A potential role for the CDH13/CDH15 gene in repeat revascularization after first percutaneous coronary intervention.

Pharmacogenomics. 2019 Dec 19;:

Authors: Xiang Q, Liu Z, Lu Y, Mao J, Chen S, Zhao X, Zhou S, Xie Q, Wang Z, Mu G, Jiang J, Gong Y, Cui Y

Abstract
Aim: Major drawbacks of percutaneous coronary intervention are the high occurrence of repeat revascularization due to restenosis and disease progression. The aim of this study was to find genetic indicators to predict the risk of repeat revascularization. Materials & methods: From April 2015 to June 2016, 143 patients with percutaneous coronary intervention with genetic test results were enrolled. SNPs were measured by OmniZhongHua-8, and the SNPs in pathways genes related to known stenosis-related processes from the KEGG, BioCarta and Gene Cards databases were selected for analysis. Results: Cell-extracellular matrix interactions were the pathways with the most significant SNP (CDH15 rs72819363) association with repeat revascularization. Compared with CDH13 rs11859453G carriers, the adjusted odds ratio for A carriers was 0.25 and 0.33 at 18 and 30 months. Conclusion: We demonstrated a potential role of the cell-extracellular matrix interactions pathway and the possible biomarker CDH13/CDH15 in the development of coronary repeat revascularization.

PMID: 31854260 [PubMed - as supplied by publisher]

Untangling the genetic basis of drug response.

Pharmacogenomics. 2019 Dec 19;:

Authors: Rohde PD, Kristensen TN

PMID: 31854253 [PubMed - as supplied by publisher]

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients.

Ther Adv Psychopharmacol. 2019;9:2045125319891386

Authors: Ansermot N, Bochatay M, Schläpfer J, Gholam M, Gonthier A, Conus P, Eap CB

Abstract
Background: Psychiatric patients are at risk of cardiovascular diseases, and many psychotropic drugs can prolong QTc interval. Requirements for electrocardiogram (ECG) monitoring have been set up in our psychiatric university hospital. The objective of this study was to determine the proportion of adult patients who had an ECG during their hospitalization, the prevalence of ECG abnormalities, the evolution of the QTc after admission, and the risk factors for QTc prolongation.
Methods: Retrospective analysis of ECGs and clinical data of all patients with a complete hospitalization in 2015. Assessment of the influence of covariates on QTc using linear mixed-effects models.
Results: At least one ECG (n = 600) was performed during 37.6% of the stays (n = 1198) and in 45.5% of the patients (n = 871). Among the patients with an ECG, 17.9% had significant ECG abnormalities, including 7.6% with a prolonged QTc. QTc measured at admission and during hospitalization did not change significantly (n = 46, 419.4 ± 29.7 ms, 417.2 ± 27.6 ms, p = 0.71). In the multivariate model (292 patients, 357 ECGs), the covariates significantly associated with the QTc were gender (+15.9 ms if female, p < 0.0001), age (+0.4 ms/year, p = 0.0001), triglyceride levels (+5.7 ms/mmol/l, p = 0.005), and drugs with known risk of torsades de pointes (+6.2 ms if ⩾1 drug, p = 0.028).
Conclusions: The prevalence of hospitalized psychiatric patients with an abnormal ECG indicates that ECGs should be performed systematically in this population. Prescription of psychotropic drugs should be done cautiously, particularly in patients with QTc prolongation risk factors.

PMID: 31853363 [PubMed]

Consumer Warning for Genetic Tests Claiming to Predict Response to Medications: Implications for Psychiatry.

Am J Psychiatry. 2019 05 01;176(5):412-413

Authors: Rosenblat JD, Goldberg JF, McIntyre RS

PMID: 31039635 [PubMed - indexed for MEDLINE]

Response to the Comments on "Determining Allele-Specific Protein Expression (ASPE) Using a Novel Quantitative Concatamer Proteomics Method".

