Soluble Epoxide Hydrolase Inhibition for Ocular Diseases: Vision for the Future

Ocular diseases cause visual impairment and blindness, imposing a devastating impact on quality of life and a substantial societal economic burden. Many such diseases lack universally effective pharmacotherapies. Therefore, understanding the mediators involved in their pathophysiology is necessary for the development of therapeutic strategies. To this end, the hydrolase activity of soluble epoxide hydrolase (sEH) has been explored in the context of several eye diseases, due to its implications in vascular diseases through metabolism of bioactive epoxygenated fatty acids. In this mini-review, we discuss the mounting evidence associating sEH with ocular diseases and its therapeutic value as a target. Substantial data link sEH with the retinal and choroidal neovascularization underlying diseases such as wet age-related macular degeneration, retinopathy of prematurity, and proliferative diabetic retinopathy, although some conflicting results pose challenges for the synthesis of a common mechanism. sEH also shows therapeutic relevance in non-proliferative diabetic retinopathy and diabetic keratopathy, and sEH inhibition has been tested in a uveitis model. Various approaches have been implemented to assess sEH function in the eye, including expression analyses, genetic manipulation, pharmacological targeting of sEH, and modulation of certain lipid metabolites that are upstream and downstream of sEH. On balance, sEH inhibition shows considerable promise for treating multiple eye diseases. The possibility of local delivery of inhibitors makes the eye an appealing target for future sEH drug development initiatives

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision-making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale

Cypc19*17 Polymorphism as a Risk-factor for Nsaids-induced Ulcers

The new risk-factors for peptic ulcers induced by the use of nonsteroidal antiinflammatory drugs, such as polymorphism of different isoenzymes of cytochrome P450 were considered in the article. The aim of the research was to study different genetic polymorphism of several ferments CYP2C9 and CYP2C19 in inclination to NSAIDS-gastropathies by the way of estimation the risk of appearance of Helicobacter pylori (HP)-positive or Hp-negative NSAIDS- induced peptic ulcers, complicated or not with upper gastrointestinal bleeding.124 persons were examined (76 men, 48 women in the age of 56,2+/–9,1 years) with Hp-positive or Hp-negative NSAIDS-induced peptic ulcers, that were performed genotyping of isoferments of cytochrome system (CYP2C9, CYP2C19). Based on investigations of 5 different isoenzymes (CYP 2C9*2, CYP 2C9*3, CYP 2C19*2, CYP 2C19*3 and CYP 2C19*17). It was founded that peptic ulcers are strictly associated only with CYP 2C19*17-genotype, possibly due to its involvement in arachidonic acid metabolism and gastroprotection. Thus, polymorphism CYP 2C19*17 can be considered as one of the risk factors for NSAID-gastropathy though the future researches are needed

Studies on Regioselective Binding Mode of Steroid Molecules in Homology Modeled Cytochrome P450-2C11

In this study, we investigated the regioselective binding mode of steroid molecules and structure requirements for steroid molecules for 16[alpha]-hydroxylation by Cytochrome P450-2C11. Docking study by using the homology Cytochrome P450-2C11 indicated that 16[alpha]-hydroxylation is favored with steroidal molecules possessing the following components, 1) a bent A-B ring configuration (5[beta]-reduced), 2) C-3[alpha]-hydroxyl group, 3) C-17[beta]-acetyl group, and 4) methyl group at both the C-18 and C-19. These respective steroid components requirements such as A-B ring configuration and functional groups at C-3 and C-17 were defined as the inhibitory contribution factor. Overall results by rat CYP2C11 revealed that steroidal structure requirements resulted in causing an effective inhibition of [^3^H]progesterone 16[alpha]-hydroxylation by the adult male rat liver microsome. As far as docking of homology modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16[alpha]-H was between 4 to 6 Å and that the related angle was in the range of 180±45°

Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population

The present study was designed to investigate whether common single-nucleotide polymorphisms (SNP) of CYP2C gene subfamily such as CYP2C8 (rs7909236 and rs1934953), CYP2C9 (rs9332242), and CYP2C19 (rs4244285) are associated with susceptibility to EH in Russian populatio

