Clinically relevant endothelial nitric oxide synthase polymorphisms and their impact on drug response.

Expert Opin Drug Metab Toxicol. 2020 Aug 04;:

Authors: Cotta Filho CK, Oliveira-Paula GH, Rondon Pereira VC, Lacchini R

Abstract
INTRODUCTION: Nitric Oxide (NO) is a molecule with multiple functions. Several drugs involve the modulation of NO levels in their mechanism of action. NO is mainly produced in vessels by endothelial NO synthase, which is encoded by NOS3 gene. This gene shows genetic polymorphisms associated with hypertension and other cardiovascular diseases, inflammation, psychiatric disorders, cancer, and others.
AREAS COVERED: Four functional polymorphisms of NOS3 were selected: rs2070744, rs3918226, rs61722009 and rs1799983 and their association with differential drug responses was explored. This review explores beyond the cardiovascular area, including drugs regardless of their clinical indications.
EXPERT OPINION: While there is good evidence of the clinical importance of NOS3 single nucleotide polymorphisms, the current knowledge is superficial in most clinical settings and further studies are needed. Basic science advances are also needed to help to interpret genetic association data. While there are controversies, most data from chronic treatment studies show a trend for loss-of-function alleles, that predispose to higher risk for disease, associating with better clinical response across different drug classes and clinical settings. Acute pharmacological responses were poorly explored, although there seem to be a trend where gain-of-function alleles associate with better clinical responses when observed in the scale of minutes to hours.

PMID: 32746648 [PubMed - as supplied by publisher]

Genetic Variants in DNA Mismatch Repair Pathway predict prognosis of Lung Cancer patients with receiving Platinum-Based Chemotherapy.

J Cancer. 2020;11(18):5281-5288

Authors: Liu JY, Zou T, Yin JY, Wang Z, Wang Y, Liu ZQ, Chen J, Chen ZW

Abstract
Objective: To investigate the relationships between genetic variants in DNA mismatch repair pathway genes and the prognosis of platinum-based chemotherapy in lung cancer patients. Methods: 346 lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited in this study. A total of 35 single nucleotide polymorphisms in 7 DNA mismatch repair genes were genotyped to investigate their associations with platinum-based chemotherapy prognosis. Result: The results revealed that patients carried MSH2 rs4608577 TT genotype had a significantly shorter progression free survival than patients with GG or GT genotypes (Additive model: P=0.003, OR =0.94, 95% CI =0.33-1.57). Patients with SAPCD1 rs707937 TT genotype had a significantly longer overall survival than patients with GG or GT genotypes (Additive model: P=0.0003, OR=0.75, 95% CI =0.35-1.14). Eight SNPs and fourteen SNPs were related to progression free survival and overall survival in subgroup analyses, respectively. Conclusion: Our findings suggest that the MSH2 rs4608577 and SAPCD1 rs707937 may be potential clinical biomarkers for predicting platinum-based chemotherapy prognosis in lung cancer patients.

PMID: 32742474 [PubMed]

KRAS inhibition in non-small cell lung cancer: Past failures, new findings and upcoming challenges.

Eur J Cancer. 2020 Jul 31;137:57-68

Authors: Passiglia F, Malapelle U, Del Re M, Righi L, Pagni F, Furlan D, Danesi R, Troncone G, Novello S

Abstract
Despite the high prevalence of Kirsten rat sarcoma (KRAS) mutations in non-small cell lung cancer (NSCLC), for a long time it has been defined as an 'undruggable target', with precision medicine not considered as an adequate approach to treat this subgroup of patients. After several years of efforts, preliminary data from early clinical trials have recently demonstrated that direct pharmacological inhibition of KRAS p.G12C mutation is possible, emerging as an effective targeted treatment for about 10-12% of patients with advanced NSCLC, with potential relevant impact on their long-term survival and quality of life. This review reports the current status of KRAS mutations detection in the Italian real-word scenario, summarises the biological basis of KRAS inhibition in NSCLC and provides an updated overview of therapeutic strategies, discussing the potential reasons for past failures and analysing the upcoming challenges related to the advent of new targeted agents in clinical practice.

PMID: 32745965 [PubMed - as supplied by publisher]

Patient perceptions of pharmacogenomic testing in the community pharmacy setting.

