Metabolomics in pharmacology - a delve into the novel field of pharmacometabolomics.

Expert Rev Clin Pharmacol. 2020 Jan 20;:1-20

Authors: Mussap M, Loddo C, Fanni C, Fanos V

Abstract
Introduction: Pharmacometabolomics is an emerging science pursuing the application of precision medicine. Combining both genetic and environmental factors, the so-called pharmacometabolomic approach guides patient selection and stratification in clinical trials and optimizes personalized drug dosage, improving efficacy and safety.Areas covered: This review illustrates the progressive introduction of pharmacometabolomics as an innovative solution for enhancing the discovery of novel drugs and improving research and development (R&D) productivity of the pharmaceutical industry. An extended analysis on published pharmacometabolomics studies both in animal models and humans includes results obtained in several areas such as hepatology, gastroenterology, nephrology, neuropsychiatry, oncology, drug addiction, embryonic cells, neonatology, and microbiomics.Expert opinion: a tailored, individualized therapy based on the optimization of pharmacokinetics and pharmacodynamics, the improvement of drug efficacy, and the abolition of drug toxicity and adverse drug reactions is a key issue in precision medicine. Genetics alone has become insufficient for deciphring intra- and inter-individual variations in drug-response, since they originate both from genetic and environmental factors, including human microbiota composition. The association between pharmacogenomics and pharmacometabolomics may be considered the new strategy for an in-deep knowledge on changes and alterations in human and microbial metabolic pathways due to the action of a drug.

PMID: 31958027 [PubMed - as supplied by publisher]

Relationship between cardiorespiratory phase coherence during hypoxia and genetic polymorphism in humans.

J Physiol. 2020 Jan 20;:

Authors: Lancaster G, Debevec T, Millet GP, Poussel M, Willis SJ, Mramor M, Goričar K, Osredkar D, Dolžan V, Stefanovska A

Abstract
KEY POINTS: High altitude-induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), where the regular oscillations corresponding to rhythmic expiration and inspiration are modulated by slow-periodic oscillations. The phase coherence between instantaneous heart rate (IHR) and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia. It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB. Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB. These novel findings provide better understanding of both the genetic and physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence.
ABSTRACT: Periodic breathing (PB) occurs in most humans at high altitudes and is characterised by low-frequency periodic alternation between hyperventilation and apnoea. In hypoxia-induced PB the dynamics and coherence between heart rate and respiration and their relationship to underlying genetic factors is still poorly understood. The aim of this study was to investigate, through novel usage of time-frequency analysis methods, the dynamics of hypoxia-induced PB in healthy individuals genotyped for a selection of antioxidative and neurodevelopmental genes. Breathing, ECG and microvascular blood flow were simultaneously monitored for 30 minutes in 22 healthy males. The same measurements were repeated under normoxic and hypoxic (normobaric (NH) and hypobaric (HH)) conditions, at real and simulated altitudes of up to 3800 m. Wavelet phase coherence and phase difference around the frequency of breathing (approximately 0.3 Hz) and around the frequency of PB (approximately 0.06 Hz) were evaluated. Subjects were genotyped for common functional polymorphisms in antioxidative and neurodevelopmental genes. During hypoxia, PB resulted in increased cardiorespiratory coherence at the PB frequency. This coherence was significantly higher in subjects with NOTCH4 polymorphism, and significantly lower in those with CAT polymorphism (HH only). Study of the phase shifts clearly indicates that the physiological mechanism of PB is different from that of the normal respiratory cycle. The results illustrate the power of time-evolving oscillatory analysis content in obtaining important insight into high altitude physiology. In particular, it provides further evidence for a genetic predisposition to PB and may partly explain the heterogeneity in the hypoxic response. This article is protected by copyright. All rights reserved.

PMID: 31957891 [PubMed - as supplied by publisher]

Assessment of pharmacogenomic SLCO1B1 assay for prediction of neuromuscular pain in type 2 diabetes mellitus and cardiovascular patients: preliminary results.