J Proteome Res. 2019 03 01;18(3):1458-1459

Authors: Shi J, Wang X, Zhu H, Jiang H, Wang D, Nesvizhskii A, Zhu HJ

Abstract
Russell and colleagues deserve credit for being the first to use a QconCAT standard to simultaneously quantify both the wild-type and mutant peptides of a protein (i.e., CYP2B6) ( J. Proteome Res. 2013, 12 (12), 5934-5942. DOI: 10.1021/pr400279u). However, the rationale of their study was entirely different from ours ( J. Proteome Res. 2018, 17 (10), 3606-3612. DOI: 10.1021/acs.jproteome.8b00620). Their study focused on the quantification of individual drug-metabolizing enzymes and transporters, whereas ours developed a targeted proteomics method to determine the allele-specific protein expression (ASPE) of a gene and advocated the use of the ASPE imbalance as the phenotype for identifying cis-regulatory genetic variants of the gene. More importantly, the digestion enzyme trypsin interacts with three to four amino acid residues around scissile bonds, and certain residues, such as negatively charged amino acids, can significantly affect the digestion efficiency. The QconCAT standard reported in our study differs from conventional QconCAT standards such as that used by Russell et al. in that at least 15 native flanking amino acids were included to ensure accurate measurement of ASPE ratios.

PMID: 30616350 [PubMed - indexed for MEDLINE]

Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age- vs. Genotype-Related Differences.

Clin Pharmacol Ther. 2019 03;105(3):625-640

Authors: Dücker CM, Brockmöller J

Abstract
Older persons may particularly benefit from pharmacogenetic diagnostics, but there is little clinical evidence on that question. We quantitatively analyzed the effects of age and genotype in drugs with consensus on a therapeutically relevant impact of a genotype. Assuming additive effects of age and genotype, drugs may be classified in groups with different priorities to consider either age, or genotype, or both, in therapy. Particularly interesting were those studies specifically analyzing the age-by-genotype interaction.

PMID: 29498032 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells.

Cancer Manag Res. 2019;11:7231-7242

Authors: Deng JL, Zhang R, Zeng Y, Zhu YS, Wang G

Abstract
Background: In recent years, statins have been frequently investigated in neoplasms. However, the potential roles of statins on prostate cancer cells and the underlying mechanisms have not been fully elucidated. In current study, we explored the effect and molecular mechanism of statins on cell proliferation and apoptosis in prostate cancer cells.
Methods: Prostate cancer cell were treated with gradient doses of simvastatin and fluvastatin for 24-72 h. Cell proliferation was analyzed by using MTS assay and colony formation. Cell apoptosis was measured by Hoechst staining, flow cytometry and caspase-3 activity. Western blotting was used to evaluate the proteins levels.
Results: Both simvastatin and fluvastatin produced a dose- and time-dependent inhibition of cell viability and colony formation while a promotion of cell apoptosis as evident with increases in caspase-3 activity, cleaved-caspase-3, cleaved-caspase-8 and cleaved-PARP levels in PC3 cells. Similar statin effects were observed in DU145 prostate cancer cells. Furthermore, statins produced a time- and dose-dependent reduction of phosphorylated-AKT and phosphorylated-FOXO1 levels in PC3 cells, and pretreatment of cells with an AKT phosphorylation inhibitor, MK2206, potentiated statins' effect.
Conclusion: Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells, which may have a potential benefit in prostate cancer prevention and therapy.

PMID: 31839714 [PubMed]

Pharmacogenomics in medication-related osteonecrosis of the jaw: a systematic literature review.