Res Social Adm Pharm. 2020 Jul 13;:

Authors: Bright D, Worley M, Porter BL

Abstract
BACKGROUND: In order to optimize community pharmacist roles and patient outcomes, a better understanding of patient perceptions of pharmacogenomic (PGx) testing may be helpful for successful integration into community pharmacy practice.
OBJECTIVE: The objective of this study was to identify patient perceptions related to PGx testing in the community pharmacy setting.
METHODS: Semi-structured, face-to-face interviews were conducted with adults ≥18 years of age to gather their perceptions of PGx testing. Interview participants were taking either an antiplatelet agent or a selective serotonin reuptake inhibitor listed in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and were patients at one of two community pharmacies in West Michigan. Interview questions were designed to follow the Theory of Planned Behavior and to take into account existing literature on patient perceptions of PGx. Interviews were recorded, transcribed by a third party transcription service, coded by a team of three researchers to identify themes, and analyzed using nVivo qualitative analysis software.
RESULTS: A total of 19 interviews were conducted over a period of 16 days in June 2016. Upon preliminary evaluation, four themes related to patient perceptions of PGx testing were consistently observed across multiple interviews: 1) trust, 2) experience, 3) risk/benefit, and 4) clarity.
CONCLUSIONS: Semi-structured patient interviews revealed four themes related to PGx testing in the community pharmacy setting. These themes may influence the desire to pursue PGx testing. Future research may seek to identify how community pharmacists can communicate with patients about PGx in the context of these themes to empower patients to make positive health care decisions.

PMID: 32741696 [PubMed - as supplied by publisher]

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

Prostate. 2020 05;80(8):632-639

Authors: Carignan D, Lessard T, Villeneuve L, Desjardins S, Magnan S, Després P, Martin AG, Foster W, Guillemette C, Lévesque É, Vigneault E

Abstract
BACKGROUND: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients.
PURPOSE: To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB).
MATERIAL AND METHODS: The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity.
RESULTS: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95  = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01).
CONCLUSIONS: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

PMID: 32201973 [PubMed - indexed for MEDLINE]

PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.

Diabetes. 2020 04;69(4):771-783

Authors: Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, Gao H, Lovato L, Prudente S, Pandolfi A, Pezzolesi MG, Sigal RJ, Paré G, Marcovina SM, Rotroff DM, Patorno E, Mercuri L, Trischitta V, Chew EY, Kraft P, Buse JB, Wagner MJ, Cresci S, Gerstein HC, Ginsberg HN, Mychaleckyj JC, Doria A

Abstract
The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes (P interaction = 3.7 × 10-4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

PMID: 31974142 [PubMed - indexed for MEDLINE]

Translational Application of Circulating DNA in Oncology: Review of the Last Decades Achievements.

Cells. 2019 10 14;8(10):

Authors: Tuaeva NO, Falzone L, Porozov YB, Nosyrev AE, Trukhan VM, Kovatsi L, Spandidos DA, Drakoulis N, Kalogeraki A, Mamoulakis C, Tzanakakis G, Libra M, Tsatsakis A

Abstract
In recent years, the introduction of new molecular techniques in experimental and clinical settings has allowed researchers and clinicians to propose circulating-tumor DNA (ctDNA) analysis and liquid biopsy as novel promising strategies for the early diagnosis of cancer and for the definition of patients' prognosis. It was widely demonstrated that through the non-invasive analysis of ctDNA, it is possible to identify and characterize the mutational status of tumors while avoiding invasive diagnostic strategies. Although a number of studies on ctDNA in patients' samples significantly contributed to the improvement of oncology practice, some investigations generated conflicting data about the diagnostic and prognostic significance of ctDNA. Hence, to highlight the relevant achievements obtained so far in this field, a clearer description of the current methodologies used, as well as the obtained results, are strongly needed. On these bases, this review discusses the most relevant studies on ctDNA analysis in cancer, as well as the future directions and applications of liquid biopsy. In particular, special attention was paid to the early diagnosis of primary cancer, to the diagnosis of tumors with an unknown primary location, and finally to the prognosis of cancer patients. Furthermore, the current limitations of ctDNA-based approaches and possible strategies to overcome these limitations are presented.

PMID: 31615102 [PubMed - indexed for MEDLINE]

Results of the European Group for the Study of Resistant Depression (GSRD) - basis for further research and clinical practice.