Eur Rev Med Pharmacol Sci. 2020 Jan;24(1):469-477

Authors: Licito A, Marotta G, Battaglia M, Benincasa G, Mentone L, Grillo MR, De Lucia V, Leonardi G, Bignucolo A, Comello F, Di Francia R, De Lucia D

Abstract
OBJECTIVE: At present, several strategies for preventing neuromuscular pain in Type 2 Diabetes Mellitus (T2DM) have been investigated. Recently, findings on genetic variants associated with adverse events to statin-based therapy have been reported. The study aimed at measuring whether Pharmacogenomics (PGx) profile can affect neuromuscular pain in patients carrying T2DM and cardiovascular diseases. An extensive panel of 5 polymorphisms on 4 candidate genes, previously validated as significant markers related to Sulphonylureas and Glitinides (SU-G) plus Simvastatin neuromuscular toxicity, is herein analyzed and discussed.
PATIENTS AND METHODS: We genotyped 76 T2DM patients carrying cardiovascular dyscrasia undergone anti-diabetic and anti-cholesterolemic polypharmacy. 35 subjects out of the total received concurrent SU-G and Statin-based therapy. Candidate variants consisted of drug transporters, such as Solute Carrier Organic 1B1 (SLCO1B1) Val174Ala ATP-binding cassette subfamily B member (ABCB1), subfamily C member 8 (ABCC8), and drug biotransformers of Cytochrome P450 Family (CYP) including CYP2C9*2 CYP2C9*3 CYP2C8*3, and CYP3A4*22. Moreover, we also focused on an early outline evaluation of the genotyping costs and benefits.
RESULTS: 6 out of 35 patients treated with SU-G plus statins (17.1% experienced adverse neuropathy events). Pharmacogenomics analysis showed a lack of any correlation between candidate gene polymorphisms and toxicity, except for the SLCO1B1 T521C allele; 14.3% of patients had a high risk for grade >2 neuromuscular pain (Odds Ratio [OR] 2.61.95% CI 0.90-7.61, p=0.03).
CONCLUSIONS: The clinical polymorphism effectiveness outlined therein will be assured by diagnostic improvements suitable for driving treatment decisions. In light of our experimental results and literature data, the analysis of the SLCO1B1 T521C variant will allow clinicians to take advantage from a better treatment planned for their patients in order to minimize neuromuscular pain and maximize benefits.

PMID: 31957862 [PubMed - in process]

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder.

Pharmacogenomics. 2020 Jan;21(2):111-123

Authors: Zastrozhin MS, Skryabin VY, Torrado M, Petrovna A, Sorokin AS, Grishina EA, Ryzhikova KA, Bedina IA, Buzik OZ, Chumakov EM, Savchenko LM, Brun EA, Sychev DA

Abstract
Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.

PMID: 31957548 [PubMed - in process]

Genotype-guided treatment of oral P2Y12 inhibitors: where do we stand?

Pharmacogenomics. 2020 Jan;21(2):83-86

Authors: Claassens DM, Ten Berg JM

PMID: 31957547 [PubMed - in process]

The emergent phenomenon of aspirin resistance: insights from genetic association studies.

Pharmacogenomics. 2020 Jan;21(2):125-140

Authors: Ferreira M, Freitas-Silva M, Assis J, Pinto R, Nunes JP, Medeiros R

Abstract
Despite the clinical benefits of aspirin, the interindividual variation in response to this antiplatelet drug is considerable. The manifestation of aspirin resistance (AR) is frequently observed, although this complex process remains poorly understood. While AR etiology is likely to be multifactorial, genetic factors appear to be preponderant. According to several genetic association studies, both genome-wide and candidate gene studies, numerous SNPs in cyclooxygenase, thromboxane and platelet receptors-related genes have been identified as capable of negatively affecting aspirin action. Thus, it is essential to understand the clinical relevance of AR-related SNPs as potential predictive and prognostic biomarkers as they may be essential to defining the AR phenotype.

PMID: 31957546 [PubMed - in process]

Footprints of clinical pharmacology in Turkey: Past, present, and future.

