Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

Erectile dysfunction in cardiovascular patients: A prospective study of the eNOS gene T-786C, G894T, and INTRON variable number of the tandem repeat functional interaction.

BACKGROUND: Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular congestion. However, the mechanisms regulating endothelial dysfunction are not understood. OBJECTIVES: Exploring the functional impact of endothelial nitric oxide synthase genetic polymorphisms on erectile dysfunction and drug therapy optimization in high-risk cardiovascular disease patients. MATERIALS AND METHODS: Patients with erectile dysfunction symptoms and candidates for andrology therapy were included (n = 112). Clinical data and endothelial nitric oxide synthase rs1799983 (G894T) and rs2070744 (T-786C), genotyped by fluorescence polarization assays, were registered. The 27-bp variable number of the tandem repeat polymorphism in intron 4 (intron4b/a) was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Association analyses were run with the R-3.2.0 software. RESULTS: A significant association between endothelial nitric oxide synthase 786-TT (p = 0.005) and the aa/ac of intron 4 variable number of the tandem repeat (p = 0.02) with higher erectile dysfunction susceptibility was observed in cardiovascular disease patients (60 ± 9 years, 66% severe erectile dysfunction, 56% ejection fraction). After 3-months of phosphodiesterase type 5 inhibitors, erectile dysfunction (International Index of Erectile Function, 50 ± 16 scores, the International Index of Erectile Function-Erectile Function 21 ± 10 scores, p < 0.001) and sexual quality of life (modified Sexual Life Quality Questionnaire 55 ± 23 scores, p < 0.001) had significantly improved. The cardiovascular ejection fraction was influenced positively with better sexual quality of life (0.1941), and also in the endothelial nitric oxide synthase G894-T allele (p = 0.076) carriers, which could merit future analyses. Erectile dysfunction was present as the primary clinical manifestation in 62% of cases, with cardiovascular disease occurring concurrently. Only former smokers and obese subjects debuted prior to cardiovascular disease than to erectile dysfunction. CONCLUSIONS: Our study provides comprehensive insights into the functional interaction linking endothelial nitric oxide synthase gene polymorphisms, erectile function, and ejection fraction in high-risk cardiovascular disease patients. Future therapeutic strategies could target endothelial nitric oxide synthase activity by including lifestyle changes and epigenetic modulations.

Clinical prediction of opioid use disorder in chronic pain patients: a cohort-retrospective study with a pharmacogenetic approach.

BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N.=669). Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were analyzed. Socio-demographic, clinical and pharmacological outcomes were also registered. A logistic regression model was performed. The model performance and diagnostic accuracy were calculated. RESULTS: OPRM1-AA genotype and CYP2D6 poor and ultrarapid metabolizers together with three other potential predictors: 1) age; 2) work disability; 3) oral morphine equivalent daily dose (MEDD), were selected with a satisfactory diagnostic accuracy (sensitivity: 0.82 and specificity: 0.85), goodness of fit (P=0.87) and discrimination (0.89). Cases were ten-year younger with lower incomes, more sleep disturbances, benzodiazepines use, and history of substance use disorder in front of controls. CONCLUSIONS: Functional polymorphisms related to OPRM1 variant and CYP2D6 phenotypes may predict a higher OUD risk. Established risk factors such as young age, elevated MEDD and lower incomes were identified. A predictive model is expected to be implemented in clinical setting among CNCP patients under long-term opioids use.

Pharmacogenetic Guided Opioid Therapy Improves Chronic Pain Outcomes and Comorbid Mental Health: A Randomized, Double-Blind, Controlled Study.

Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, µ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1-5] vs. 1 [0-2], p < 0.01) and 42% opioid dose (35 [22-61] vs. 60 [40-80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58-0.82] vs. 0.51 [0.13-0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30-34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation.

CYP2D6 Genotype and Pharmacovigilance Impact on Autism Spectrum Disorder: A Naturalistic Study with Extreme Phenotype Analysis.

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants' electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2-4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.

Impact of CYP2D6 genotype on opioid use disorder deprescription: an observational prospective study in chronic pain with sex-differences.