Eur Rev Med Pharmacol Sci. 2019 Dec;23(23):10184-10194

Authors: Bastida-Lertxundi N, Leizaola-Cardesa IO, Hernando-Vázquez J, Muguerza-Iraola R, Aguilar-Salvatierra A, Gómez-Moreno G, Crettaz JS

Abstract
OBJECTIVE: Medication-related osteonecrosis of the jaw (ONJ) is an adverse, severe and debilitating effect, which although infrequent, affects patients with osteoporosis or neoplasm who take bisphosphonates, antiresorptive drugs, and/or antiangiogenic drugs. Its etiopathogenesis is unknown, although genetic causes have been postulated.
MATERIALS AND METHODS: This review analyzed articles published to date that have studied genetic factors associated with ONJ. Fifteen case-control studies were included, published between 2008 and 2018.
RESULTS: Five set out to determine genetic causes by means of genome-centered techniques, while ten do so by investigating gene-centered variants. Nine works found statistically significant associations between one or various single nucleotide polymorphisms (SNPs) and the appearance of ONJ. None of the studies coincided as to which genes present some association.
CONCLUSIONS: The review observed the moderate impact of genetic factors on the appearance of ONJ. It also showed the heterogeneity of the studies that have investigated ONJ to date. In future studies, involving international and interhospital collaboration will be necessary to recruit sample sizes of sufficient size, elaborate adequate study designs, obtain clear results, and advance our understanding of ONJ and make it possible to single out individual patients at risk.

PMID: 31841171 [PubMed - in process]

Transcriptomic analysis of patients with immune thrombocytopenia treated with eltrombopag.

Platelets. 2019 Dec 14;:1-8

Authors: Hernández-Sánchez JM, Bastida JM, Alonso-López D, Benito R, González-Porras JR, De Las Rivas J, Hernández Rivas JM, Rodríguez-Vicente AE

Abstract
In the last years, the use of thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has improved the management of immune thrombocytopenia (ITP). Moreover, eltrombopag is also active in patients with aplastic anemia and myelodysplastic syndrome. However, their mechanisms of action and signaling pathways still remain controversial. In order to gain insight into the mechanisms underlying eltrombopag therapy, a gene expression profile (GEP) analysis in patients treated with this drug was carried out. Fourteen patients with chronic ITP were studied by means of microarrays before and during eltrombopag treatment. Median age was 78 years (range, 35-87 years); median baseline platelet count was 14 × 109/L (range, 2-68 × 109/L). Ten patients responded to the therapy, two cases relapsed after an initial response and the remaining two were refractory to the therapy. Eltrombopag induced relevant changes in the hematopoiesis, platelet activation and degranulation, as well as in megakaryocyte differentiation, with overexpression of some transcription factors and the genes PPBP, ITGB3, ITGA2B, F13A1, F13A1, MYL9 and ITGA2B. In addition, GP1BA, PF4, ITGA2B, MYL9, HIST1H4H and HIST1H2BH, genes regulated by RUNX1 were also significantly enriched after eltrombopag therapy. Furthermore, in non-responder patients, an overexpression of Bcl-X gene and genes involved in erythropoiesis, such as SLC4A1 and SLC25A39, was also observed. To conclude, overexpression in genes involved in megakaryopoiesis, platelet adhesion, degranulation and aggregation was observed in patients treated with eltrombopag. Moreover, an important role regarding heme metabolism was also present in non-responder patients.

PMID: 31838946 [PubMed - as supplied by publisher]

Results of the CYP-GUIDES randomized controlled trial: Total cohort and primary endpoints.

Contemp Clin Trials. 2019 Dec 12;:105910

Authors: Ruaño G, Robinson S, Holford T, Mehendru R, Baker S, Tortora J, Goethe JW

Abstract
CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) is a randomized controlled trial (RCT) comparing 2 outcomes in hospitalized patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary outcome was the Re-Admission Rate (RAR) 30 days after discharge. The trial setting was the Institute of Living at Hartford Hospital. CYP2D6 genotyping was implemented to detect common polymorphisms resulting in an enzyme with sub-normal, normal or supra-normal function. The electronic medical record (EMR) was utilized to transmit clinically actionable drug prescribing guidance based on the patient's CYP2D6 genotype to the physician. The RCT recruited 1500 patients, genotyped CYP2D6 in 1459, and randomized 477 to standard therapy (Group S), for whom treatment-as-usual guidance was delivered without consideration of patient CYP2D6 genotype, and 982 to genetically-guided therapy (Group G) where CYP2D6-based treatment recommendations were provided via EMR to physicians. For inpatients in Group G whose CYP2D6 function was sub- or supra-normal, medications primarily metabolized by the CYP2D6 enzyme were proscribed. The RCT developed a database of potential benefit to the field. The genetic, pharmacologic and clinical information is being simultaneously published. Results did not reveal differences in LOS or RAR between Group G and Group S, but confounders may have obscured the effects of pharmacogenetic guidance. We present strategies to assess effects of pharmacogenetic guidance on the most vulnerable patients at either extreme of CYP2D6 function treated with multiple psychotropics.

