Pharmacogenomics
Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments.
Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments.
J Clin Pharmacol. 2018 Oct;58 Suppl 10:S36-S47
Authors: Rieder M
Abstract
Adverse drug reactions (ADRs) are common and important complications of drug therapy for children. The risk for ADRs changes over childhood, as do the nature and types of ADRs. Importantly, the risk and nature of ADRs in children are markedly different from those of adults, and adult data cannot be relied on to guide safe drug therapy in children. There are groups of children, notably those with complex and chronic diseases, who are at substantial risk for ADRs. The evaluation of an undesired effect during therapy is ideally accomplished by an organized approach that is a skill that clinicians who care for children-especially those children at high risk for ADRs must have. Additionally, clinicians as well as drug regulatory agencies and industry need to be both vigilant and astute as well as aware that ADRs in children are often different in nature and frequency from those in adults. The increasing use of pharmacogenomics to guide drug dosing and the increasing number of biological agents will provide new sets of challenges to clinicians over the next decade.
PMID: 30248196 [PubMed - in process]
Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice.
Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice.
Biol Pharm Bull. 2018;41(5):707-712
Authors: Yi-Wen Z, Mei-Hua B, Xiao-Ya L, Yu C, Jing Y, Hong-Hao Z
Abstract
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as dietary supplement or therapeutic drug, while the effects of oridonin on CYP450 were still unclear. The pregnane X receptor (PXR) is an important regulatory factor for major drug metabolism enzyme CYPs, and it has been reported to have species-specific differences. Therefore, this study has employed more reliable models PXR-humanized mouse to investigate the influence of oridonin on PXR and downstream metabolism enzyme. Eight-week-old male PXR-humanized mice were treated with oridonin by orally (0, 25, 50, 100, 200 mg/kg) for 15 d. The effects of oridonin on major downstream CYPs of PXR were examined at both the mRNA and enzyme activity levels by RT-PCR and HPLC-MS/MS. In general, there was no significant toxic reaction in liver of PXR-humanized mice. The mRNA expression of CYPs and cytochrome P450 oxidoreductase (POR) were increased with oridonin treatment in a dose-dependent manner. CYP2c and CYP3a family catalytic activity were increased significantly in two higher doses groups. These results indicate that oridonin induced the expression and activation of CYP2c and CYP3a family, which might contribute to potential drug-drug interactions and appear to be a risk when co-administered with other clinical drugs.
PMID: 29709908 [PubMed - indexed for MEDLINE]
Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population.
Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population.
Int J Neurosci. 2018 Aug;128(8):705-714
Authors: Ajmi M, Boujaafar S, Zouari N, Amor D, Nasr A, Rejeb NB, Amor SB, Omezzine A, Benammou S, Bouslama A
Abstract
PURPOSE: We aimed in this study to investigate the association between the ATP-Binding Cassette sub-family B, member1 (ABCB1) polymorphisms: C1236T (rs1128503), G2677T (rs2032582) and C3435T (rs1045642), and the resistance to antiepileptic drugs (AEDs).
MATERIALS AND METHODS: The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping of ABCB1 polymorphisms was conducted on 153 Tunisian epileptic patients treated with AEDs.
RESULTS: Two genetic polymorphisms of the ABCB1 gene seemed to influence the response to AEDs. In fact, the G2677T T and the C3435T T alleles appeared to increase the risk of developing AEDs resistance (ORs* = 3.13; 95%CI = [1.16-8.98]; p = 0.024 and ORs* = 3.10; 95%CI = [1.15-8.37]; p = 0.025), respectively. However, the C1236T T allele did not seemed to influence the response to AEDs (ORs* = 1.14; 95%CI = [0.53-3.88]; p = 0.471). Haplotypic analysis indicated high-degree linkage disequilibrium of ABCB1 polymorphisms. Our results showed a synergic effect, in fact patients with the CTT and TTT haplotypes were more likely to be drug resistant than patients with the CGC haplotype, these associations remained significant even after adjustment for confounding parameters (ORs* = 2.68; 95%CI = [1.11-8.25]; p = 0.033 and ORs* = 3.76; 95%CI = [1.69-21.05]; p = 0.006, respectively).