Introduction: Opioid deprescription is the process of supervised tapering and safe withdrawal when a potentially inappropriate use is detected. This represents a challenge in chronic non-cancer pain (CNCP) patients who may respond differently to the procedure. Our aim was to analyze the potential impact of CYP2D6 phenotypes and sex on the clinical and safety outcomes during an opioid use disorder (OUD) tapering process. Methods: A prospective observational study was conducted on CNCP ambulatory OUD patients (cases, n = 138) who underwent a 6-month opioid dose reduction and discontinuation. Pain intensity, relief and quality of life (Visual analogue scale, VAS 0-100 mm), global activity (GAF, 0-100 scores), morphine equivalent daily dose (MEDD), analgesic drugs adverse events (AEs) and opioid withdrawal syndrome (OWS, 0-96 scores) were recorded at basal and final visits. Sex differences and CYP2D6 phenotypes (poor (PM), extensive (EM) and ultrarapid (UM) metabolizers based on CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, *41, 2D6*5, 2D6 × N, 2D6*4 × 2 gene variants) were analyzed. Results: Although CYP2D6-UM consumed three-times less basal MEDD [40 (20-123) mg/day, p = 0.04], they showed the highest number of AEs [7 (6-11), p = 0.02] and opioid withdrawal symptoms (46 ± 10 scores, p = 0.01) after deprescription. This was inversely correlated with their quality of life (r = -0.604, p < 0.001). Sex-differences were evidenced with a tendency to a lower analgesic tolerability in females and lower quality of life in men. Discussion: These data support the potential benefits of CYP2D6-guided opioid deprescription, in patients with CNCP when OUD is detected. Further studies are required to understand a sex/gender interaction.

Long-term deprescription in chronic pain and opioid use disorder patients: Pharmacogenetic and sex differences.

More than half of patients with opioid use disorder for chronic non-cancer pain (CNCP) reduced their dose through a progressive opioid withdrawal supported by a rotation to buprenorphine and/or tramadol. The aim of this research is to analyse the long-term effectiveness of opioid deprescription taking into account the impact of sex and pharmacogenetics on the inter-individual variability. A cross-sectional study was carried out from October 2019 to June 2020 on CNCP patients who had previously undergone an opioid deprescription (n = 119 patients). Demographic, clinical (pain, relief and adverse events) and therapeutic (analgesic use) outcomes were collected. Effectiveness (< 50 mg per day of morphine equivalent daily dose without any aberrant opioid use behaviour) and safety (number of side-effects) were analysed in relation to sex differences and pharmacogenetic markers impact [OPRM1 genotype (rs1799971) and CYP2D6 phenotypes]. Long-term opioid deprescription was achieved in 49 % of the patients with an increase in pain relief and a reduction of adverse events. CYP2D6 poor metabolizers showed the lowest long-term opioid doses. Here, women showed a higher degree of opioid deprescription, but increased use of tramadol and neuromodulators, as well as an increased number of adverse events. Long-term deprescription was successful in half of the cases. Understanding sex and gender interaction plus a genetic impact could help to design more individualized strategies for opioid deprescription.

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain.

Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.

Sex Differences in Oxycodone/Naloxone vs. Tapentadol in Chronic Non-Cancer Pain: An Observational Real-World Study.

Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other opioids (OPO) commonly prescribed for chronic non-cancer pain (CNCP). An observational and cross-sectional study was conducted on ambulatory CNCP patients (n = 571). Sociodemographic, clinical (pain intensity, relief, and quality of life), safety (adverse events (AEs), adverse drug reactions), hospital frequentations and pharmacological (morphine equivalent daily dose (MEDD)) variables were collected. Multiple linear regressions were carried out to assess the association between sex and outcomes. Sex differences were observed, with lower female tolerability and higher hospital frequentation, especially in the OXN group (OR AEs report = 2.8 [1.8−4.4], p < 0.001). Here, females showed higher hospital use (23% hospital admission, 30% prescription change, p < 0.05), requiring a higher MEDD (127 ± 103 mg/day, p < 0.05), compared to OXN men. Regardless of the opioid group, CNCP women were significantly older than men (three years), with significantly higher benzodiazepine use (OR = 1.6 [1.1−2.3]), more constipation (OR = 1.34 [0.93−1.90]) and headache (OR = 1.45 [0.99−2.13]) AEs, than men who were more likely to refer sexual dysfunction (OR = 2.77 [1.53−5.01]), and loss of libido (OR = 1.93 [1.22−3.04]). Sex-differences were found related to poorer female drug tolerability and higher hospital resources, even worst in OXN female users. Other differences related to older female ages and benzodiazepine prescription, need to be further analysed from a gender perspective.

Sex-Differences in Pain and Opioid Use Disorder Management: A Cross-Sectional Real-World Study.

(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids (n = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11-3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52-5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12-5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs.

CYP2D6 phenotypes and opioid metabolism: the path to personalized analgesia.