PMID: 31838256 [PubMed - as supplied by publisher]

The influence of carboxylesterase 1 polymorphism and cannabidiol on the hepatic metabolism of heroin.

Chem Biol Interact. 2019 Dec 11;:108914

Authors: Qian Y, Gilliland TK, Markowitz JS

Abstract
Heroin (diamorphine) is a highly addictive opioid drug synthesized from morphine. The use of heroin and incidence of heroin associated overdose death has increased sharply in the US. Heroin is primarily metabolized via deacetylation (hydrolysis) forming the active metabolites 6-monoacetylmorphine (6-MAM) and morphine. A diminution in heroin hydrolysis is likely to cause higher drug effects and toxicities. In this study, we sought to determine the contribution of the major hepatic hydrolase carboxylesterase 1 (CES1) to heroin metabolism in the liver as well as the potential influence of one of its known genetic variants, G143E (rs71647871). Furthermore, given the potential therapeutic application of cannabidiol (CBD) for heroin addiction and the frequent co-abuse of cannabis and heroin, we also assessed the effects of CBD on heroin metabolism. In vitro systems containing human liver, wild-type CES1, and G143E CES1 S9 fractions were utilized in the assessment. The contribution of CES1 to the hydrolysis of heroin to 6-MAM was determined as 3.66%, and CES1 was unable to further catalyze 6-MAM under our assay conditions. The G143E variant showed a 3.2-fold lower intrinsic clearance of heroin as compared to the WT. CBD inhibited heroin and 6-MAM hydrolysis in a reversible manner, with IC50s of 14.7 and 12.1 μM, respectively. Our study results suggested only minor involvement of CES1 in heroin hydrolysis in the liver. Therefore, the G143E variant is unlikely to cause significant impact despite a much lower hydrolytic activity. CBD exhibited potent in vitro inhibition toward both heroin and 6-MAM hydrolysis, which may be of potential clinical relevance.

PMID: 31837295 [PubMed - as supplied by publisher]

Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury.

Endocrinology. 2019 Dec 14;:

Authors: Xie Y, Barbosa ACS, Xu M, Oberly PJ, Ren S, Gibbs RB, Poloyac SM, Song W, Fan J, Xie W

Abstract
Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. In this report, we showed that the expression of Est was markedly induced in the liver, but not in the lung of female mice subject to hemorrhagic shock and resuscitation (HS/R). Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the pulmonoprotective effect was estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue-specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.

PMID: 31837219 [PubMed - as supplied by publisher]

Vitamin D Supplementation Ameliorates Severity of Major Depressive Disorder.

J Mol Neurosci. 2019 Dec 13;:

Authors: Alghamdi S, Alsulami N, Khoja S, Alsufiani H, Tayeb HO, Tarazi FI

Abstract
Major depressive disorder is a serious neuropsychiatric disease that leads to significant impairment in social functioning and increased morbidity and mortality. Low vitamin D (25-OH D) levels have been hypothesized to contribute to the pathophysiology of MDD. To investigate the therapeutic role of vitamin D in MDD, we recruited 62 male and female patients diagnosed with MDD and randomized them into two groups: the first group (49 patients) received vitamin D supplementation as cholecalciferol vitamin D3 (50,000 I.U.) for 3 months, in addition to standard of care (SOC) which included pharmacological treatment and psychological support, and the second group (13 patients) received only SOC without vitamin D supplementation for 3 months. The Beck depression inventory (BDI) scale was used to assess the severity of MDD symptoms. Immunoassays were utilized to determine levels of serum vitamin D3 and serotonin in all patients. The results showed significant gender differences; female patients showed the most improvement in their depressive symptoms after 3-month vitamin D supplementation. Females with moderate, severe, and extreme depression had significantly lower BDI scores after vitamin D treatment (p < 0.05). Among males, only those diagnosed with severe depression showed significant improvement in their BDI scores (p < 0.05). Serum serotonin levels were significantly increased after vitamin D supplementation compared to baseline in both male and female patients. No significant changes in other biochemical parameters were detected between the two groups. These findings suggest that vitamin D supplementation may ameliorate symptoms of MDD, particularly in females, via a serotonin-dependent mechanism.

PMID: 31836995 [PubMed - as supplied by publisher]

Economic Burden of Depression and Associated Resource Use in Manitoba, Canada.

Can J Psychiatry. 2019 Dec 13;:706743719895342

Authors: Tanner JA, Hensel J, Davies PE, Brown LC, Dechairo BM, Mulsant BH

Abstract
OBJECTIVES: To characterize the health-care utilization and economic burden associated with depression in Manitoba, Canada.
METHODS: Patient-level data were retrieved from the Manitoba Centre for Health Policy administrative, clinical, and laboratory databases for the study period of January 1, 1996, through December 31, 2016. Patients were assigned to the depression cohort based on diagnoses recorded in hospitalizations and outpatient physician claims, as well as antidepressant prescription drug claims. A comparison cohort of nondepressed subjects, matched with replacement for age, gender, place of residence (urban vs. rural), and index date, was created. Demographics, comorbidities, intentional self-harm, mortality, health-care utilization, prescription drug utilization, and costs of health-care utilization and social services were compared between depressed patients and matched nondepressed patients, and incidence rate ratios and hazard ratios were reported.
RESULTS: There were 190,065 patients in the depression cohort and 378,177 patients in the nondepression cohort. Comorbidities were 43% more prevalent among depressed patients. Intentional self-harm, all-cause mortality, and suicide mortality were higher among patients with depression than the nondepression cohort. Health-care utilization-including hospitalizations, physician visits, physician-provided psychotherapy, and prescription drugs-was higher in the depression than the nondepression cohort. Mean health-care utilization costs were 3.5 times higher among depressed patients than nondepressed patients ($10,064 and $2,832, respectively). Similarly, mean social services costs were 3 times higher ($1,522 and $510, respectively). Overall, depression adds a total average cost of $8,244 (SD = $40,542) per person per year.
CONCLUSIONS: Depression contributes significantly to health burden and per patient costs in Manitoba, Canada. Extrapolation of the results to the entire Canadian health-care system projects an excess of $12 billion annually in health system spending.

PMID: 31835904 [PubMed - as supplied by publisher]

Mechanisms of resistance and predictive biomarkers of response to targeted therapies and immunotherapies in metastatic melanoma.

Curr Opin Oncol. 2019 Dec 10;:

Authors: Mourah S, Louveau B, Dumaz N

Abstract
PURPOSE OF REVIEW: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients.
RECENT FINDINGS: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients.
SUMMARY: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.

PMID: 31833956 [PubMed - as supplied by publisher]

Basic Concepts in Genetics and Pharmacogenomics for Pharmacists.

Drug Target Insights. 2019;13:1177392819886875

Authors: Orrico KB

Abstract
This basic review of genetic principles will aid pharmacists in preparing for their eventual role of translating gene-drug associations into clinical practice. Genes, which are stretches of deoxyribonucleic acid (DNA) contained on the 23 pairs of human chromosomes, determine the size and shape of every protein a living organism builds. Variation in pharmacogenes which encode for proteins central to drug action and toxicity serves as the basis of pharmacogenomics (PGx). Important online resources such as PharmGKB.org, cpicpgx.org, and PharmVar.org provide the clinician with curated and summarized PGx associations and clinical guidelines. As genetic testing becomes increasingly affordable and accessible, the time is now for pharmacists to embrace PGx-guided medication selection and dosing to personalize and improve the safety and efficacy of drug therapy.