CONCLUSION: The G2677T T and C3435T T alleles as well as the TT, CTT and TTT haplotypes seemed to be significantly associated with drug-resistance epilepsy in our population. Genetic predisposition, involved in this resistance, may contribute to the establishment of a personal optimized therapy for newly diagnosed epileptic patients.
PMID: 29198163 [PubMed - indexed for MEDLINE]
Barriers to medication adherence and links to cardiovascular disease risk factor control: the Framingham Heart Study.
Barriers to medication adherence and links to cardiovascular disease risk factor control: the Framingham Heart Study.
Intern Med J. 2018 04;48(4):414-421
Authors: Hennein R, Hwang SJ, Au R, Levy D, Muntner P, Fox CS, Ma J
Abstract
BACKGROUND: In the elderly, impaired cognition may weaken medication adherence and compromise treatment for cardiovascular disease (CVD).
AIM: We examined risk factors for medication adherence and the relationship between adherence and levels of CVD risk factors among older participants with hypertension, dyslipidaemia and diabetes in the Framingham Heart Study.
METHODS: The four-item Morisky Medication Adherence Scale was administered to 1559 participants, median age 70 years, 53% women. We created an adherence score, ranging from 0 to 4, with low adherence defined as a score ≥2. CVD risk factors were assessed using standard protocols. Cognition was measured using the Mini-Mental State Examination (MMSE) and depressive symptoms were measured using the Center for Epidemiologic Studies of Depression (CES-D) scale.
RESULTS: Among participants who self-reported taking antihypertensive, lipid-lowering and/or hyperglycaemic medication(s), 12% (n = 191) had low medication adherence. The risk of low adherence increased by 45% (95% confidence interval (CI): 25-68%, P < 0.001) per five-unit increase in CES-D score. In participants taking antihypertensive medication (n = 1017), low adherence was associated with higher mean diastolic blood pressure (73 mmHg, 95% CI: 71-75 vs 71 mmHg, 95% CI: 70-71; P = 0.04) after adjusting for covariates. Among participants taking lipid-lowering medication (n = 937), low adherence was associated with higher mean low-density lipoprotein cholesterol (92 mg/dL, 95% CI: 87-96 vs 86 mg/dL, 95% CI: 84-88; P = 0.03). Low adherence was not associated with fasting plasma glucose (P = 0.10) or haemoglobin A1c (P = 0.68) in the subgroup of participants (n = 192) taking hypoglycaemic medication.
CONCLUSIONS: Depressive symptoms might act as a barrier for medication adherence, which exacerbates CVD risk factors in older-aged adults.
PMID: 29193523 [PubMed - indexed for MEDLINE]
Future prospect of faecal microbiota transplantation as a potential therapy in asthma.
Future prospect of faecal microbiota transplantation as a potential therapy in asthma.
Allergol Immunopathol (Madr). 2018 May - Jun;46(3):307-309
Authors: Kang Y, Cai Y
Abstract
There is convincing evidence from both human and animal studies suggesting that the gut microbiota plays an important role in regulating immune responses associated with the development of asthma. Certain intestinal microbial strains have been demonstrated to suppress or impair immune responsiveness in asthma experimental models, suggesting that specific species among gut commensal microbiota may play either a morbific or phylactic role in the progression of asthma. Evidence to date suggests that the intestinal microbiota represent fertile targets for prevention or management of asthma. The faecal microbiota transplantation (FMT) is a rather straightforward therapy that manipulates the human gastrointestinal (GI) microbiota, by which a healthy donor microbiota is transferred into an existing but disturbed microbial ecosystem. The FMT may therefore represent a therapeutic approach for asthma treatment in the foreseeable future. At present, FMT therapy for asthma is very limited and should be actively studied. Considerable efforts are needed to increase our knowledge in the field of FMT therapy for asthma. In this review, we aimed to provide several insights into the development of FMT therapy for asthma.
