Effects of Herbal Medicines on Pain Management.

Am J Chin Med. 2020;48(1):1-16

Authors: Luo Y, Wang CZ, Sawadogo R, Tan T, Yuan CS

Abstract
Pain is an unpleasant sensory and emotional experience in many diseases and is often caused by intense or damaging stimuli. Pain negatively affects the quality of life and increases high health expenditures. Drugs with analgesic properties are commonly used to relieve pain, but these Western medications could be overwhelmed by side effects including tolerance and addiction. Herbal medicines may provide alternative measures for pain management. In this review paper, after introduction of Chinese medicine theory and treatment modality, emphasis is placed on the application of Chinese herbs and herbal formulations in pain management. Three of the most commonly used herbs, i.e., Corydalis yanhusuo, Ligusticum chuanxiong, and Aconitum carmichaeli, are reviewed. Subsequently, using this ancient medical remedy, Chinese herbal formulation in treating common medical conditions associated with pain, such as headache/migraine, chest pain, abdominal pain, low back pain, neuropathic pain, osteoarthritis, and cancer pain, is presented. Chinese herbal medicines could be considered as a complementary and integrative approach in the modern armamentarium in combating pain.

PMID: 32054304 [PubMed - indexed for MEDLINE]

Genetic variations in the drug metabolizing enzyme, CYP2E1, among various ethnic populations of Pakistan.

PeerJ. 2020;8:e9721

Authors: Ahmed S, Altaf N, Ejaz M, Zulfiqar Z, Janjua K, Festila D, Cristina N

Abstract
Genetic polymorphism in cytochrome P450 (CYP) monooxygenase genes is an important source of interindividual variability of drug response. CYP enzyme activities may change as a result of such polymorphisms which then, may affect drug metabolism. This would result in a change in the severity and frequency of adverse effects in addition to the non-responder phenomenon. CYP2E1, a member of CYP superfamily, affects the metabolism of several clinically important drugs such as halothane, paracetamol, etc. Genetic variation in CYP2E1 is known to cause significant inter-individual differences in drug response and adverse effects. The degree of genetic variation is found to be different in different populations around the world. The frequencies of two important polymorphisms in the CYP2E1*7C, NC_000010.10:g.135340548A>G (rs2070672) and CYP2E1, NC_000010.10:g.135339244G>C (rs3813865), are not known in the Pakistani population. In the present investigation, 636 healthy human volunteers were screened for these two single nucleotide polymorphism. Our results indicate that about 18% (rs2070672) and 28% (rs3813865) of the Pakistani population has a genotype containing at least one low activity allele. A significant interethnic variation in the frequencies of both the polymorphisms was observed. These results suggest that pharmacogenetics screening for low activity genotypes would be a helpful tool for clinicians when they prescribe medications metabolized by CYP2E1, as a significant fraction of the Pakistani population is expected to have a variable response to these drugs.

PMID: 32879799 [PubMed]

Is vitamin D status reflected by testosterone concentration in elite athletes?

Biol Sport. 2020 Sep;37(3):229-237

Authors: Krzywański J, Pokrywka A, Młyńczak M, Mikulski T

Abstract
Vitamin D is a nutrient whose active form affects tissues as a hormone and possibly enhances performance. One plausible mechanism is by increasing testosterone concentration, which is established as an important factor for athletic performance. Therefore the aim of the study was to examine the relationship between plasma concentration of 25(OH)D and testosterone in Polish elite track and field athletes depending on vitamin D status, season, training period, body composition, sex, type of training, sun exposure and vitamin D supplementation. Plasma concentrations of 25(OH)D and testosterone were measured in all seasons within two years in athletes (70 females, 79 males) who represent strength (n = 103) and endurance (n = 46) kinds of sports, in the preparatorycompetitive season and transition period. There were no differences in 25(OH)D concentration between male and female athletes, insufficiency [25(OH)D < 30 ng/ml] was observed in 32.9%, whereas deficiency [25(OH)D < 20 ng/ ml] in 3.2%. Circannual rhythm was noted for vitamin D but not for testosterone concentration; no correlations between them were found either in strength or endurance athletes or between 25(OH)D and body composition. Testosterone concentration was higher in the transition period than in the preparatory-competition period only in male athletes. Higher 25(OH)D was observed in athletes who trained during winter in Africa (higher sun exposure) or used oral supplementation, whereas the respective testosterone levels were unchanged. In athletes, testosterone concentration did not reflect vitamin D status. The widespread of inadequate vitamin D status among athletes, makes it vital to recommend them the regular monitoring of 25(OH)D concentration and use of reasonable supplementation.