PMID: 31832012 [PubMed]

Unveiling the guidance heterogeneity for genome-informed drug treatment interventions among regulatory bodies and research consortia.

Pharmacol Res. 2019 Dec 09;:104590

Authors: Koutsilieri S, Tzioufa F, Sismanoglou DC, Patrinos GP

Abstract
Pharmacogenomics and personalized medicine interventions hold promise to optimize drug treatment modalities and hence, improve the quality of life of the patients by minimizing the occurrence of adverse drug reactions and/or maximizing drug treatment efficacy. To this end, proper guidance for accurately prescribing the correct drug at the right dose is empowered by major regulatory bodies, namely the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and well-recognized research consortia, like the Clinical Pharmacogenetics Implementation Consortium (CPIC), that propose therapeutic recommendations after the thorough evaluation of the existing scientific evidence base. In this context, the consistency of these recommendations is crucial for smoothly integrating pharmacogenomics into the clinic. Here, we collected all of the important and clinically actionable pharmacogenomic information provided by the aforementioned renowned sources and documented it in order to assess potential similarities and, most importantly, differences. Our data show that the level of concordance regarding the guidance provided for the same drug-gene association pairs varies significantly, despite the fact that it all derives from a single evidence base. In particular, apart from the expected similarities in a number of association pairs, especially the ones related to cancer genomics, there are still major discrepancies that create confusion as to which guidance should be followed in order to properly inform drug prescribing. This regulatory deficiency calls for the fruitful engagement of the regulatory agencies involved with the contribution of other experts engaged in the field of pharmacogenomics in an effort to harmonize the existing arsenal of guidelines for genome-informed drug prescription. The achievement of harmonization would in turn expedite bringing personalized medicine closer to clinical fruition.

PMID: 31830522 [PubMed - as supplied by publisher]

Long-term efficacy of metformin in obese PCOS: longitudinal follow up of retrospective cohort.

Endocr Connect. 2019 Dec 01;:

Authors: Jensterle M, Kravos NA, Ferjan S, Goricar K, Dolzan V, Janez A

Abstract
OBJECTIVE: Long-term efficacy of metformin in polycystic ovarian syndrome (PCOS) apart from in those with impaired glucose tolerance or diabetes remains unproven. We aimed to evaluate the impact of metformin in overweight-obese patients with PCOS and normal baseline glycemic homeostasis.
METHODS: 10 year longitudinal follow up of retrospective cohort comprising of 159 patients with PCOS defined by Rotterdam criteria, BMI≥ 25kg/m2 and normal initial glucose homeostasis (age 28.4±6.4 years, BMI 34.9±6.6 kg/m2) that had been receiving metformin 1000 mg BID. Collection data contained 6085time-points including anthropometric, hormonal and metabolic parameters.
RESULTS: After the 1st year body mass(BM) decreased for 3,9±6.8kg (p<0.001) and remained stable during the following 3 years. Menstrual frequency (MF) increased for3.0±3.9 bleeds/year (p<0.001) after 1st year to over 11 bleeds/year in the following years. The total testosterone and androstenedione decreased for 15.4±47.9% and 11.3±46.4% within 1st year, with further decrease in total testosterone and androstenedione for 37.8±61.8 and 24.8±40.5% at the 5th year of the follow up. The total conversion rate to prediabetes and diabetes was extremely low throughout observation period. Less than 25% of patients continued with metformin for more than five years with further dropout to only 6% on metformin therapy at the 10th year of follow up.
CONCLUSIONS: Long-term metformin treatment of overweight-obese women with PCOS and normal baseline glycemic homeostasis resulted in reduction and stabilization of BM, improvements of MF and androgen profile and low conversion rate to diabetes.

PMID: 31829964 [PubMed - as supplied by publisher]