Clin Ther. 2020 Jan 16;:

Authors: Gulmez SE, Aydin V, Akici A

Abstract
Clinical pharmacology is an interdisciplinary field that encompasses all components of the relationship between drugs and humans. All clinical pharmacology professionals aim to support an improved quality of drug-oriented health services by providing teaching, research, and routine health care services that ensure more tolerable and more effective, suitable, and cost-effective use of drugs. Subsections of clinical pharmacology include clinical trials, pharmacoepidemiology and drug use, pharmacovigilance, pharmacoeconomics, the rational use of medicines, pharmacotherapy consultation, drug monitoring, counseling to authorities and industry, pharmacogenetics, and other practices. By approaching these subsections as part of 3 main aspects of clinical pharmacology-education, research, and health care-this review aims to provide local and international practitioners with detailed information about clinical pharmacology practices in Turkey and to contribute to building the network of communication and collaboration. This review also aims to play an encouraging and pioneering role for Turkey's national community and other countries that have not yet made clinical pharmacology functional in improving the quality of health services, promoting the dissemination of rational use of medicines, helping the set-up of clinical pharmacology organizations, enhancing quantity and quality of the clinical pharmacology workforce, and increasing the infrastructural facilities.

PMID: 31955969 [PubMed - as supplied by publisher]

Pharmacokinetics of fixed-dose combination of atorvastatin and metformin compared with individual tablets.

Drug Des Devel Ther. 2019;13:1623-1632

Authors: Ghim JL, Phuong NTT, Kim MJ, Kim EJ, Song GS, Ahn S, Shin JG, Kim EY

Abstract
Purpose: The aims of this study was to investigate the mutual pharmacokinetic interactions between steady-state atorvastatin and metformin and the effect of food on the fixed-dose combined (FDC) tablet of atorvastatin and metformin extended release (XR). Subjects and methods: Study 1, an open-labeled, fixed sequence, multiple-dose pharmacokinetic drug-drug interaction study, was divided into 2 parts. Atorvastatin (40 mg) or metformin (1,000 mg) XR tablets were administered once daily via mono- or co-therapy for 7 days. Plasma levels of atorvastatin and 2-OH-atorvastatin, were quantitatively determined for 36 h in part A (n=50) while metformin plasma concentration was measured up to 24 h in part B (n=16) after the last dosing. Study 2, a randomized, open-labeled, single-dose, two-treatment, two-period, two-sequence crossover study, involved 27 healthy subjects to investigate the impact of food intake on the pharmacokinetics of a combined atorvastatin/metformin XR 20/500 mg (CJ-30056 20/500 mg) tablet. Results: After multiple doses of mono- or co-therapy of atorvastatin (40 mg) and metformin (1,000 mg) XR, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) were 1.07 (0.94-1.22) and 1.05 (0.99-1.10) for atorvastatin, 1.06 (0.96-1.16) and 1.16 (1.10-1.21) for 2-OH-atorvastatin, and 1.00 (0.86-1.18) and 0.99 (0.87-1.13) for metformin, respectively. Food delayed time to reach maximum concentration (tmax), decreased atorvastatin Cmax by 32% with a GMR (90% CI) of 0.68 (0.59-0.78), and increased metformin AUCt by 56% with a GMR (90% CI) of 1.56 (1.43-1.69). Conclusion: No clinically relevant pharmacokinetic interaction was seen when atorvastatin was co-administered with metformin. Food appeared to change the absorption of atorvastatin and metformin from an FDC formulation. These alterations were in accordance with those described with the single reference drugs when ingested with food.

PMID: 31190741 [PubMed - indexed for MEDLINE]

Constitutive Activation of the Human Aryl Hydrocarbon Receptor in Mice Promotes Hepatocarcinogenesis Independent of Its Coactivator Gadd45b.

Toxicol Sci. 2019 02 01;167(2):581-592

Authors: Lu P, Cai X, Guo Y, Xu M, Tian J, Locker J, Xie W

Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.

PMID: 30346592 [PubMed - indexed for MEDLINE]

Multiple genetic factors affecting the pharmacokinetic and pharmacodynamic processes of tacrolimus in Chinese myasthenia gravis patients.

Eur J Clin Pharmacol. 2020 Jan 18;:

Authors: Meng HY, Li X, Jin WL, Yan CK, Dong XH, Xu Q, Peng YY, Li ZB, Li Y, Luo ZH, Xu LQ, Yang H