PMID: 32879544 [PubMed]

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Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.

Toxicol Appl Pharmacol. 2020 Aug 29;:115216

Authors: Aslamkhan AG, Xu Q, Loughlin A, Vu H, Pacchione S, Bhatt B, Garfinkel I, Styring TG, LaFranco-Scheuch L, Pearson K, Reynolds S, Li J, Zhou H, Miller JR, Solban N, Bass A, Glaab WE

Abstract
Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunophenotyping, comprehensive histopathological analysis, and serum clinical chemistry. Multiple metabolomic changes were seen in KO mice. For catabolism of Trp to Kyn and anthranilic acid, both substrates were decreased in liver of Tdo2 and dual KO mice. Metabolism of Trp to serotonin and its metabolites resulted in an increase in 5-Hydroxyindole-3-acetic acid in the Tdo2 and dual KO mice. Ido1 and dual KO mice displayed a Kyn reduction in plasma but not in liver. Nicotinamide synthesis and conversion of glucose to lactic acid were not impacted. A slight decrease in serum alkaline phosphatase was seen in all KOs, and small changes in liver gene expression of genes unrelated to tryptophan metabolism were observed. Regarding other parameters, no genotype-specific changes were observed. In summary, this work shows metabolomic pathway changes for metabolites downstream of tryptophan in these KO mice, and suggests that inhibition of the IDO1 and TDO2 enzymes would be well tolerated whether inhibited individually or in combination since no safety liabilities were uncovered.

PMID: 32871117 [PubMed - as supplied by publisher]

Using a pharmacogenetic clinical decision support system to improve psychopharmacotherapy dosing in patients with affective disorders.

Drug Metab Pers Ther. 2020 Sep 01;:

Authors: Zastrozhin M, Skryabin V, Sorokin A, Buzik O, Bedina I, Grishina E, Ryzhikova K, Shipitsyn V, Bryun E, Sychev D

Abstract
Objectives Although pharmacogenetic tests provide the information on a genotype and the predicted phenotype, these tests do not themselves provide the interpretation of data for a physician. Currently, there are approximately two dozen pharmacogenomic clinical decision support systems (CDSSs) used in psychiatry. Implementation of the CDSSs forming the recommendations on drug and dose selection according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task will allow increasing the efficacy of therapy and decreasing the risk of undesirable side effects. Methods The study included 118 male patients (48 in the main group and 70 in the control group) with affective disorders and comorbid alcohol use disorder. To evaluate the efficacy and safety of therapy, several international psychometric scales and rating scales to measure side effects were used. Genotyping was performed using the real-time polymerase chain reaction with allele-specific hybridization. Pharmacogenetic testing results were interpreted using free software PGX2 (LLE Medicine, Russian Federation, Biomedical Cluster of Skolkovo, Moscow Innovative Cluster; www.pgx2.com). Results The statistically significant differences across the scores on psychometric scales were revealed. For instance, the total score on the Hamilton Rating Scale for Depression by day 9 was 9.0 [8.0; 10.0] for the main group and 11.0 [10.0; 12.0] (p<0.001) for the control group and by day 16 it was 4.0 [2.0; 6.0] for the main group and 14.0 [13.0; 14.0] (p<0.001) for the control group. The UKU Side-Effect Rating Scale (UKU) also revealed a statistically significant difference. The total score on the UKU scale by day 9 was 4.0 [4.0; 5.0] for the main group and 5.0 [5.0; 6.0] (p<0.001) for the control group and by day 16 this difference grew significantly: 3.0 [0.0; 4.2] for the main group and 9.0 [7.0; 11.0] (p<0.001) for the control group. Conclusions Pharmacogenetic-guided personalization of the drug dose in patients with affective disorders and comorbid alcohol use disorder can reduce the risk of undesirable side effects and pharmacoresistance. It allows recommending the use of pharmacogenetic CDSSs for optimizing drug dosage.

PMID: 32870807 [PubMed - as supplied by publisher]

QT prolongation with hydroxychloroquine and azithromycin for the treatment of COVID-19: The need for pharmacogenetic insights.

J Cardiovasc Electrophysiol. 2020 Sep 01;:

Authors: Lopez-Medina AI, Campos-Staffico AM, Luzum JA

PMID: 32870576 [PubMed - as supplied by publisher]

Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact.