INTRODUCTION: Opioids play a fundamental role in chronic pain, especially considering when 1 of 5 Europeans adults, even more in older females, suffer from it. However, half of them do not reach an adequate pain relief. Could pharmacogenomics help to choose the most appropriate analgesic drug? AREAS COVERED: The objective of the present narrative review was to assess the influence of cytochrome P450 2D6 (CYP2D6) phenotypes on pain relief, analgesic tolerability, and potential opioid misuse. Until December 2021, a literature search was conducted through the MEDLINE, PubMed database, including papers from the last 10 years. CYP2D6 plays a major role in metabolism that directly impacts on opioid (tramadol, codeine, or oxycodone) concentration with differences between sexes, with a female trend toward poorer pain control. In fact, CYP2D6 gene variants are the most actionable to be translated into clinical practice according to regulatory drug agencies and international guidelines. EXPERT OPINION: CYP2D6 genotype can influence opioids' pharmacokinetics, effectiveness, side effects, and average opioid dose. This knowledge needs to be incorporated in pain management. Environmental factors, psychological together with genetic factors, under a sex perspective, must be considered when you are selecting the most personalized pain therapy for your patients.

Oxycodone/naloxone versus tapentadol in real-world chronic non-cancer pain management: an observational and pharmacogenetic study.

Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of OPRM1 (rs1799971, A118G) and COMT (rs4680, G472A) genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8-13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0-6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.

Food Protein-Induced Enterocolitis Syndrome in Adulthood: Clinical Characteristics, Prognosis, and Risk Factors.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) in adults is being increasingly recognized; however, little is known about its characteristics. OBJECTIVE: To describe the clinical characteristics, prognosis, and associated factors in adult FPIES. METHODS: A 10-year prospective study was conducted in the Allergy Section of Alicante General Hospital in adults diagnosed with FPIES. Detailed interviews with patients and oral food challenges (OFCs) were performed to confirm diagnosis or evaluate for tolerance. Comorbidities and possible risk factors were analyzed retrospectively through electronic medical records to assess their association with the disease. RESULTS: One hundred and seven adults with FPIES (93.5% female) were followed for a median of 6.2 years. Abdominal pain was the most common manifestation (96.3%), followed by diarrhea (72%) and vomiting (60.7%). Seafood (59.8%), egg (14%), and milk (10.3%) were the most common triggers, whereas 43.9% reacted to more than 1 food group. We performed 49 OFCs: 9 to confirm diagnosis and 40 to evaluate for tolerance. After a median 3.5 years, 16.8% achieved tolerance. Resolution was correlated inversely with duration of the disease (P = .04) and seafood (P = .023) but not with age of onset. The prevalence of gastrointestinal pathologies such as irritable bowel syndrome (IBS), eosinophilic esophagitis, inflammatory bowel disease, and celiac disease was higher than in the general population. A higher number of FPIES triggers were correlated with also having a diagnosis of IBS (P = .02). CONCLUSIONS: Although adult FPIES normally persists, some patients achieve tolerance. Adults with FPIES have a relatively high prevalence of gastrointestinal pathologies. The predominance of women may be related to hormonal factors. The clinical differences with pediatric FPIES warrant a revision of diagnostic criteria in adults.

Intestinal microbiota is modified in pediatric food protein-induced enterocolitis syndrome.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food hypersensitivity that affects the gastrointestinal system, especially in children, who often present with more severe clinical manifestations than adults do. Although its pathogenesis is poorly understood and biomarkers are still lacking, scientific evidence suggests that gut microbiota may play an important role in the development of FPIES. Objective: We aimed to compare the composition of gut microbiota in children with FPIES with that in age- and sex-matched healthy controls. Methods: We analyzed the gut microbiota profiles in fecal samples of 17 patients with FPIES (case patients) and 12 age-matched healthy children (controls) by tag sequencing of the 16S ribosomal RNA gene hypervariable V4-V5 regions. Subjects' sociodemographic, clinical, and food diary variables were described and compared between groups by using inferential statistical tests. Nonparametric linear discriminant analysis was performed for intestinal microbiota data. Results: Patients with confirmed cases FPIES (n = 17; average patient age, 7.5 ± 3.2 years) and controls without FPIES or any atopy (n = 12, average patient age, 6.9 ± 2.7 years) were included. Fish was the main FPIES-inducing allergen in 65% of the cases. The patients with FPIES showed higher proportions of Lachnospiraceae spp (P < .0286) and a lower proportion of Ruminococcaceae spp (P < .0066), Lactobacillaceae spp (P < .0075), and Leuconostocaceae spp (P < .0173) than the controls. Conclusions: Our data clearly show a different gut microbial signature in patients with FPIES, suggesting a new potential avenue for aiding the diagnosis and clinical management of FPIES. Larger studies are needed to confirm these results.