World J Biol Psychiatry. 2019 07;20(6):427-448

Authors: Bartova L, Dold M, Kautzky A, Fabbri C, Spies M, Serretti A, Souery D, Mendlewicz J, Zohar J, Montgomery S, Schosser A, Kasper S

Abstract
Objectives: The overview outlines two decades of research from the European Group for the Study of Resistant Depression (GSRD) that fundamentally impacted evidence-based algorithms for diagnostics and psychopharmacotherapy of treatment-resistant depression (TRD). Methods: The GSRD staging model characterising response, non-response and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries. Results: In case of non-response, dose escalation and switching between different AD classes did not show superiority over continuation of original AD treatment. Predictors for TRD were symptom severity, duration of the current major depressive episode (MDE), suicidality, psychotic and melancholic features, comorbid anxiety and personality disorders, add-on treatment, non-response to the first AD, adverse effects, high occupational level, recurrent disease course, previous hospitalisations, positive family history of MDD, early age of onset and novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC, ST8SIA2, CHL1, GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signalling and chromatin silencing. A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Applying machine-learning algorithms, a signature of three SNPs of the BDNF, PPP3CC and HTR2A genes and lacking melancholia predicted treatment response. Conclusions: The GSRD findings offer a unique and balanced perspective on TRD representing foundation for further research elaborating on specific clinical and genetic hypotheses and treatment strategies within appropriate study-designs, especially interaction-based models and randomized controlled trials.

PMID: 31340696 [PubMed - indexed for MEDLINE]

Pharmacogenetics in psychiatric care, a call for uptake of available applications.

Psychiatry Res. 2020 Jul 27;292:113336

Authors: Lunenburg CATC, Gasse C

Abstract
In this narrative, we evaluate the role of pharmacogenetics in psychiatry from a pragmatic clinical perspective and address current barriers of clinical implementation of pharmacogenetics. Pharmacogenetics has been successfully implemented to improve drug therapy in several clinical areas, but not psychiatry. Yet, psychotropics account for more than one-third of the drugs for which pharmacogenetic guidelines are available and drug therapy in mental disorders is suboptimal with insufficient effectiveness and frequent adverse events. The limited application of pharmacogenetics in psychiatry is influenced by several factors; e.g. the complexity of psychotropic drug metabolism, possibly impeding the clinical understanding of the benefits of pharmacogenetics. Also, recommendations for most psychotropics classify pharmacogenetic testing only as (potentially) beneficial, not as essential, possibly because life-threatening adverse events are often not involved in these drug-gene interactions. Implementing pharmacogenetics in psychiatry could improve the current practice of time-consuming switching of therapies causing undue delays associated with worse outcomes. We expect pharmacogenetics in psychiatry to expedite with panel-based genotyping, including clinically relevant variants, which will address the complex enzymatic metabolism of psychotropic drugs. Until then, we stress that available pharmacogenetic testing should be seen as an integrated companion, not a competitor, in current clinical psychiatric care.

PMID: 32739644 [PubMed - as supplied by publisher]

Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 29;:110050

Authors: Fabbri C, Kasper S, Zohar J, Souery D, Montgomery S, Albani D, Forloni G, Ferentinos P, Rujescu D, Mendlewicz J, De Ronchi D, Riva MA, Lewis CM, Serretti A

Abstract
About 20-30% of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) and finding new effective treatments for TRD has been a challenge. This study aimed to identify new possible pharmacological options for TRD. Genes in pathways included in predictive models of TRD in a previous whole exome sequence study were compared with those coding for targets of drugs in any phase of development, nutraceuticals, proteins and peptides from Drug repurposing Hub, Drug-Gene Interaction database and DrugBank database. We tested if known gene targets were enriched in TRD-associated genes by a hypergeometric test. Compounds enriched in TRD-associated genes after false-discovery rate (FDR) correction were annotated and compared with those showing enrichment in genes associated with MDD in the last Psychiatric Genomics Consortium genome-wide association study. Among a total of 15,475 compounds, 542 were enriched in TRD-associated genes (FDR p < .05). Significant results included drugs which are currently used in TRD (e.g. lithium and ketamine), confirming the rationale of this approach. Interesting molecules included modulators of inflammation, renin-angiotensin system, proliferator-activated receptor agonists, glycogen synthase kinase 3 beta inhibitors and the rho associated kinase inhibitor fasudil. Nutraceuticals, mostly antioxidant polyphenols, were also identified. Drugs showing enrichment for TRD-associated genes had a higher probability of enrichment for MDD-associated genes compared to those having no TRD-genes enrichment (p = 6.21e-55). This study suggested new potential treatments for TRD using a in silico approach. These analyses are exploratory only but can contribute to the identification of drugs to study in future clinical trials.