PMID: 28803667 [PubMed - indexed for MEDLINE]
Mass isotopomer-guided decluttering of metabolomic data to visualize endogenous biomarkers of drug toxicity.
Mass isotopomer-guided decluttering of metabolomic data to visualize endogenous biomarkers of drug toxicity.
Biochem Pharmacol. 2018 Sep 19;:
Authors: Beyoğlu D, Zhou Y, Chen C, Idle JR
Abstract
Metabolomics offers the opportunity to uncover endogenous biomarkers that can lead to metabolic pathways and networks and that underpin drug toxicity mechanisms. A novel protocol is presented and discussed that is applicable to drugs which generate urinary metabolites when administered to mice sensitive to its toxicity. The protocol would not apply to drugs that are not metabolized or eliminated by a different route. Separate stable isotope-labeled and unlabeled drug administration to mice is made together with collection of urines from control animals. Untargeted mass spectrometry-based metabolomic analysis of these three urine groups is conducted in addition to principal components analysis (PCA). In the case of unlabeled acetaminophen and [acetyl-2H3]acetaminophen, each given at a hepatotoxic dose (400 mg/kg i.p.) to the sensitive mouse strain (wild-type 129), the PCA loadings plot showed a distribution of ions in the shape of a "fallen-Y" with the deuterated metabolites in one arm and the paired nondeuterated metabolites in the other arm of the fallen-Y. Ions corresponding to the endogenous toxicity biomarkers sat in the mouth of the fallen-Y. This protocol represents an innovative means to separate endogenous biomarkers from drug metabolites, thereby aiding the identification of biomarkers of drug toxicity. For acetaminophen, increased hepatic oxidative stress, mitochondrial damage, Ca2+ signaling, heme catabolism, and saturation of glucuronidation, together with decreased fatty acid β-oxidation and cellular energy dysregulation were all implied from the discovered biomarkers. The protocol can be applied to other drugs and may now be translated to clinical studies.
PMID: 30243960 [PubMed - as supplied by publisher]
[The serotonin syndrome: An updated literature review].
[The serotonin syndrome: An updated literature review].
Rev Med Interne. 2018 Sep 19;:
Authors: Jurek L, Nourredine M, Megarbane B, d'Amato T, Dorey JM, Rolland B
Abstract
The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome.
PMID: 30243558 [PubMed - as supplied by publisher]
MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion.
MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion.
Endocrine. 2018 Sep 21;:
Authors: Chen ZR, He FZ, Liu MZ, Hu JL, Xu H, Zhou HH, Zhang W
Abstract
PURPOSE: Diabetes mellitus is a major chronic disease and causes over one million deaths. KCNJ11 genetic polymorphisms influence the response of first-line oral antidiabetic agent sulfonylureas. Hsa-miR-4532 correlates with diabetic nephropathy and has a high abundance in urine. MIR4532 rs60452575 G>A variant changes the mature sequence of hsa-miR-4532. We studied whether the genetic polymorphisms of MIR4532 rs60452575 would influence KCNJ11 expression and sulfonylurea-stimulated insulin secretion or not.
METHODS: To estimate the influence that rs60452575 G>A variant has on the interaction of hsa-miR-4532 and KCNJ11, we constructed a pmirGLO vector containing 3' UTR of KCNJ11 and co-transfected it with wild-type and mutant hsa-miR-4532 mimics into HEK293 cells; and we overexpressed wild-type and mutant hsa-miR-4532 mimics into HEK293 cells and MIN6 cells to access its effects on KCNJ11 expression and response of sulfonylureas.
RESULTS: MIR4532 rs60452575 G>A variant appeared to disrupt the repression of KCNJ11 expression in both cell lines, and reduce the sulfonylurea-stimulated insulin secretion by breaking the binding of the hsa-miR-4532 to 3' UTR of KCNJ11 in MIN6 cells.
