Synergism interaction between genetic polymorphisms in drug metabolizing enzymes and NSAIDs on upper gastrointestinal haemorrhage: a multicenter case-control study.

BACKGROUND: Interindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH. MATERIALS AND METHODS: We conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin). RESULTS: We observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [ORaspirin(+),wild-type: 2.22 (95%CI: 0.69-7.17) vs. ORaspirin(+),genetic-variation: 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation. CONCLUSIONS: The joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption.KEY MESSAGESMulticenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin).There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects.Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs.

A multicenter case-control study of the effect of e-nos VNTR polymorphism on upper gastrointestinal hemorrhage in NSAID users.

Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case-control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): -1.35 (95% CI -5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: -2.68 (95% CI -6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype.

Pharmacotherapeutic management of Parkinson's disease inpatients: how about asking hospital pharmacists?

INTRODUCTION: Parkinson's disease (PD) is considered to be the fastest growing neurological disorder in the world. Patients with PD are hospitalised more frequently, have longer admissions and experience more complications during hospitalisation than age-matched control groups. The incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs are the most important risk factors for motor function deterioration during hospital admission, and have been associated with longer hospital stays and even increased mortality. Despite their crucial role in pharmacotherapy, little attention has been paid to the perspective of hospital pharmacists. The objective of this study was to identify key issues in the pharmacotherapeutic management of inpatients with PD by the implementation of a national Spanish survey specifically designed to analyse the perspective of hospital pharmacists. METHODS: An internet-based questionnaire covering the following areas was designed: hospital and participant characteristics, drug formulary, medication compliance and reconciliation, protocols and contraindicated drugs and areas for improvement. RESULTS: A total of 76 pharmacists from 59 hospitals answered the survey. Some weaknesses were identified in the availability of drugs: (1) pharmacy services closed at certain times (86.4%); (2) low variety of antiparkinsonian drugs (18.4% store >21 different drugs); (3) delay in antiparkinsonian drug administration if unavailable (>12 hours in 39.5% of cases); (4) lack of flexibility in administration times; (5) low availability of transdermal rotigotine and subcutaneous apomorphine (<50%). The participants ranked highly the designing of specific protocols for patients with PD and implementation of concrete actions to optimise PD inpatient pharmacotherapy. CONCLUSIONS: The participants detected some improvement opportunities and proposed realistic and applicable recommendations and strategies aiming to enhance the safety of patients with PD. Protocols for antiparkinsonian drug interchange, administration timing and nil by mouth status, medication reconciliation, and handling nausea/vomiting or psychotic symptoms are considered the main improvement areas.

Corrigendum: Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

[This corrects the article DOI: 10.3389/fphar.2020.00860.].

Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

Background: Despite the wide benefits of aspirin and its cost-effectiveness, aspirin prescriptions have been reduced due to idiosyncratic responses in susceptible individuals. Low-dose aspirin and single-nucleotide polymorphisms (SNPs) are independently associated with increased risk of gastrointestinal hemorrhage; however, to-date, no studies investigated the SNP-aspirin interaction effect on upper gastrointestinal hemorrhage (UGIH). Therefore, we aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH. Methods: A multicenter, full case-control study was conducted in patients exposed and unexposed to aspirin. Three hundred twenty-six cases diagnosed with UGIH were matched with 748 controls (1:3) by age, gender, health center, and recruitment date. Only adults of European origin were included. Participants were stratified by aspirin exposure and genotype [(Aspirin(-), wild-type), (Aspirin(+), wild-type), (Aspirin(+), genetic variation), (Aspirin(-), genetic variation)]. For each SNP, the Odds Ratio of UGIH and their 95% confidence intervals were estimated in each subgroup by using the generalized linear mixed models for dependent binomial variables. SNP-aspirin interaction effect was estimated through Relative Excess Risk due to Interaction (RERI) measures. Results: We observed two categories of SNPs that might modify the risk magnitude of UGIH in aspirin consumers. Seven SNPs (rs1387180 A > G, rs2238631 T > C, rs1799964 T > C, rs5050 T > C/T > G, rs689466 T > C, rs1799983 T > A/T > G, and rs7756935 C > A) were "positive modifiers" associated with an excess of risk from aspirin exposure and carrying that genetic variation (1.75 ≤ RERI ≤ 4.95). On the contrary, the following nine SNPs (rs2243086 G > T, rs1131882 G > A, rs4311994 C > T, rs10120688 G > A, rs4251961 T > C, rs3778355 G > C, rs1330344 C > T, rs5275 A > G/A > T, and rs3779647 C > T) were "negative modifiers" and associated with a reduced risk in aspirin users (-2.74 ≤ RERI ≤ -0.95). Conclusion: This preliminary study suggests that polymorphisms in genes involved in platelets activity, angiogenesis and inflammatory response might modify the risk of aspirin-related UGIH. Further studies with larger sample size and in different populations are needed to confirm our findings. If confirmed, this might have great impact on public health, thanks to aspirin's prophylactic properties in diseases of high incidence and severity.

