The PACIFIC ontology for heterogeneous data management in cardiology.

With the emergence of health data warehouses and major initiatives to collect and analyze multi-modal and multisource data, data organization becomes central. In the PACIFIC-PRESERVED (PhenomApping, ClassIFication, and Innovation for Cardiac Dysfunction - Heart Failure with PRESERVED LVEF Study, NCT04189029) study, a data driven research project aiming at redefining and profiling the Heart Failure with preserved Ejection Fraction (HFpEF), an ontology was developed by different data experts in cardiology to enable better data management in a complex study context (multisource, multiformat, multimodality, multipartners). The PACIFIC ontology provides a cardiac data management framework for the phenomapping of patients. It was built upon the BMS-LM (Biomedical Study -Lifecycle Management) core ontology and framework, proposed in a previous work to ensure data organization and provenance throughout the study lifecycle (specification, acquisition, analysis, publication). The BMS-LM design pattern was applied to the PACIFIC multisource variables. In addition, data was structured using a subset of MeSH headings for diseases, technical procedures, or biological processes, and using the Uberon ontology anatomical entities. A total of 1372 variables were organized and enriched with annotations and description from existing ontologies and taxonomies such as LOINC to enable later semantic interoperability. Both, data structuring using the BMS-LM framework, and its mapping with published standards, foster interoperability of multimodal cardiac phenomapping datasets.

Drug-induced osteoporosis/osteomalacia: analysis in the French and Spanish pharmacovigilance databases.

INTRODUCTION: Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia. PURPOSE: The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases. METHODS: Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded. RESULTS: A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis. CONCLUSION: Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.

Only full adherence to proton pump inhibitors protects against drug-induced upper gastrointestinal bleeding.

PURPOSE: The use of gastroprotective agents has allowed significant progress in the prevention of upper gastrointestinal bleeding (UGIB) associated with non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet agents. Nevertheless, some concerns remain regarding the gastroprotective dosage and treatment duration. Our aim was to study the effect of gastroprotective agents in UGIB induced by NSAIDs and single- or dual-antiplatelet therapy. METHODS: A multicenter case-control study was conducted including 577 cases diagnosed with UGIB and 1343 sex-, age-, and hospital-matched controls. To estimate exposure to NSAIDs and gastroprotective agents, consumption was calculated for the 4 weeks prior to hospital admission in terms of defined daily doses (DDDs). Risk groups for UGIB induced by NSAIDs and single- or dual-antiplatelet therapy were defined as a function of each drug dose, use of gastrointestine-damaging drugs, and risk factors for UGIB. Odds ratios (ORs) with 95% confidence intervals (CIs) were adjusted for single- (model 1) and dual- (model 2) antiplatelet therapy. RESULTS: Full adherence (> 0.80DDD) to proton pump inhibitors (PPIs) was the only gastroprotective therapy that significantly reduced the risk of UGIB, considering NSAID risk (OR: 0.53; 95% CI: 0.30-0.95) and dose (OR: 0.48; 95% CI: 0.27-0.87) with ORs adjusted for single-antiplatelet therapy (model 1) and NSAID risk (OR: 0.55; 95% CI: 0.31-0.98) and dose (OR: 0.49; 95% CI: 0.28-0.89) with ORs adjusted for dual-antiplatelet therapy (model 2). CONCLUSIONS: These results reinforce the recommendation of adding a PPI at effective doses (full adherence) to prevent UGIB induced by NSAIDs, or single- or dual-antiplatelet therapy.

Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis.

INTRODUCTION: It is currently admitted that adverse drug reactions (ADRs) account for a great burden of disease. Of particular concern are ADR-induced hospital admissions, particularly in the elderly; they receive most of the medications and they are the most prone to develop ADRs. Therefore, our aim was to carry out a study of ADR-induced hospital admissions focused on the elderly population. METHODS: For the purpose, a systematic review and meta-analysis was performed of those studies addressing ADR-induced hospital admissions in patients over 60 years of age. A computerized search of the literature was carried out in the main databases. The search spans from 1988 to 2015. A pooled prevalence figure was calculated with 95% CIs; heterogeneity was also explored. RESULTS: The final number of selected articles was 42; all of them were published between January 1988 and August 2015. The overall average percentage of hospital admissions was 8.7% (95% CI, 7.6-9.8%). NSAIDs are one of the medication classes more frequently related to these admissions (percentages range from 2.3 to 33.3%). Inappropriate medication as a risk factor was studied in nine studies, four found a statistically significant relationship between those medications and hospital admissions. CONCLUSIONS: Circa one in ten hospital admissions of older patients are due to ADRs. A great burden of disease is due to a few and identifiable medication classes; in most of the cases, the reactions are well known and probably preventable. A sense of purpose and determination is needed by health authorities to face this problem. Doctors, on their part, should be aware when prescribing some specific identifiable medications to these patients. KEY POINTS: 1. One in ten hospital admissions in older patients are due to ADRs; NSAIDs are the medications the most related with these admissions, followed by other common medications used in patients of this age, such as beta-blockers. 2. A great burden of disease is due to medications that are intended to cure or alleviate disease; this burden of disease is not only painful for the patients but also costly. 3. Identified risk factors are particular medication classes and polymedication. In most of the cases, reactions are probably preventable.

CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study.