CONCLUSIONS: Our study indicates that MIR4532 rs60452575 variant influences KCNJ11 expression and sulfonylurea response. It might be a potential predictive factor of sulfonylureas therapy.
PMID: 30242599 [PubMed - as supplied by publisher]
Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.
Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.
Pharmacogenomics J. 2018 Sep 21;:
Authors: Tangamornsuksan W, Lohitnavy M
Abstract
Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.
PMID: 30242287 [PubMed - as supplied by publisher]
Konjaku flour reduces obesity in mice by modulating the composition of the gut microbiota.
Konjaku flour reduces obesity in mice by modulating the composition of the gut microbiota.
Int J Obes (Lond). 2018 Sep 21;:
Authors: Kang Y, Li Y, Du Y, Guo L, Chen M, Huang X, Yang F, Hong J, Kong X
Abstract
BACKGROUND: Changes in the intestinal flora composition is referred to as dysbiosis, which is related to obesity development, thus supporting the potential roles of nutrients acting on intestinal flora to exert salutary effects on energetic metabolism of host. Dietary fiber has been known to affect the composition of intestinal flora. The aim of the present study was to investigate the functional effects of konjac flour (KF) on obesity control in respect to improving inflammation, metabolism, and intestinal barrier function, and the possible association of the effects with intestinal flora composition changes.
METHODS: Mice (n = 30) were randomly divided into control group (n = 10), high-fat-diet (HFD) group (n = 10), and KF intervention group (n = 10), followed by feeding for 12 weeks and with adding a KF daily supplementation for the treatment group. Body weight, fat accumulation, inflammation, and energetic metabolism markers in multiple tissues and the gut microbiota of the mice were examined at the end of the experiment.
RESULTS: The KF supplementation significantly reduced the gains in weight, fat mass, as well as adipocyte size of HFD mice and lowered the serum TC, leptin (LEP), thiobarbituric acid-reacting substance (TBARS), IL-6, and lipopolysaccharide (LPS) levels in HFD mice. KF also upregulated the expression of intestinal mucosa protein gene Intection and tight junction ZO-1 in HFD mice, as well as upregulate the expression of energy metabolism genes PPARα and CPT-1 as well as the fat metabolism gene HLS in livers and fat tissues, and downregulate that of fat synthesis gene PPARγ (p < 0.05). The KF treatment increases the α-diversity and change the β-diversity of the intestinal microflora in HFD mice and boosted the abundances of some obesity-related beneficial microorganisms (such as Megasphaera elsdenii) in the intestinal microflora of HFD mice, while reduced those of harmful microorganisms (such as Alistipes, Alloprevotella, Bacteroides acidifaciens, and Parabacteroides goldsteinii). The abundance of Alistipes was positively correlated with weight, fat mass, serum TC, TG, LEP, IL-6, and LPS contents as well as PPARγ gene expression; while notably and negatively related to the expression of CPT-1 and HLS genes (p < 0.01). KF remarkably increased the abundance of Aerococcaceae, while reduced that of Alistipes finegoldii (p < 0.01).
CONCLUSIONS: Supplementation with KF achieves favorable effects on treating obesity, improving inflammatory response, metabolism, and intestinal barrier function, by regulating intestinal microfloral structure in HFD-fed mice.
PMID: 30242233 [PubMed - as supplied by publisher]
Biomarkers of dementia in obstructive sleep apnea.
Biomarkers of dementia in obstructive sleep apnea.