Elife. 2020 Sep 01;9:

Authors: Chiasson MA, Rollins NJ, Stephany JJ, Sitko KA, Matreyek KA, Verby M, Sun S, Roth FP, DeSloover D, Marks DS, Rettie AE, Fowler DM

Abstract
Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR's pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.

PMID: 32870157 [PubMed - as supplied by publisher]

Precision medicine in acute myeloid leukemia: where are we now and what does the future hold?

Expert Rev Hematol. 2020 Sep 01;:

Authors: Megías-Vericat JE, Martínez-Cuadrón D, Solana-Altabella A, Montesinos P

Abstract
INTRODUCTION: Precision medicine has revolutionized the diagnostic and therapeutic management of acute myeloid leukemia (AML), from standardized schemes based on chemotherapy to tailored approaches according to molecular and genetic profile and targeted therapy.
AREAS COVERED: The main topics of precision medicine in AML were reviewed in MEDLINE, EMBASE and Cochrane Central Register databases, and future directions in this therapeutic area were addressed. This review included targeted therapies, drug-sensitivity tests and predictive biomarkers, and genetic studies employing pharmacogenetic and deep sequencing strategies.
EXPERT OPINION: Precision medicine has opened the door to personalized therapy for specific AML patient populations with promising results. Several targeted therapies have been approved or are being tested for specific mutations (i.e. FLT3, IDH, BCL-2, TP53), obtaining improvements in clinical outcomes and less toxicity as compared with intensive treatment, allowing potential combination therapy. Ongoing trials and real data will establish the role of these molecules in monotherapy or combined in different AML settings (front-line, relapsed/refractory or post-transplant). Experience in drug-sensitivity predictors and pharmacogenetic biomarkers are encouraging and could be useful tools in the next years, but we need a better understanding of AML biology and pathogenesis as well as confirmatory studies to demonstrate the utility in clinical practice.

PMID: 32869672 [PubMed - as supplied by publisher]

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

ESC Heart Fail. 2020 Sep 01;:

Authors: de Denus S, Mottet F, Korol S, Feroz Zada Y, Provost S, Mongrain I, Asselin G, Oussaïd E, Busseuil D, Lettre G, Rioux J, Racine N, O'Meara E, White M, Rouleau J, Tardif JC, Dubé MP

Abstract
AIMS: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups.
METHODS AND RESULTS: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found.
CONCLUSIONS: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

PMID: 32869539 [PubMed - as supplied by publisher]

Identification of appropriate endogenous biomarker for risk assessment of multidrug and toxin extrusion protein-mediated drug-drug interactions in healthy volunteers.

Clin Pharmacol Ther. 2020 Aug 31;:

Authors: Miyake T, Kimoto E, Luo L, Mathialagan S, Horlbogen LM, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, Rodrigues AD, Muto C, Furihata K, Sugiyama Y, Kusuhara H

Abstract
Endogenous biomarkers are emerging to advance clinical drug-drug interactions (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidney. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates [creatinine and N1 -methylnicotinamide (1-NMN)], N1 -methyladenosine (m1 A) was included as novel biomarker. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well correlated with metformin CLr changes. CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.

PMID: 32866300 [PubMed - as supplied by publisher]

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism.

Basic Clin Pharmacol Toxicol. 2020 Aug 31;:

Authors: Zimdahl Kahlin A, Helander S, Wennerstrand P, Vikingsson S, Mårtensson LG, Appell ML

Abstract
The discovery and implementation of thiopurine methyltransferase (TPMT) pharmacogenetics has been a success story and has reduced the suffering from serious adverse reactions during thiopurine treatment of childhood leukaemia and inflammatory bowel disease. This MiniReview summarizes four studies included in Dr Zimdahl Kahlin's doctoral thesis as well as the current knowledge on this field of research. The genotype-phenotype concordance of TPMT in a cohort of 12,663 individuals with clinically analysed TPMT status is described. Notwithstanding the high concordance, the benefits of combined genotyping and phenotyping for TPMT status determination are discussed. The results from the large cohort also demonstrate that the factors of gender and age affect TPMT enzyme activity. In addition, characterization of four previously undescribed TPMT alleles (TPMT*41, *42, *43, *44) shows that a defective TPMT enzyme could be caused by several different mechanisms. Moreover, the folate analogue methotrexate (MTX), used in combination with thiopurines during maintenance therapy of childhood leukaemia, affects the metabolism of thiopurines and interacts with TPMT, not only by binding and inhibiting the enzyme activity but also by regulation of its gene expression.