Fractures Related to Tenofovir: A Case/Noncase Study in the European Pharmacovigilance Database.

BACKGROUND: There is no clear consensus on the relationship between tenofovir (TDF) and fracture risk because the studies published so far present contradictory findings. STUDY QUESTION: Our objective was to detect, from the European pharmacovigilance database (EudraVigilance), a signal of fracture risk during TDF exposure in patients infected with HIV. METHODS: Herein, we analyze all the cases of fractures suspected to be related to TDF recorded in EudraVigilance between 2001 and November 10, 2016. A case/noncase method was used to assess the association between fractures and TDF, calculating proportional reporting ratios (PRRs) and their 95% confidence intervals (CIs) as a measure of disproportionality. According to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, osteoporotic fractures are included in High Level Group Term (HLGT) "Fractures" and traumatic fractures in HLGT "Bone and joint injuries," so, we selected cases included in both HLGTs. The noncases used as controls were all the remaining adverse drug reaction reports recorded in EudraVigilance during the same period. RESULTS: There were 68,113 cases of fractures in the 4,776,472 reports recorded in EudraVigilance during the study period. TDF was involved in 181 cases. The median latency period until the appearance of fracture was 995 days. TDF was present as the only suspect drug in 140 cases. The PRR of TDF and fractures was 1.11 (95% CI, 0.96-1.28). Nevertheless, disproportionality was observed for some types of fractures: osteoporotic fractures (PRR 17.24; 95% CI, 9.90-30.01), bone fissure (PRR 16.60; 95% CI, 6.11-45.10), and pathological fracture (PRR 4.40; 95% CI, 2.77-7.00). CONCLUSIONS: Our findings do not show a disproportionality for fractures in patients treated with TDF, although disproportionality was found for some types of fractures, mainly osteoporotic fractures.

Síndrome de Kounis inducido por ranitidina / Kounis syndrome induced by ranitidine

No disponible

Effect of concomitant use of montelukast and efavirenz on neuropsychiatric adverse events.

OBJECTIVE: To report the case of an HIV patient who developed neuropsychiatric disturbances when montelukast was added to her therapy containing efavirenz. CASE SUMMARY: A 41-year-old woman with HIV infection had been on treatment with efavirenz, emtricitabine, and tenofovir disoproxil fumarate since 2007 with good tolerance. In November 2011, montelukast was started for asthma and shortly thereafter neuropsychiatric symptoms appeared, consisting of disturbed sleep, vivid dreams, irritability, confusion, and concentration difficulties. In January 2012, 2 months after the introduction of montelukast, she continued to report unbearable symptoms without any improvement; so, montelukast was withdrawn and the psychiatric symptoms completely disappeared. DISCUSSION: The combination of efavirenz and montelukast has not previously been associated with any pharmacokinetic interactions or worsening of neuropsychiatric symptoms. This case report indicates the possibility of adverse effects developing when the 2 drugs are used together. These symptoms might either be related to a drug-drug interaction or increased by the similar side effect profiles of the 2 drugs. The higher score on the Karch-Lasagna scale suggests that an adverse effect is the more likely explanation. We cannot, however, rule out a drug interaction, given that efavirenz inhibits the CYP 2C9, 2C19, and 3A4 isoenzymes and CYP 3A4, 2C9, and 2C8 are involved in the metabolism of montelukast. CONCLUSIONS: Considering that efavirenz is frequently used in antiretroviral therapy and that neuropsychiatric symptoms can limit its use, clinicians should consider the possibility of worsening of these symptoms, such as mood disorders and abnormal dreams, when montelukast is introduced.