Abstract
PURPOSE: Tacrolimus is a novel effective immunosuppressant for myasthenia gravis (MG) patients. However, the narrow therapeutic window, and high inter- and intrapatient variation in bioavailability largely limited its clinical application. This article intended to find the SNPs influencing clinical outcome and discover the possible mechanisms.
METHODS: Based on the tagSNPs genotyped by Improved Multiple Ligase Detection Reaction, Plink 1.07 was used to find the SNPs having close interaction to tacrolimus serum concentration, QMG score changes or even reasonable drug dose. Then we searched several databases to predict the possible miRNA binding rs15524 sequence. Based on the prediction, dual-luciferase reporter assay and miRNA transfection were used to discover the mechanism of how SNP rs15524 controls tacrolimus serum concentration through influencing CYP3A5 expression.
RESULTS: In this article, we found multiple SNPs on CYP3A4, CYP3A5, FKBP1A, NFATC2 genes were predicted closely related to tacrolimus serum concentration, therapeutic effect which reflected by QMG score changes or even reasonable drug dose. After in silico miRNA selection, possible relationship between hsa-miR-500a and rs15524 was found. With the help of dual-luciferase reporter assay, wild-type rs15524 (T allele) was found having a stronger binding affinity for hsa-miR-500a. Higher expression of CYP3A5 may also led by lower hsa-miR-500a level.
CONCLUSIONS: SNP rs15524 may control CYP3A5 expression by affecting the binding affinity between CYP3A5 3'UTR and hsa-miR-500a. Wild type (T allele) 3'UTR of CYP3A5 has stronger binding affinity to hsa-miR-500a and cause lower CYP3A5 expression and higher tacrolimus serum concentration.

PMID: 31955224 [PubMed - as supplied by publisher]

Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 16;:109867

Authors: Marshe VS, Islam F, Maciukiewicz M, Fiori LM, Yerko V, Yang J, Turecki G, Foster JA, Kennedy SH, Blumberger DM, Karp JF, Kennedy JL, Mulsant BH, Reynolds CF, Lenze EJ, Müller DJ

Abstract
BACKGROUND: MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression.
METHODS: Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission.
RESULTS: At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10-4), particularly at weeks 10 and 12 (p < .05). In addition, individuals with higher miR-135a-5p expression reached remission faster than those with lower expression (HR = 0.6 [0.4, 0.9], FDR-corrected p = .055).
LIMITATIONS: Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response.
CONCLUSIONS: However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.

PMID: 31954757 [PubMed - as supplied by publisher]

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.

Neuron. 2020 Jan 07;:

Authors: Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A

Abstract
Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

PMID: 31954621 [PubMed - as supplied by publisher]

Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Value Health. 2020 Jan;23(1):61-73

Authors: Dong OM, Wheeler SB, Cruden G, Lee CR, Voora D, Dusetzina SB, Wiltshire T

Abstract
OBJECTIVE: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective.
METHODS: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.
RESULTS: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).
CONCLUSIONS: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.

PMID: 31952675 [PubMed - in process]

Pharmacogenomics at the center of precision medicine: challenges and perspective in an era of Big Data.

Pharmacogenomics. 2020 Jan 17;:

Authors: Primorac D, Bach-Rojecky L, Vađunec D, Juginović A, Žunić K, Matišić V, Skelin A, Arsov B, Boban L, Erceg D, Ivkošić IE, Molnar V, Ćatić J, Mikula I, Boban L, Primorac L, Esquivel B, Donaldson M

Abstract
Pharmacogenomics (PGx) is one of the core elements of personalized medicine. PGx information reduces the likelihood of adverse drug reactions and optimizes therapeutic efficacy. St Catherine Specialty Hospital in Zagreb/Zabok, Croatia has implemented a personalized patient approach using the RightMed® Comprehensive PGx panel of 25 pharmacogenes plus Facor V Leiden, Factor II and MTHFR genes, which is interpreted by a special counseling team to offer the best quality of care. With the advent of significant technological advances comes another challenge: how can we harness the data to inform clinically actionable measures and how can we use it to develop better predictive risk models? We propose to apply the principles artificial intelligence to develop a medication optimization platform to prevent, manage and treat different diseases.

PMID: 31950879 [PubMed - as supplied by publisher]

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

Pharmacogenomics J. 2020 Jan 17;:

Authors: King C, McKenna A, Farzan N, Vijverberg SJ, van der Schee MP, Maitland-van der Zee AH, Arianto L, Bisgaard H, BØnnelykke K, Berce V, Potočnik U, Repnik K, Carleton B, Daley D, Chew FT, Chiang WC, Sio YY, Cloutier MM, Den Dekker HT, Duijts L, de Jongste JC, Dijk FN, Koppelman GH, Flores C, Hernandez-Pacheco N, Pino-Yanes M, Mukhopadhyay S, Basu K, Bignell L, Tantisira KG, Turner S, Verhamme KM, Francis B, Pirmohamed M, Sinha I, Hawcutt DB

Abstract
A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

PMID: 31949291 [PubMed - as supplied by publisher]

SWEDEGENE-a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions.