PMID: 32738352 [PubMed - as supplied by publisher]

The prevalence and characteristics of non-functioning and autonomous cortisol secreting adrenal incidentaloma after patients' stratification by body mass index and age.

BMC Endocr Disord. 2020 Jul 31;20(1):118

Authors: Podbregar A, Janez A, Goricar K, Jensterle M

Abstract
BACKGROUND: The escalating prevalence of adrenal incidentaloma (AI) has been associated with the improvement of radiologic techniques and widespread imaging in aging population. It is currently unclear whether patients with obesity more likely develop AI and the current rise in the prevalence of AI could be at least partly associated with the respective rise in obesity. We compared the prevalence and characteristics of non-functional (NF) and autonomous cortisol secreting (ACS) adrenal incidentalomas (AIs) after the study population was stratified by different body mass indexes (BMI) and age groups.
METHODS: Retrospective cross-sectional study comprising of 432 patients (40.6% male, 59.4% female) with NFAI (N = 290) and ACS (N = 142), of median age 63.4 (54.0-71.6) years and median BMI 28.6 (25.5-31.7) kg/m2. The data collection contained 11.132 points including demographic, anthropometric, radiologic, hormonal and metabolic parameters.
RESULTS: We observed 68-87% higher prevalence of AI across different age groups in NFAI and ACS in obese/overweight compared to normal weight subjects. Patients with ACS were older (P = 0.008), with higher basal cortisol (P < 0.001), lower basal DHEAS (P = 0.001), lower suppression DHEAS (P = 0.027) and higher aldosterone (P = 0.039). AIs with ACS were larger than NFAI (P < 0.001). Interestingly, ACS group had lower body mass (P = 0.023) and did not differ in BMI, blood pressure, heart rate, lipid profile, fasting glucose and presence of diabetes mellitus type 2 when compared to NFAI., By contrast to the similarity of metabolic profiles in ACS and NFAI, some components of adverse metabolic traits were rather associated with higher BMI and older age, in particular in NFAI.
CONCLUSION: The prevalence of NFAI and ACS were significantly higher in overweight/obese subgroup across the age distribution. Stratification by age and BMI displayed significant differences in some metabolic traits, in particular in NFAI.

PMID: 32736549 [PubMed - as supplied by publisher]

Personalized medicine in Hypercholesterolemia: The Role of Pharmacogenetics in Statin Therapy.

Ann Med. 2020 Jul 31;:1-17

Authors: Ahangari N, Doosti M, Ghayour Mobarhan M, Sahebkar A, Ferns GA, Pasdar A

Abstract
Statins are the first-line choice in Lipid-lowering therapy to reduce cardiovascular risk. In a continuous attempt to optimize treatment success, there is a need for additional research on genes and related molecular pathways that can determine theefficacy and toxicity of lipid-lowering drugs. Several variations within genes associated with lipid metabolism, including those involved in uptake, distribution and metabolism of statins have been reported. The purpose of this study was to evaluate the effect of genetic variationsinthe key genes responsible for statins' metabolism and their role in personalized medicine and pharmacogenetic testing (PGx) in patients treated with such drugs.Genetic assessment for specific known SNPs within the most known genes such as ABCG2, SLCO1B1, CYP3A4 and HMGCR, appears likely to predictthe efficacy of statin therapyand prevent their side effects but does not necessarily reduce the risk of cardiovascular events. Key Messages:Hypercholesterolemia patients show different response to statin therapy.Several variations within genes associated with statin metabolism have been investigated.*Genetic assessment for specific known SNPs within the most known genes may improve the efficacy of statins treatment and prevent their side effects.

PMID: 32735150 [PubMed - as supplied by publisher]

Description of Pharmacogenomic Testing Among Patients Admitted to the Intensive Care Unit After Cardiovascular Surgery.