Therapeutic alliance impact on analgesic outcomes in a real-world clinical setting: An observational study.

A good therapeutic alliance is relevant for healthcare providers exposed to patients' suffering, especially since patients and physicians may understand the painful experience differently. Our aim was to explore the impact of therapeutic alliance on analgesic outcomes in a real-world interdisciplinary pain unit (PU). A cross-sectional observational study was conducted on outpatients (n = 69) using opioids on a long-term basis for the treatment of chronic non-cancer pain, where clinical pharmacologists and pharmacists advised patients about their opioid treatment. Responses to the patient-doctor relationship questionnaire (PDRQ), sociodemographic and clinical information (pain level, quality of life and hospital use) were collected, whereas pharmacology data (analgesic prescription, adverse events, and compliance) were obtained from electronic health records. Patients were predominantly middle-aged (75 % women, 72 % retired), experiencing moderate pain (VAS 40-70 mm) on average, and under a high morphine equianalgesic dosage (95 ± 88 mg per day, mainly tapentadol or fentanyl). Patients with better PDRQ outcomes, and therefore better therapeutic alliance, showed lower pain intensity than patients with worse PDRQ outcomes (pain intensity: high scores 60 ± 47 mm and medium scores 60 ± 45 mm vs. low scores 80 ± 75 mm, p < 0.01). Along with this, pain intensity was lower when patients affirmed that, thanks to the health-care providers, they "gained new insight", "felt better", or "felt content with their doctor's treatment". What´s more, patients who affirmed "I benefit from the treatment" experienced increased pain relief (benefit 40 ± 30 vs. non-benefit 19 ± 26 mm, p = 0.010) and improved quality of life (benefit 33 ± 25 vs. non-benefit 18 ± 16 mm, p = 0.031). However, there was a percentage of patients who did not fully understand the provided information, which is something to be taken into account to improve in clinical routine. Therapeutic alliance supported by pharmacist experts on pain management can be an effective strategy to improve analgesic outcomes. Further efforts are needed to improve communication strategies for pain management. Future directions of research should include the analysis of the role of the pharmacist in poly-professional consultations as related to the advice of patients about their medication, and the mutual trust with the patients.

The challenge of detecting adverse events in adults with autism spectrum disorder who have intellectual disability.

Adults with autism spectrum disorder (ASD) and associated intellectual disability (ID) take a high number of different psychotropic drugs simultaneously. Nowadays, little is known about this multidrug pattern efficacy and safety. The present study has endeavored to fill this gap creating a local pharmacovigilance system. A 36-month, retrospective and prospective, observational, and multicenter pharmacovigilance study was carried out in adults with ASD and ID (n = 83). Information regarding ongoing medications (polypharmacy: taking simultaneously >4 drugs; safety profile: adverse events' number, adverse drug reactions' number, and affected system; and observed-to-expected [O/E] ratio using the summary of product characteristics), and current diagnoses were recorded. A median of four ongoing medications per participant was registered, half of the sample was under polypharmacy regimen. Regarding all ongoing medications, 50% were antipsychotic drugs, and 47% of participants had >1 antipsychotic prescribed. In contrast, only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related either to nervous or metabolic systems, and almost a third were not previously described in the corresponding drug summary of products characteristics. Extrapyramidalism, gynecomastia, hypercholesterolemia, and urinary retention were some AEs that occurred more frequently than expected (O/E ratio > 6 times) according to our data. The highest O/E ratio scores (>120 times) were for hypercholesterolemia and rhabdomyolysis caused by valproic acid. According to the number of adverse events and adverse drug reactions reported in electronic health records locally and nationally by clinicians, we need to increase awareness about medications safety. LAY SUMMARY: A 36-month study in adults with autism, ID, and polypharmacy (>4 drugs) was done to investigate drug safety on everyone. A median of four medications per person was registered, half were antipsychotic drugs, and 47% of participants had >1 antipsychotic medication simultaneously. Only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related to nervous or metabolic systems and a third were not previously described in the drug information sheet.

Fluorescent in situ hybridization (FISH): A useful diagnostic tool for childhood conjunctival melanoma.