PMID: 32865889 [PubMed - as supplied by publisher]

Biocompatibility of Materials for Biomedical Engineering.

Adv Exp Med Biol. 2020;1250:125-140

Authors: Tyan YC, Yang MH, Chang CC, Chung TW

Abstract
In the tissue engineering research field, nanobiomaterials highlight the impact of novel bioactive materials in both current applications and their potentials in future progress for tissue engineering and regenerative medicine. Tissue engineering is a well-investigated and challenging biomedical field, with promising perspectives to improve and support quality of life for the patient. To assess the response of those extracellular matrices (ECMs), induced by biomedical materials, this review will focus on cell response to natural biomaterials for biocompatibility.

PMID: 32601942 [PubMed - indexed for MEDLINE]

Identifying Cancer Patients at Risk for Heart Failure Using Machine Learning Methods.

AMIA Annu Symp Proc. 2019;2019:933-941

Authors: Yang X, Gong Y, Waheed N, March K, Bian J, Hogan WR, Wu Y

Abstract
Cardiotoxicity related to cancer therapies has become a serious issue, diminishing cancer treatment outcomes and quality of life. Early detection of cancer patients at risk for cardiotoxicity before cardiotoxic treatments and providing preventive measures are potential solutions to improve cancer patients' quality of life. This study focuses on predicting the development of heart failure in cancer patients after cancer diagnoses using historical electronic health record (EHR) data. We examined four machine learning algorithms using 143,199 cancer patients from the University of Florida Health (UF Health) Integrated Data Repository (IDR). We identified a total number of 1,958 qualified cases and matched them to 15,488 controls by gender, age, race, and major cancer type. Two feature encoding strategies were compared to encode variables as machine learning features. The gradient boosting (GB) based model achieved the best AUC score of 0.9077 (with a sensitivity of 0.8520 and a specificity of 0.8138), outperforming other machine learning methods. We also looked into the subgroup of cancer patients with exposure to chemotherapy drugs and observed a lower specificity score (0.7089). The experimental results show that machine learning methods are able to capture clinical factors that are known to be associated with heart failure and that it is feasible to use machine learning methods to identify cancer patients at risk for cancer therapy-related heart failure.

PMID: 32308890 [PubMed - indexed for MEDLINE]

Evaluation of posaconazole plasma concentrations achieved with the delayed-release tablets in Korean high-risk patients with haematologic malignancy.

Mycoses. 2020 Feb;63(2):131-138

Authors: Chae H, Cho SY, Yi Y, Lee JJ, Cha K, Kim M, Kim Y, Kim YJ, Kim HJ, Lee DG

Abstract
BACKGROUND: Posaconazole (PCZ) is a triazole approved for prophylaxis of invasive fungal infections.
OBJECTIVES: Herein, the impact of clinical variables on PCZ plasma concentrations (PPCs) attained with PCZ delayed-release tablet (DRT) was investigated and compared with a historical cohort treated with PCZ oral suspension (OS).
PATIENTS/METHODS: Steady-state PCZ PPCs in 513 patients with haematologic malignancy treated with PCZ-DRT were assessed and impact of variables were analysed. Also, a comparison with matched historical cohort treated with PCZ-OS was made.
RESULTS: The median PPC in the PCZ-DRT group was 1,308.9 ng/mL (range: 29.8-10 455.9). Use of proton pump inhibitor (1181 vs 1344 ng/mL, P = .0337) in the AML/myelodysplastic syndrome remission induction group, diarrhoea (867 vs 1543 ng/mL, P = .0325) and gastrointestinal graft-versus-host disease (870 vs 1713 ng/mL, P = .0178) in the HSCT group were associated with lower PPCs. There was lack of evidence that hepatotoxicity was related with PCZ-DRT. Higher prevalence of UGT1A4*3 allele (33.0%) was noted compared to allele frequency in Koreans in those with PPCs < 500 mg/mL. The median PPC in the PCZ-DRT group was significantly higher than that in the PCZ-OS group (1308.9 vs 713.0 ng/mL, P < .0001). Significantly less patients had PPCs < 700 ng/mL in the PCZ-DRT group compared to the PCZ-OS group (18.7% vs 48.0%, P < .0001).
CONCLUSIONS: Our study demonstrates that PCZ-DRT has enhanced absorption and bioavailability than PCZ-OS in real-world clinical settings. In addition, specific factors associated with lower PPCs should prompt consideration of therapeutic drug monitoring in patients treated with PCZ-DRT.