J Intensive Care Med. 2020 Jul 31;:885066620946303

Authors: Peterson PE, Nicholson WT, Moyer AM, Arendt CJ, Smischney NJ, Seelhammer TG, Krecke CA, Haney RM, Yaw EJ, Chlan LL

Abstract
BACKGROUND: Pharmacogenomic (PGx) testing has the potential to provide information on specific drug-metabolizing enzymes that may lead to an absence, reduction, or increase in medication effect in patients. There is a paucity of prospective studies examining PGx testing in the intensive care unit (ICU) setting.
RESEARCH AIMS: To (1) obtain a PGx panel in a sample of cardiovascular (CV) surgical patients with a planned ICU stay and identify phenotypes, and (2) identify PGx variants that may inform treatment regimens and may warrant prescribing adjustments.
DESIGN AND METHODS: Descriptive, single cohort cross-sectional design. Adult (≥18 years) CV patients with an anticipated postoperative ICU stay were enrolled from a large Midwestern tertiary academic medical center. Eligible patients provided informed consent at the time of their CV clinic appointment; PGx testing was then ordered. Pharmacogenomic testing consisted of the Focused Pharmacogenomics panel which included 10 genes and 55 medications.
RESULTS: Of the 272 patients screened, 100 (68% male) patients completed PGx testing (mean age 66.2 ± 9.6 years, mean Acute Physiology, Age and Chronic Health Evaluation III score 76.1 ± standard deviation). Pharmacogenomic results were available in the medical record within a median of 52.4 hours (interquartile range: 33.4-80.3). Pharmacogenomic testing results identified 5 CYP2C19 poor metabolizers, 26 CYP2C19 rapid metabolizers, 5 CYP2C19 ultrarapid metabolizers, 6 CYP2D6 poor metabolizers, 5 CYP2D6 poor to intermediate metabolizers, and 2 CYP2D6 rapid metabolizers identified. Overall, 98% of patients had actionable or potentially actionable PGx results, including 82% for warfarin, 65% for propafenone, 65% for tramadol, 46% for oxycodone, 45% for metoprolol, 33% for clopidogrel, 32% for proton pump inhibitors, 25% for statins, and 12% for haloperidol.
CONCLUSIONS: A significant portion of patients had identified genetic variants that may warrant changes in medication management during and after CV-ICU stay. It remains to be seen if PGx testing leads to improvements in ICU patient outcomes.

PMID: 32734840 [PubMed - as supplied by publisher]

Mitofusin 2 Dysfunction and Disease in Mice and Men.

Front Physiol. 2020;11:782

Authors: Dorn GW

Abstract
A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago. During the intervening period much has been learned about MFN2 functioning in mitochondrial fusion, calcium signaling, and quality control, and the consequences of these MFN2 activities on cell metabolism, fitness, and development. Nevertheless, the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet. Here, a different perspective of why, in humans, MFN2 dysfunction preferentially impacts peripheral nerves is provided based on recent insights into its role in determining whether individual mitochondria will be fusion-competent and retained within the cell, or are fusion-impaired, sequestered, and eliminated by mitophagy. Evidence for and against a regulatory role of mitofusins in mitochondrial transport is reviewed, nagging questions defined, and implications on mitochondrial fusion, quality control, and neuronal degeneration discussed. Finally, in the context of recently described mitofusin activating peptides and small molecules, an overview is provided of potential therapeutic applications for pharmacological enhancement of mitochondrial fusion and motility in CMT2A and other neurodegenerative conditions.

PMID: 32733278 [PubMed]

The Influence of Concentration of Micro-RNA hsa-miR-370-3p and CYP2D6*4 on Equilibrium Concentration of Mirtazapine in Patients With Major Depressive Disorder.

Psychopharmacol Bull. 2020 Jul 23;50(3):58-75

Authors: Zastrozhin, Smirnov, Petukhov, Pankratenko, Zastrozhina, Grishina, Ryzhikova, Bure, Skryabin, Vlasovskih, Bryun, Sychev