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

Adverse reactions of amiodarone

Adverse drug reaction is defined by the World Health Organization as any response to a drug that is noxious and unintended and occurs at a dose normally used in man. Older people are at elevated risk of adverse drug reactions-because of changes in pharmacodynamics, concurrent use of multiple medications and the related drug interactions. However, adverse drug reactions are significantly underestimated in the elderly population that is also exposed to inappropriate drugs. Amiodarone is an antiarrhythmic drug used commonly for the treatment of atrial fibrillation and is increasingly prescribed in older people. While amiodarone is an efficient drug for rhythm control, it's a carrier of different adverse reactions, and pro and cons must be carefully evaluated before its use especially in older people

Pharmacokinetic interactions of pioglitazone

Pioglitazone is a thiazolidinedione compound used in the treatment of type 2 diabetes. It has been reported to be metabolised by multiple cytochrome P450 (CYP) enzymes, including CYP2C8, CYP2C9 and CYP3A4 in vitro. The aims of this work were to identify the CYP enzymes mainly responsible for the elimination of pioglitazone in order to evaluate its potential for in vivo drug interactions, and to investigate the effects of CYP2C8- and CYP3A4-inhibiting drugs (gemfibrozil, montelukast, zafirlukast and itraconazole) on the pharmacokinetics of pioglitazone in healthy volunteers. In addition, the effect of induction of CYP enzymes on the pharmacokinetics of pioglitazone in healthy volunteers was investigated, with rifampicin as a model inducer. Finally, the effect of pioglitazone on CYP2C8 and CYP3A enzyme activity was examined in healthy volunteers using repaglinide as a model substrate. Study I was conducted in vitro using pooled human liver microsomes (HLM) and human recombinant CYP isoforms. Studies II to V were randomised, placebo-controlled cross-over studies with 2-4 phases each. A total of 10-12 healthy volunteers participated in each study. Pretreatment with clinically relevant doses with the inhibitor or inducer was followed by a single dose of pioglitazone or repaglinide, whereafter blood and urine samples were collected for the determination of drug concentrations. In vitro, the elimination of pioglitazone (1 µM) by HLM was markedly inhibited, in particular by CYP2C8 inhibitors, but also by CYP3A4 inhibitors. Of the recombinant CYP isoforms, CYP2C8 metabolised pioglitazone markedly, and CYP3A4 also had a significant effect. All of the tested CYP2C8 inhibitors (montelukast, zafirlukast, trimethoprim and gemfibrozil) concentration-dependently inhibited pioglitazone metabolism in HLM. In humans, gemfibrozil raised the area under the plasma concentration-time curve (AUC) of pioglitazone 3.2-fold (P < 0.001) and prolonged its elimination half-life (t½) from 8.3 to 22.7 hours (P < 0.001), but had no significant effect on its peak concentration (Cmax) compared with placebo. Gemfibrozil also increased the excretion of pioglitazone into urine and reduced the ratios of the active metabolites M-IV and M-III to pioglitazone in plasma and urine. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. Rifampicin decreased the AUC of pioglitazone by 54% (P < 0.001) and shortened its dominant t½ from 4.9 to 2.3 hours (P < 0.001). No significant effect on Cmax was observed. Rifampicin also decreased the AUC of the metabolites M-IV and M-III, shortened their t½ and increased the ratios of the metabolite to pioglitazone in plasma and urine. Montelukast and zafirlukast did not affect the pharmacokinetics of pioglitazone. The pharmacokinetics of repaglinide remained unaffected by pioglitazone. These studies demonstrate the principal role of CYP2C8 in the metabolism of pioglitazone in humans. Gemfibrozil, an inhibitor of CYP2C8, increases and rifampicin, an inducer of CYP2C8 and other CYP enzymes, decreases the plasma concentrations of pioglitazone, which can necessitate blood glucose monitoring and adjustment of pioglitazone dosage. Montelukast and zafirlukast had no effects on the pharmacokinetics of pioglitazone, indicating that their inhibitory effect on CYP2C8 is negligible in vivo. Pioglitazone did not increase the plasma concentrations of repaglinide, indicating that its inhibitory effect on CYP2C8 and CYP3A4 is very weak in vivo.Diabeteslääke pioglitatsonin yhteisvaikutukset Aikuistyypin diabetesta sairastavat potilaat joutuvat usein käyttämään monia lääkkeitä samanaikaisesti ja ovat siten erityisen alttiita lääkeaineiden haitallisille yhteisvaikutuksille. Pioglitatsoni on uudehko tablettimuotoinen diabeteslääke, joka poistuu elimistöstä pääasiassa hajoamalla (metaboloitumalla) maksan sytokromi P450 (CYP) entsyymien välityksellä. Muut lääkkeet voivat estää (inhiboida) tai kiihdyttää (indusoida) näiden entsyymien kautta tapahtuvaa lääkeainemetaboliaa. Ennen tätä väitöstutkimusta pioglitatsonin yhteisvaikutuksista oli vain vähän julkaistua tutkimustietoa. Ensimmäisessä tutkimuksessa selvitettiin koeputkiolosuhteissa (in vitro -menetelmillä) pioglitatsonin metaboliaa eri CYP-entsyymien välityksellä sekä useiden CYP-estäjien vaikutusta pioglitatsonin metaboliaan. Siinä havaittiin pioglitatsonin metaboloituvan pääasiassa CYP2C8- ja jonkin verran myös CYP3A4-entsyymin välityksellä ja että pioglitatsonilla saattaisi olla merkittäviä yhteisvaikutuksia näitä entsyymejä estävien lääkkeiden kanssa. Kliinisissä lääketutkimuksissa (in vivo -tutkimukset) selvitettiin viiden eri lääkkeen vaikutusta pioglitatsonin pitoisuuksiin elimistössä. Lisäksi tutkittiin pioglitatsonin vaikutusta toisen diabeteslääkkeen, repaglinidin, pitoisuuksiin. Tutkimukset tehtiin terveillä vapaaehtoisilla koehenkilöillä käyttäen lumekontrolloitua vaihtovuoroista koeasetelmaa. Koehenkilöille annettiin tavanomaisina hoitoannoksina tutkimuslääkkeitä muutaman päivän ajan ja tämän jälkeen kerta-annoksena pioglitatsonia tai repaglinidia. Koehenkilöiltä kerättiin useita verinäytteitä, joista määritettiin lääkepitoisuudet herkillä massaspektrometrisillä menetelmillä. CYP2C8-entsyymiä estävä lipidilääke gemfibrotsiili keskimäärin yli kolminkertaisti pioglitatsonin pitoisuudet. Toisaalta CYP3A4-entsyymiä estävä sienilääke itrakonatsoli ei vaikuttanut pioglitatsonin pitoisuuksiin. Astmalääkkeet montelukasti ja tsafirlukasti (CYP2C8-estäjiä in vitro) eivät myöskään vaikuttaneet pioglitatsonin pitoisuuksiin, vaikka ne estivät hyvin voimakkaasti pioglitatsonin metaboliaa in vitro -tutkimuksissa. Rifampisiini-antibiootin aiheuttama CYP-entsyymien induktio pienensi pioglitatsonin pitoisuuksia keskimäärin yli 50 %. Pioglitatsoni ei vaikuttanut repaglinidin pitoisuuksiin (metaboloituu CYP2C8- ja CYP3A4-entsyymien välityksellä). Tehdyt havainnot ovat käytännön lääkehoidon kannalta merkityksellisiä. Gemfibrotsiilin tai muiden CYP2C8-entsyymiä estävien lääkkeiden yhteiskäyttö voi lisätä pioglitatsonin tehoa ja annosriippuvaisia haittavaikutuksia. Rifampisiinin tai muiden CYP2C8-entsyymiä indusoivien lääkkeiden aloittaminen pioglitatsonia käyttävälle potilaalle voi heikentää verensokeritasapainoa. Itrakonatsoli ei vaikuttanut pioglitatsonin pitoisuuksiin viitaten siihen, ettei CYP3A4-entsyymi ole tärkeä pioglitatsonin metaboliassa in vivo. Montelukasti ja tsafirlukasti eivät vaikuta normaaleilla hoitoannoksilla merkittävästi estävän CYP2C8-välitteistä lääkemetaboliaa. Pioglitatsoni ei myöskään itse vaikuta estävän CYP2C8- tai CYP3A4-välitteistä lääkemetaboliaa