susceptibility to platinum-related toxicities. Method: We conducted a systematic search in PubMed and Embase for pharmacogenomics reports that focused on commonly reported platinum-induced toxicities, such as gastrointestinal (GI), hematological, neurological, and other toxicities, in patients diagnosed with lung cancer. Meta-analyses were conducted to determine the association between genetic polymorphisms and platinum-induced toxicity by checking the odds ratio (OR) and 95% confidence interval (CI) using random or fixed-effects models as appropriate. Results: Twenty eligible studies that met the inclusion criteria with sufficient data were extracted and presented comprehensively. A total of 16 polymorphisms from 11 genes were included in the meta-analysis. MTHFR rs1801131 and MDM2 rs1690924 were significantly correlated with platinum-induced GI toxicity (P = 0.04 and P = 0.02, respectively). Patients with the MTHFR rs1801131AA and MDM2 rs1690924TC/CC genotype tended to have a higher risk of GI toxicity than patients with other genotypes did (OR = 1.73, 95% CI = 0.86-2.18; and OR = 0.51, 95% CI = 0.29-0.88, respectively). Compared to carriers of the MTHFR rs1801133CC genotype, carriers of the CT/TT genotype had a significantly increased risk of hematological toxicity (P = 0.01, OR = 1.68, 95% CI = 1.12-2.52). Conclusion: In the future, physicians should pay careful attention to MTHFR and MDM2 for personalized chemotherapy treatment among patients with lung cancer.

PMID: 32257953 [PubMed - as supplied by publisher]

Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?

Curr Fungal Infect Rep. 2020 Mar;14(1):63-75

Authors: Miller MA, Lee YM

Abstract
Purpose of Review: This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice.
Recent Findings: The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic-pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed.
Summary: Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.

PMID: 32256938 [PubMed - as supplied by publisher]

Analysis of the Deleterious Single-Nucleotide Polymorphisms Associated With Antidepressant Efficacy in Major Depressive Disorder.

Front Psychiatry. 2020;11:151

Authors: Xin J, Yuan M, Peng Y, Wang J

Abstract
Major depressive disorder (MDD) is a serious mental disease with negative effects on both mental and physical health of the patient. Currently, antidepressants are among the major ways to ease or treat MDD. However, the existing antidepressants have limited efficacy in treating MDD, with a large fraction of patients either responding inadequately or differently to antidepressants during the treatment. Pharmacogenetics studies have found that the genetic features of some genes are associated with the antidepressant efficacy. In order to obtain a better understanding on the relationship between the genetic factors and antidepressant treatment response, we compiled a list of 233 single-nucleotide polymorphisms (SNPs) significantly associated with the antidepressant efficacy in treating MDD. Of the 13 non-synonymous SNPs in the list, three (rs1065852, rs3810651, and rs117986340) may influence the structures and function of the corresponding proteins. Besides, the influence of rs1065852 on the structure of CYP2D6 was further investigated via molecular dynamics simulations. Our results showed that compared to the native CYP2D6 the flexibility of the F-G loop was reduced in the mutant. As a portion of the substrate access channel, the lower flexibility of F-G loop may reduce the ability of the substrates to enter the channel, which may be the reason for the lower enzyme activity of mutant. This study may help us to understand the impact of genetic variation on antidepressant efficacy and provide clues for developing new antidepressants.

PMID: 32256400 [PubMed - as supplied by publisher]

Pharmacogenetics of Pediatric Asthma: Current Perspectives.

Pharmgenomics Pers Med. 2020;13:89-103

Authors: Perez-Garcia J, Espuela-Ortiz A, Lorenzo-Diaz F, Pino-Yanes M

Abstract
Asthma is a chronic respiratory disease that affects 339 million people worldwide and has a considerable impact on the pediatric population. Asthma symptoms can be controlled by pharmacological treatment. However, some patients do not respond to therapy and continue suffering from symptoms, which impair the quality of life of patients and limit their daily activity. Genetic variation has been shown to have a role in treatment response. The aim of this review is to update the main findings described in pharmacogenetic studies of pediatric asthma published from January 1, 2018 to December 31, 2019. During this period, the response to short-acting beta-agonists and inhaled corticosteroids in childhood asthma has been evaluated by eleven candidate-gene studies, one meta-analysis of a candidate gene, and six pharmacogenomic studies. The findings have allowed validating the association of genes previously related to asthma treatment response (ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1), and identifying novel associations (PRKG1, DNAH5, IL1RL1, CRISPLD2, MMP9, APOBEC3B-APOBEC3C, EDDM3B, and BBS9). However, some results are not consistent across studies, highlighting the need to conduct larger studies in diverse populations with more homogeneous definitions of treatment response. Once stronger evidence was established, genetic variants will have the potential to be applied in clinical practice as biomarkers of treatment response enhancing asthma management and improving the quality of life of asthma patients.