Abstract
Introduction: Mirtazapine is commonly prescribed to patients diagnosed with major depressive disorder.Some proportion of these patients do not show adequate response to treatment regimen containing mirtazapine, whereas many of them experience dose-dependent adverse drug reactions. Results of the previous studies showed that CYP2D6 is involved in the biotransformation of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it.
Objective: The objective of our study was to investigate the influence of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of mirtazapine, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma levelsin patients suffering from recurrent depressive disorder.
Material and Methods: Our study included 192 patients with major depressive disorder (age - 41.4 ± 15.6 years). Treatment regimen included mirtazapine in an average daily dose of 37.4 ± 13.5 mg per week. Treatment efficacy was evaluated using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction. The activity of CYP2D6 was assessed with HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring (TDM) has been performed using HPLC-MS/MS.
Results: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 10.0 [9.0; 11.0] and (GA) 12.0 [11.0; 12.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 4.0 [3.0; 5.0], p < 0.001. We didn't reveal a statistical significance for concentration/dose indicator of mirtazapine in patients with different genotypes: (GG) 0.229 [0.158; 0.468] and (GA) 0.290 [0.174; 0.526], p = 0.196. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 23.6 [17.6; 28.0], (GA) 21.8 [17.2; 27.0], p = 0.663. At the same time, correlation analysis didn't reveal a statistically significant relationship between the mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the hsa-miR-370-3p plasma concentration: rs = 0.05, p = 0.460. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.11, p = 0.124. In addition, we revealed the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.32, p < 0.001. At the same time, correlation analysis revealed a statistically significant relationship between the mirtazapine concentration and the hsa-miR-370-3p plasma concentration: rs = 0.31, p < 0.001.
Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of mirtazapine was demonstrated in a group of 192 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p remains a promising biomarker for assessing the level of CYP2D6 expression, because it correlates with encoded isoenzyme activity.

PMID: 32733112 [PubMed - in process]

Impact of Polymorphism of CYP2D6 on Equilibrium Concentration of Duloxetine in Patients Suffering from Major Depressive Disorder.

Psychopharmacol Bull. 2020 Jul 23;50(3):47-57

Authors: Zastrozhin, Petukhov, Pankratenko, Grishina, Ryzhikova, Skryabin, Koporov, Bryun, Sychev

Abstract
Introduction: Duloxetine is commonly prescribed to patients with recurrent depressive disorder. Some part of patients in this group do not respond adequately to treatment regimen containing duloxetine, while many of them experience dose-dependent adverse drug reactions. Previous research investigated that CYP2D6 is involved in the biotransformation of duloxetine, the activity of which is highly dependent on the polymorphism of the gene encoding it.
Objective: The objective of this study was to evaluate the influence of 1846G > A polymorphism of the CYP2D6 gene on the concentration/dose indicator of duloxetine, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from recurrent depressive disorder.
Material and Methods: This study enrolled 118 patients with recurrent depressive disorder (average age - 40.6±17.1 years). Therapy included duloxetine in an average daily dose of 103.7±37.1 mg per day. Treatment efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping we performed the real-time polymerase chain reaction (PCR Real-time). Therapeutic drug monitoring has been performed using HPLC-MS/MS.
Results: Our findings revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 9.0 [7.0; 10.0] and (GA) 11.0 [8.5; 14.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [3.0; 4.0] and (GA) 4.0 [3.0; 4.0], p = 0.007. We revealed a statistical significance for concentration/dose indicator of duloxetine in patients with different genotypes: (GG) 0.776 [0.529; 1.067] and (GA) 1.388 [0.942; 1.732], p < 0.001.
Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of duloxetine was demonstrated in a group of 118 patients with recurrent depressive disorder.

PMID: 32733111 [PubMed - in process]

CTLA-4 rs231775 and risk of acute renal graft rejection: an updated meta-analysis with trial sequential analysis.

Sci Rep. 2020 Jul 30;10(1):12850

Authors: Cargnin S, Galli U, Shin JI, Terrazzino S

Abstract
Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We herein conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. In addition, noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). A comprehensive search was performed through PubMed, Web of Knowledge, Cochrane Library and Open Grey up to October 2019. Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. Overall, no association was detected with the allelic (OR 1.07, 95% CI 0.88-1.30, P = 0.49), dominant (OR 0.94, 95% CI 0.73-1.22, P = 0.66) or the recessive (OR 1.18, 95% CI 0.97-1.43, P = 0.096) model of CTLA-4 rs231775. In each genetic model, the cumulative Z-curve in TSA crossed the futility boundary and entered the futility area. In addition, none of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported meta-analyses were found to be noteworthy by FPRP. In conclusion, this study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation.

PMID: 32732985 [PubMed - in process]

Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response.