PMID: 31698506 [PubMed - indexed for MEDLINE]

Evolution of Next Generation Therapeutics: Past, Present, and Future of Precision Medicines.

Clin Transl Sci. 2019 11;12(6):560-563

Authors: Ramamoorthy A, Karnes JH, Finkel R, Blanchard R, Pacanowski M

PMID: 31444855 [PubMed - indexed for MEDLINE]

Correlating Transcriptional Networks to Acute Rejection in Human Kidney Transplant Biopsies.

Crit Rev Eukaryot Gene Expr. 2019;29(5):401-412

Authors: Liu R, Zou Y, Zhang W, Zhou HH

Abstract
Acute rejection (AR) in kidney transplants remains a major cause of allograft failure. This study investigates the association between gene networks and AR in human kidney transplant biopsies with weighted gene co-expression network analysis (WGCNA). The gene expression profiles of 403 (training set) and 702 (validation set) kidney transplant patients' biopsies were analyzed. WGCNA was conducted, and 11 co-regulated gene modules were identified. Each module was investigated with a t-test for AR and survival analysis for graft loss. The association between modules and AR molecular subtypes was also evaluated. Three transcriptional gene modules were associated with AR and graft loss of kidney transplant. One module constitutes unregulated immune response genes in AR and is associated with shorter graft survival (HR = 4.22, p-value = 4.29 × 10-6). This module is more significantly up-regulated in T cell-mediated acute rejection (TCMR) than in non-TCMRs. Hub genes such as HLA-DMA, CORO1A, PYCARD, and CD53 were identified. The expression of the other two modules was down-regulated in AR patients and associated with a good graft prognosis (HR = 0.41 and 0.24, respectively). A systems biology network approach may help uncover gene networks in kidney transplant biopsies associated with AR and contribute to identifying new biomarkers.

PMID: 32421997 [PubMed - indexed for MEDLINE]

Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy.

World J Transplant. 2020 May 29;10(5):90-103

Authors: Salvadori M, Tsalouchos A

Abstract
In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.

PMID: 32864355 [PubMed]

Pharmacogenomics of COVID-19 therapies.

NPJ Genom Med. 2020;5:35

Authors: Takahashi T, Luzum JA, Nicol MR, Jacobson PA

Abstract
A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

PMID: 32864162 [PubMed]

Long term outcome of chronic myeloid leukemia patients treated with imatinib: Report from a developing country.

Pak J Pharm Sci. 2020 Mar;33(2(Supplementary)):861-870

Authors: Absar M, Akhtar T, Jameel A, Mahmood A, Ullah A, Aleem A, Qureshi K, Rehman N, Iqbal Z

Abstract
The outcome of chronic myeloid leukemia has been greatly improved by the use of Imatinib (IM), a selective BCR/ABL kinase inhibitor. The aim of present study was to report long term follow-up & outcome of IM-treated CML patients along with their clinicopathological features, risk group stratification, adverse events and to compare it with CML patients reported from western countries. The mean follow-up of 123 CML patients was 5.5 years in present study, who were treated with frontline IM 400mg daily in a tertiary care hospital in Pakistan. Risk stratification scores, response to treatment (ELN guidelines) and survival outcomes estimated by Kaplan-Meier analysis. Mean age: 35 years (9-67 years) and M: F: 1.5:1, mean follow up time: 5.5 years (1-15 years). Overall survival (OS): at 5.5, 8, 10 and 12 years were 93%, 88%, 81% and 73%, respectively. Progressions free survival (PFS) was 95%, 83%, 83% and 78% at 5.5, 8, 10 and 12 years, respectively. OS estimate by Sokal score was significant (P-value: 0.0019). Additional chromosomal aberrations: 1.6%. Eighteen (14.6%) patients progressed to AP/BC. Adverse events were moderate and tolerable. We present findings from a long term follow up of CML patients treated with IM in a developing country. CML mean age at onset was considerably lower than the western populations. Furthermore, 5.5 years OS are comparable to western CML population. IM in our patients as frontline choice proved to be very effective. IM was found to be well tolerated, safe with manageable moderate side effects.

PMID: 32863263 [PubMed - in process]