Sleep Med Rev. 2018 Aug 13;:
Authors: Baril AA, Carrier J, Lafrenière A, Warby S, Poirier J, Osorio RS, Ayas N, Dubé MP, Petit D, Gosselin N, Canadian Sleep and Circadian Network
Abstract
Epidemiologic and mechanistic evidence is increasingly supporting the notion that obstructive sleep apnea is a risk factor for dementia. Hence, the identification of patients at risk of cognitive decline due to obstructive sleep apnea may significantly improve preventive strategies and treatment decision-making. Cerebrospinal fluid and blood biomarkers obtained through genomic, proteomic and metabolomic approaches are improving the ability to predict incident dementia. Therefore, fluid biomarkers have the potential to predict vulnerability to neurodegeneration in individuals with obstructive sleep apnea, as well as deepen our understanding of pathophysiological processes linking obstructive sleep apnea and dementia. Many fluid biomarkers linked to Alzheimer's disease and vascular dementia show abnormal levels in individuals with obstructive sleep apnea, suggesting that these conditions share common underlying mechanisms, including amyloid and tau protein neuropathology, inflammation, oxidative stress, and metabolic disturbances. Markers of these processes include amyloid-β, tau proteins, inflammatory cytokines, acute-phase proteins, antioxydants and oxidized products, homocysteine and clusterin (apolipoprotein J). Thus, these biomarkers may have the ability to identify adults with obstructive sleep apnea at high risk of dementia and provide an opportunity for therapeutic intervention. Large cohort studies are necessary to establish a specific fluid biomarker panel linking obstructive sleep apnea to dementia risk.
PMID: 30241998 [PubMed - as supplied by publisher]
The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices.
The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices.
Int J Mol Sci. 2018 Sep 20;19(10):
Authors: Senthebane DA, Jonker T, Rowe A, Thomford NE, Munro D, Dandara C, Wonkam A, Govender D, Calder B, Soares NC, Blackburn JM, Parker MI, Dzobo K
Abstract
BACKGROUND: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments.
METHODS: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM; cancer cell-derived ECM; combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µM cisplatin, 3.5 µM 5-fluorouracil and 2.5 µM epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints.
RESULTS: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20⁻60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30⁻50%, and reduced colony formation and cancer cell migration.
CONCLUSION: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.
PMID: 30241395 [PubMed - in process]
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RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.
RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.
Front Physiol. 2018;9:1234
Authors: Lian X, Beer-Hammer S, König GM, Kostenis E, Nürnberg B, Gollasch M
Abstract
Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the Gi-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive. Methods: We used Gαi2- (Gnai2-/-) and Gαi3-deficient (Gnai3-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested. Results: Relaxin-2 (∼50% relaxation at 10-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2-/- mice, but not from Gnai3-/- mice. The effects were not affected by FR900359 (Gαq protein inhibitor) or PI-103 (PI3Kα inhibitor), but inhibited by TGX-221 (PI3Kβ inhibitor) or AS-252424 (PI3Kγ inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue. Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to Gi2-PI3K-eNOS pathway. Targeting vasodilatory Gi-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease.
PMID: 30233409 [PubMed]
The Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION): registry overview and protocol for a propensity score-matched study of opioid prescribing in patients with low back pain.
The Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION): registry overview and protocol for a propensity score-matched study of opioid prescribing in patients with low back pain.
J Pain Res. 2018;11:1751-1760
Authors: Licciardone JC, Gatchel RJ, Phillips N, Aryal S
Abstract
Background: Low back pain is the leading cause of disability worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as the first-line pharmacologic therapy for subacute or chronic low back pain, with opioids reserved for patients who fail on NSAIDs. CYP2D6, CYP2C9, and CYP2C19 genes have variants that place patients using analgesics at risk for adverse events. However, precision medicine based on pharmacogenetically informed prescribing is becoming more feasible as genotyping costs decline. This study aims to compare opioids vs NSAIDs in treating adults with subacute or chronic low back pain under the alternative models of usual care and precision medicine.