Ann Rheum Dis. 2020 Jul 30;:

Authors: Cherlin S, Lewis MJ, Plant D, Nair N, Goldmann K, Tzanis E, Barnes MR, McKeigue P, Barrett JH, Pitzalis C, Barton A, MATURA Consortium, Cordell HJ

Abstract
OBJECTIVES: In this study, we sought to investigate whether there was any association between genetically regulated gene expression (as predicted using various reference panels) and anti-tumour necrosis factor (anti-TNF) treatment response (change in erythrocyte sedimentation rate (ESR)) using 3158 European ancestry patients with rheumatoid arthritis.
METHODS: The genetically regulated portion of gene expression was estimated in the full cohort of 3158 subjects (as well as within a subcohort consisting of 1575 UK patients) using the PrediXcan software package with three different reference panels. Estimated expression was tested for association with anti-TNF treatment response. As a replication/validation experiment, we also investigated the correlation between change in ESR with measured gene expression at the Interleukin 18 Receptor Accessory Protein (IL18RAP) gene in whole blood and synovial tissue, using an independent replication data set of patients receiving conventional synthetic disease modifying anti-rheumatic drugs, with directly measured (via RNA sequencing) gene expression.
RESULTS: We found that predicted expression of IL18RAP showed a consistent signal of association with treatment response across the reference panels. In our independent replication data set, IL18RAP expression in whole blood showed correlation with the change in ESR between baseline and follow-up (r=-0.35, p=0.0091). Change in ESR was also correlated with the expression of IL18RAP in synovial tissue (r=-0.28, p=0.02).
CONCLUSION: Our results suggest that IL18RAP expression is worthy of further investigation as a potential predictor of treatment response in rheumatoid arthritis that is not specific to a particular drug type.

PMID: 32732242 [PubMed - as supplied by publisher]

3D printed gummies: personalized drug dosage in a safe and appealing way.

Int J Pharm. 2020 Jul 27;:119687

Authors: Herrada-Manchón H, Rodríguez-González D, Alejandro Fernández M, Suñé-Pou M, Pérez-Lozano P, García-Montoya E, Aguilar E

Abstract
Obtention of customized dosage forms is one of the main attractions of 3D printing in pharmaceuticals. In this sense, children are one of the groups within the population with a greater need for drug doses adapted to their requirements (age, weight, pathological state...), but most 3D printed oral dosages are solid forms and, therefore, not suitable for them. This work developed patient-tailored medicinal gummies, an alternative oral dosage form with eye-catching appearance and appropriate organoleptic characteristics. Four inks were formulated, characterised and 3D printed by means of syringe-based extrusion mechanism. Different tests were performed to ensure reproducibility of the process and validate work methodology for dosage unit fabrication applying basic manufacturing standards. Rheological test helped in evaluating inks printability. Visual characterization concluded that drugmies, apart from a high fidelity in the 3D model shape reproduction, had a bright and uniformly coloured appearance and a pleasant aroma, which made them highly appetising and attractive. The printed gummy oral dosages complied comfortably with the mass uniformity assay regardless of the formulated ink used or the 3D model selected for printing. Ranitidine hydrochloride individual contents were determined using uv-vis spectrophotometry, showing successful results both in dose accuracy, uniformity of drug content and dissolution.

PMID: 32730802 [PubMed - as supplied by publisher]

An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins.

Expert Opin Drug Metab Toxicol. 2020 Jul 30;:

Authors: Hirota T, Fujita Y, Ieiri I

Abstract
INTRODUCTION: Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lower cholesterol synthesis in patients with hypercholesterolemia. Increased statin exposure is an important risk factor for skeletal muscle toxicity. Potent inhibitors of cytochrome P450 (CYP) 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin, and atorvastatin. Fluvastatin is metabolized by CYP2C9, whereas pravastatin, rosuvastatin, and pitavastatin are unaffected by inhibition by either CYP. Statins also have different affinities for membrane transporters involved in processes such as intestinal absorption, hepatic absorption, biliary excretion, and renal excretion.
AREAS COVERED: In this review, the pharmacokinetic aspects of drug-drug interactions with statins and genetic polymorphisms of CYPs and drug transporters involved in the pharmacokinetics of statins are discussed.
EXPERT OPINION: Understanding the mechanisms underlying statin interactions can help minimize drug interactions and reduce the adverse side effects caused by statins. Since recent studies have shown the involvement of drug transporters such as OATP and BCRP as well as CYPs in statin pharmacokinetics, further clinical studies focusing on the drug transporters are necessary. The establishment of biomarkers based on novel mechanisms, such as the leakage of microRNAs into the peripheral blood associated with the muscle toxicity, is important for the early detection of statin side effects.

PMID: 32729746 [PubMed - as supplied by publisher]