PMID: 32256100 [PubMed - as supplied by publisher]

Drug Attitude, Insight, and Patient's Knowledge About Prescribed Antipsychotics in Schizophrenia: A Cross-Sectional Survey.

Neuropsychiatr Dis Treat. 2020;16:781-787

Authors: Nagai N, Tani H, Yoshida K, Gerretsen P, Suzuki T, Ikai-Tani S, Mimura M, Uchida H

Abstract
Introduction: While patients' perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia.
Materials and Methods: One hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients' knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized.
Results: The mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (β=-0.226, P=0.009; β=0.250, P=0.008; β=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis.
Conclusion: Better insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

PMID: 32256074 [PubMed - as supplied by publisher]

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomised multiple-dose trial.

Br J Clin Pharmacol. 2020 Apr 06;:

Authors: Koller D, Saiz-Rodríguez M, Zubiaur P, Ochoa D, Almenara S, Román M, Romero-Palacián D, de Miguel-Cáceres A, Martín S, Navares M, Mejía G, Wojnicz A, Abad-Santos F

Abstract
AIMS: Pupillography is a non-invasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics.
METHODS: Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by qPCR. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by HPLC-MS/MS.
RESULTS: Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (p < 0.05). Olanzapine only altered minimum pupil size (p = 0.046). Polymorphisms in CYP3A, HTR2A, UDP-glucuronosyltransferase 1-1 (UGT1A1), DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1and UGT1A1 genes.
CONCLUSIONS: In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

PMID: 32250470 [PubMed - as supplied by publisher]

A holistic approach is needed to control the perpetual burden of soil-transmitted helminth infections among indigenous schoolchildren in Malaysia.

Pathog Glob Health. 2020 Apr 05;:1-15

Authors: Nasr NA, Al-Mekhlafi HM, Lim YAL, Elyana FN, Sady H, Atroosh WM, Dawaki S, Al-Delaimy AK, Al-Areeqi MA, Wehaish AA, Anuar TS, Mahmud R

Abstract
A cross-sectional survey was conducted among 1,142 Orang Ali schoolchildren in six states of Peninsular Malaysia to investigate the current prevalence and risk factors of STH infections. Faecal samples were examined using direct smear, formalin-ether sedimentation, Kato-Katz, and Harada-Mori methods. A pre-tested questionnaire was used to collect information on the demographic, socioeconomic, personal hygiene, and health status of the participants. Overall, 70.1% (95% CI = 67.4, 72.7) of the participants were infected with at least one of the STH species. The prevalence of Ascaris lumbricoides, Trichuris trichiura, and hookworm infections was 63.1%, 61.8% and 11.5%, respectively. Moderate-to-heavy STH infections accounted for 61.3% of the total infections. Univariate and logistic regression analyses revealed different sets of risk factors, with age (> 10 years) being the significant risk factor of all three STH species. Moreover, other species-specific risk factors were identified including being a member of the Senoi tribe, family size (≥ 7 members), school size (150-250 pupils), maternal unemployment, unimproved source of drinking water, lacking improved toilet in the house, inadequate WASH facilities at school, not washing hands before eating, and not washing fruits before eating; presence of domestic animals, and not wearing shoes when outside. The high prevalence of STH infections found in the study population exceeds the WHO policy intervention threshold (20% prevalence). Thus, an innovative holistic approach should be adopted to control STH infections among these children as part of the efforts to improve the quality of life of the entire Orang Asli population. .

PMID: 32249689 [PubMed - as supplied by publisher]

Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection.

Clin Pharmacol Ther. 2020 Apr 04;:

Authors: Du YX, Chen XP

Abstract
An outbreak of 2019-nCoV infection in China has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs such as interferon-ɑ, lopinavir/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.

PMID: 32246834 [PubMed - as supplied by publisher]