Methods: An observational cohort study within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) will be used to simulate a randomized controlled trial. Patients using opioids and NSAIDs will be optimally matched at baseline using propensity scores. A saliva sample will also be collected to determine patient genotypes for drug metabolism based on CYP2D6 (single-gene model) and CYP2D6, CYP2C9, and CYP2C19 (multigene model). Prescribing that is concordant with pharmacogenetically informed care under these models will be considered "low risk", whereas discordant prescribing will be considered "high risk". Primary outcomes will be assessed over 6 months using a Numerical Rating Scale for pain, the Roland-Morris Disability Questionnaire, and the Drug Adverse Events Index. Secondary outcomes will be assessed using quality-of-life measures. An estimated 600 patients will be enrolled to acquire at least 400 patients after attrition and allowing for unmatched patients. This will achieve a statistical power of at least 80% in detecting the effect sizes ranging from 0.35 (small-medium effect) to 0.69 (medium-large effect).
Discussion: This PRECISION Pain Research Registry study builds on the concepts espoused in the Precision Medicine Initiative and addresses long-term goals established by the National Institutes of Health by assessing how precision medicine may prevent and treat chronic pain.
PMID: 30233232 [PubMed]
Challenging obesity, diabetes, and addiction: the potential of lorcaserin extended release.
Challenging obesity, diabetes, and addiction: the potential of lorcaserin extended release.
Diabetes Metab Syndr Obes. 2018;11:469-478
Authors: Hurt RT, Mundi MS, Ebbert JO
Abstract
Obesity is a global epidemic that is a leading cause of preventable death. In addition to lifestyle modification, there are numerous obesity treatments for clinicians to consider, including medications. Lorcaserin immediate release/extended release (IR/XR) is a US Food and Drug Administration approved medication for overweight and obese patients to be used with lifestyle modifications. Lorcaserin is thought to reduce weight by targeting the serotonin (5HT2c) system to induce satiety. Lorcaserin IR has been shown to be effective in reducing weight in overweight (body mass index [BMI] > 27 kg/m2) and obese (BMI > 30 kg/m2) participants in three large Phase III trials. In addition, lorcaserin has been shown to reduce post-cessation weight gain and improved smoking cessation in a randomized placebo-controlled trial. A recent meta-analysis suggested in overweight diabetic patients lorcaserin may be added to first-line oral hypoglycemic medications to enhance reduction in glycated hemoglobin. Lorcaserin is generally well tolerated with the most common side effect being headache, which is typically self-limiting. Lorcaserin XR (once daily) was recently approved and has been shown to be bioequivalent to lorcaserin IR (twice daily) in a pivotal study. Lorcaserin XRs, main advantage over the IR formulation is the once daily dosing regimen, which likely would lead to improved adherence and thus improved clinical effectiveness. The present review will evaluate the lorcaserin clinical studies (obesity, diabetes, and addiction), XR bioequivalence studies, pharmacogenomics of the serotonin (5HT2c) system, and adherence data in once daily versus twice daily medications.
PMID: 30233224 [PubMed]
Pharmacogenetics of Antiretroviral Drug Response and Pharmacokinetic Variations in Indigenous South African Populations.
Pharmacogenetics of Antiretroviral Drug Response and Pharmacokinetic Variations in Indigenous South African Populations.
OMICS. 2018 Sep;22(9):589-597
Authors: O'Connell KS, Swart M, McGregor NW, Dandara C, Warnich L
Abstract
Interindividual and interethnic differences in response to antiretroviral drugs (ARVs) are influenced by genetic variation. The few genomic studies conducted among African-Americans and African ethnic groups do not reflect the extensive genetic diversity within African populations. ARVs are widely used in Africa. Therefore, genomic characterization of African populations is required before genotype-guided dosing becomes possible. The aim of this study was to determine and report on the frequency of genetic variants in genes implicated in metabolism and transport of ARVs in South African populations. The study comprised 48 self-reported South African Colored (SAC) and 296 self-reported Black African (BA) individuals. Allele and genotype frequency distributions for 93 variants contributing to metabolism and transport of ARVs were compared between groups, and other global populations. Fifty-three variants had significant differences in allele and genotype frequencies when comparing SAC and BA groups. Thirteen of these have strong clinical annotations, affecting efavirenz and tenofovir pharmacokinetics. This study provides a summary of the genetic variation within genes implicated in metabolism and transport of ARVs in indigenous South African populations. The observed differences between indigenous population groups, and between these groups and global populations, demonstrate that data generated from specific African populations cannot be used to infer genetic diversity within other populations on the continent. These results highlight the need for comprehensive characterization of genetic variation within indigenous African populations, and the clinical utility of these variants in ARV dosing for global precision medicine. Population pharmacogenetics is a nascent field of global health and warrants further research and education.