INTRODUCTION: Conjunctival melanoma is extremely rare in children and has low rates of resolution. Definitive histopathological diagnosis based exclusively on microscopic findings is sometimes difficult. Thus, early diagnosis and adequate treatment are essential to improve clinical outcomes. CLINICAL CASE: We present the first case in which the fluorescent in situ hybridization (FISH) diagnostic technique was applied to a 10-year-old boy initially suspected of having amelanotic nevi in his right eye. Based on the 65% of tumor cells with 11q13 (CCND1) copy number gain and 33% with 6p25 (RREB1) gain as measured by the FISH analysis, and on supporting histopathological findings, the diagnosis of conjunctival melanoma could be made. Following a larger re-excision, adjuvant therapy with Mitomycin C (MMC), cryotherapy and an amniotic membrane graft, the patient has remained disease-free during 9 years of long-term follow-up. CASE DISCUSSION: Every ophthalmologist should remember to consider and not forget the possibility of using FISH analyses during the differential diagnosis of any suspicious conjunctival lesions. Genetic techniques, such as FISH, have led to great advances in the classification of ambiguous lesions. Evidence-based guidelines for diagnosing conjunctival melanoma in the pediatric population are needed to determine the most appropriate strategy for this age group.

[Erectile dysfunction in patients with cardiovascular disease and the potential influence of genetic markers]. / Disfunción eréctil en pacientes con enfermedad cardiovascular y potencial influencia de marcadores genéticos.

INTRODUCTION: The association between erectile dysfunction (ED) and cardiovascular disease (CVD) is well known, the latter being an early independent risk factor that can appear up to 5 years before the onset of cardiovascular symptoms. The enzyme endothelial nitric oxide synthase (eNOS) could be implicated in its pathophysiology as an endogenous vasodilator. Our objective was to analyse the influence of variants of the eNOS gene, in the response to treatment of ED, in patients with CVD. METHODOLOGY: Observational, prospective study in patients with ED of the Cardiac Rehabilitation Programme. Demographic variables were collected (International Index of Erectile Function (IIEF), quality of sexual life (mSLQQ), anxiety and depression (HAD), along with cardiovascular risk factors (CVRF). Genetic analysis of polymorphisms T-786C, G894T of the eNOS gene was performed by RT-PCR with TaqMan probe, and the data were analysed using SPSS 25. RESULTS: Patients (n = 35, 60.8 ± 8.44 years) showed a median CVD (IQR 1-3) with severe ED (IIEF-EF of 9.4 ± 6.73 points) and a low perception of their quality of sexual life (-19.4 ± 8.37 points). At the final visit (n = 15), there were 71% responders to treatment with iPDE5, with a significant improvement in their ED (IIEF = 49.4 ± 17.29, IIEF-FE = 18.5 ± 9.60 scores) and of their quality of sexual life (7 ± 12 scores), with a higher percentage of responders among the native homozygous genotypes -786-TT and 864-TT. CONCLUSION: Variants of the NOS3 gene could influence the response to iPDE5. Full analysis of the patient sample will be required to confirm these preliminary results.

Personality and psychiatric disorders in chronic pain male affected by erectile dysfunction: prospective and observational study.

The prevalence of personality disorders (PDs) and sexual dysfunction in chronic pain patients is higher than in general population. Our main objective was to analyse the influence of PD in patients with erectile dysfunction and chronic non-cancer pain and their response to andrological treatment. One-hundred one patients were included along 30 months. Pain intensity, quality of life, sexual life quality, anxiety and depression were analysed together with opioid dose. Erectile functioning was measured with the International Index of Erectile Function (IIEF) and PDs with Millon Clinical Multiaxial Inventory (MCMI-III). The mean age was 57 ± 12 years old, with moderate to severe pain, 70% were sexually active and presented moderate to severe ED. PDs were very frequent (31%, cut-off 85 and 84% cut-off 75 scores) mostly anxiety, compulsive, though disorder, somatoform and narcissistic. Self-defeating feature presence was significantly correlated (r = -0.4, 95% CI = -0.605 to -0.145, p = 0.002) with a more severe baseline ED and narcissistic, and a better response to andrological treatment (p = 0.010, d = 1.082). Patients with dysthymia features required significantly higher opioid doses vs. control (238 vs. 102 mg/day, respectively). These findings underline the importance of diagnosing PDs to rigorously treat patients with chronic pain and ED.

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects.

BACKGROUND: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. OBJECTIVE: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters. METHODS: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. RESULTS: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. CONCLUSION: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.