Pharmacogenomics J. 2020 Jan 17;:

Authors: Hallberg P, Yue QY, Eliasson E, Melhus H, Ås J, Wadelius M

Abstract
SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

PMID: 31949290 [PubMed - as supplied by publisher]

Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.

BMC Psychiatry. 2020 Jan 16;20(1):24

Authors: Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J

Abstract
BACKGROUND: Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known.
METHODS: The first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data from all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for all major psychiatric disorders (neurological conditions and pain were omitted).
RESULTS: The present evidence in the emerging field of cannabinoid therapeutics in psychiatry is nascent, and thereby it is currently premature to recommend cannabinoid-based interventions. Isolated positive studies have, however, revealed tentative support for cannabinoids (namely cannabidiol; CBD) for reducing social anxiety; with mixed (mainly positive) evidence for adjunctive use in schizophrenia. Case studies suggest that medicinal cannabis may be beneficial for improving sleep and post-traumatic stress disorder, however evidence is currently weak. Preliminary research findings indicate no benefit for depression from high delta-9 tetrahydrocannabinol (THC) therapeutics, or for CBD in mania. One isolated study indicates some potential efficacy for an oral cannabinoid/terpene combination in ADHD. Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding.
CONCLUSIONS: There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.

PMID: 31948424 [PubMed - in process]

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.

Int J Cancer. 2019 10 01;145(7):1902-1912

Authors: Coussy F, de Koning L, Lavigne M, Bernard V, Ouine B, Boulai A, El Botty R, Dahmani A, Montaudon E, Assayag F, Morisset L, Huguet L, Sourd L, Painsec P, Callens C, Chateau-Joubert S, Servely JL, Larcher T, Reyes C, Girard E, Pierron G, Laurent C, Vacher S, Baulande S, Melaabi S, Vincent-Salomon A, Gentien D, Dieras V, Bieche I, Marangoni E

Abstract
Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

PMID: 30859564 [PubMed - indexed for MEDLINE]

Interaction between IGF2-PI3K axis and cancer-associated-fibroblasts promotes anal squamous carcinogenesis.

Int J Cancer. 2019 10 01;145(7):1852-1859

Authors: Cacheux W, Lièvre A, Richon S, Vacher S, El Alam E, Briaux A, El Botty R, Mariani P, Buecher B, Schnitzler A, Barbazan J, Roman-Roman S, Bièche I, Dangles-Marie V

Abstract
Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

PMID: 30714617 [PubMed - indexed for MEDLINE]

Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics.

Hum Genomics. 2020 Jan 15;14(1):4

Authors: Koromina M, Koutsilieri S, Patrinos GP

Abstract
BACKGROUND: Genome-wide association studies (GWAS) have significantly contributed to the association of many clinical conditions and phenotypic characteristics with genomic variants. The majority of these genomic findings have been deposited to the GWAS catalog. So far, findings uncovering associations of single nucleotide polymorphisms (SNPs) with treatment efficacy in mood disorders are encouraging, but not adequate.
METHODS: Statistical, genomic, and literature information was retrieved from EBI's GWAS catalog, while we also searched for potential clinical information/clinical guidelines in well-established pharmacogenomics databases regarding the assessed drug-SNP correlations of the present study.
RESULTS: Here, we provide an overview of significant genome-wide associations of SNPs with the response to commonly prescribed antipsychotics and antidepressants. Up to date, this is the first study providing novel insight in previously reported pharmacogenomics associations for antipsychotic/antidepressant treatment. We also show that although there are published CPIC guidelines for antidepressant agents, as well as the FDA labels include genome-based drug prescription information for both antipsychotic and antidepressant treatments, there are no specific clinical guidelines for the assessed drug-SNP correlations of this study.
CONCLUSIONS: Our present findings suggest that more effort should be implemented towards identifying GWA-significant antipsychotic and antidepressant pharmacogenomics correlations. Moreover, additional functional studies are required in order to characterise the potential role of the assessed SNPs as biomarkers for the response of patients to antipsychotic/antidepressant treatment.

PMID: 31941550 [PubMed - in process]