PMID: 30235109 [PubMed - in process]
The dawn of precision medicine in HIV: state of the art of pharmacotherapy.
The dawn of precision medicine in HIV: state of the art of pharmacotherapy.
Expert Opin Pharmacother. 2018 Sep 20;:1-15
Authors: Mu Y, Kodidela S, Wang Y, Kumar S, Cory TJ
Abstract
INTRODUCTION: Combination antiretroviral therapy (ART) reduces viral load to under the limit of detection, successfully decreasing HIV-related morbidity and mortality. Due to viral mutations, complex drug combinations and different patient response, there is an increasing demand for individualized treatment options for patients. Areas covered: This review first summarizes the pharmacokinetic and pharmacodynamic profile of clinical first-line drugs, which serves as guidance for antiretroviral precision medicine. Factors which have influential effects on drug efficacy and thus precision medicine are discussed: patients' pharmacogenetic information, virus mutations, comorbidities, and immune recovery. Furthermore, strategies to improve the application of precision medicine are discussed. Expert opinion: Precision medicine for ART requires comprehensive information on the drug, virus, and clinical data from the patients. The clinically available genetic tests are a good starting point. To better apply precision medicine, deeper knowledge of drug concentrations, HIV reservoirs, and efficacy associated genes, such as polymorphisms of drug transporters and metabolizing enzymes, are required. With advanced computer-based prediction systems which integrate more comprehensive information on pharmacokinetics, pharmacodynamics, pharmacogenomics, and the clinically relevant information of the patients, precision medicine will lead to better treatment choices and improved disease outcomes.
PMID: 30234392 [PubMed - as supplied by publisher]
Sleep quality in opioid-naive and opioid-dependent patientson methadone maintenance therapy in Malaysia.
Sleep quality in opioid-naive and opioid-dependent patientson methadone maintenance therapy in Malaysia.
Turk J Med Sci. 2016 Dec 20;46(6):1743-1748
Authors: Zahari Z, Inrahim MA, Tan SC, Mohamad N, Ismail R
Abstract
BACKGROUND/AIM: Sleep disturbances may contribute to poor treatment outcomes in opioid-dependent patients. The extent to which the sleep profiles of opioid-dependent patients differ from those of the general Malaysian population is not documented. This study compared opioid-naive subjects and opioid-dependent patients on methadone maintenance therapy (MMT) in terms of their sleep quality.
MATERIALS AND METHODS: Participants comprised Malay male opioid-naive subjects (n = 159) and opioid-dependent patients (n = 160) from MMT clinics in Kelantan, Malaysia, between March and October 2013. Sleep quality was evaluated using the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI).
RESULTS: The opioid-dependent patients exhibited higher global PSQI scores [adjusted mean (95% CI) = 5.46 (5.02, 5.90)] than the opioid-naive group [4.71 (4.26, 5.15)] [F (1, 313) = 4.77, P = 0.030].
CONCLUSION: This study confirmed the poorer sleep quality among opioid-dependent patients on MMT, as manifested by their higher global PSQI scores. The sleep complaints in this patient population are a factor to consider and, when necessary, sleep evaluation and treatment should be undertaken to improve MMT patients' quality of sleep and overall treatment outcome.
PMID: 28081321 [PubMed - indexed for MEDLINE]
NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model.
NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model.
EBioMedicine. 2017 Jul;21:3-4
Authors: Nadon NL, Strong R, Miller RA, Harrison DE
PMID: 27923560 [PubMed - indexed for MEDLINE]