OBJECTIVE: The aim of this study was to assess whether the CYP2C9*2 and/or *3 variants might modify the risk for NSAID-related upper gastrointestinal bleeding (UGIB) in NSAID users. PATIENTS AND METHODS: We conducted a multicenter, case-control study in which cases were patients aged more than 18 years with a diagnosis of UGIB, and controls were matched (1 : 3) by sex, age, date of admission, and hospital. Exposure was defined as the mean number of defined daily doses (DDDs) of NSAIDs metabolized by CYP2C9 in the week preceding the index date. Three DDD categories were defined (0, ≤ 0.5, and > 0.5). Exposure was constructed taking both NSAID use and CYP2C9 polymorphisms into account. Patients of non-European origin were excluded from the analysis. RESULTS: A total of 577 cases and 1343 controls were finally included in the analysis: 103 cases and 89 controls consumed NSAIDs metabolized by CYP2C9, and 88 cases and 177 controls were CYP2C9*3 carriers. The adjusted odds ratios (aORs) of UGIB associated with the CYP2C9*2 and wild-type alleles proved to be similar [OR=8.79 (4.50-17.17) and 10.15 (2.92-35.35), respectively] and lower than those of the CYP2C9*3 allele [aOR=18.07 (6.34-51.53)] for consumers taking more than 0.5 DDDs of NSAIDs metabolized by CYP2C9. Grouping genotypes into carriers and noncarriers of the CYP2C9*3 variant resulted in aORs of 16.92 (4.96-57.59) for carriers and 9.72 (4.55-20.76) for noncarriers, where DDDs were greater than 0.5. CONCLUSION: The presence of the CYP2C9*3 variant increases the risk for UGIB associated with NSAID for DDDs greater than 0.5. The presence of the CYP2C9*2 allele shows no such effect.

Emergency contraceptive pill safety profile. Comparison of the results of a follow-up study to those coming from spontaneous reporting.

BACKGROUND: The emergency contraceptive pill (ECP) containing levonorgestrel is dispensed without a prescription in Spain since 2009. An easy access could diminish unwanted pregnancies; however, there is a risk of misuse and, in any case, of developing some adverse events. The aim of the present study is to further learn the adverse effects of this ECP. METHODS: An ad hoc follow-up study was carried out in three community pharmacies in a city of Central Spain; the sample was composed of those women asking for the ECP; they were interviewed by telephone after at least a month since the last menses. We completed the safety profile obtained with that coming from spontaneous reporting in Spain. RESULTS: Out of 139 women surveyed, 113 developed any adverse event--two considered as severe; the most frequently reported events were menstrual disturbances, which accounted for 21% of all events. Through spontaneous reporting, 36 cases of whatever adverse events related to levonorgestrel as ECP were identified. Twenty-five cases were considered as severe. Both types of reaction and severity were significantly different in the follow-up study and in the spontaneous reporting. Some of the reactions identified, such as miscarriage, febrile neutropenia, and porphyria, are not included in the Summary of Product Characteristics. CONCLUSIONS: Levonorgestrel as an ECP is mostly safe. Attention should be paid to some severe events and particularly to those risk factors for them to appear. Combining spontaneous reporting with an ad hoc follow-up study, the whole safety profile of a given medication can be obtained.

Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems.

Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4-9.7)], France (ROR, 2.4 [95% CI, 1.5-3.7]), and Italy (ROR, 5.1 [95% CI, 1.7-14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

A European community pharmacy-based survey to investigate patterns of prescription fraud through identification of falsified prescriptions.

AIM: To identify prescription drugs involved in falsified prescriptions in community pharmacies in 6 European countries. METHODS: A cross-sectional survey among 2,105 community pharmacies in Belgium, France, Italy, the Netherlands, Spain and Sweden was carried out to collect all suspect prescription forms. For each reported drug, the number of reported falsified prescriptions per thousand inhabitants was estimated. A falsification ratio was calculated by dividing the number of reports by the number of defined daily doses per 1,000 inhabitants per day for this drug, computed from national sale or reimbursement data. RESULTS: On 862 prescription forms, benzodiazepines (zolpidem, bromazepam, alprazolam), buprenorphine (as an opioid maintenance drug) and tramadol were the most frequently reported. Depending on their level of use in each country, methylphenidate, morphine and flunitrazepam presented the highest falsification ratios, particularly in Spain, Belgium and France. CONCLUSIONS: Stimulants, opioids and some benzodiazepines were the most frequently reported drugs in this survey on falsified prescriptions, but differences between countries were observed.

Open-label evaluation of a novel skin brightening system containing 0.01% decapeptide-12 in combination with 20% buffered glycolic acid for the treatment of mild to moderate facial melasma.

Melasma is a cutaneous disorder that primarily affects females of Hispanic and Asian descent. Previous studies have shown that use of a brightening system comprised of 0.01% decapeptide-12 cream, an antioxidant cleanser, a 20% buffered glycolic acid lotion, and a broad spectrum SPF 30 sunscreen yields good clearance of mild-to-moderate melasma in Caucasian and Asian volunteers. The present open-label, prospective, and multicenter study sought to determine the tolerability and efficacy of the above-mentioned brightening system on mild-to-moderate melasma in 33 Hispanic females over 16 weeks. Clinical measures included self-assessment of tolerability, clinical grading, determination of Melasma Area and Severity Index (MASI) scores, and standardized clinical photography. Results showed that the system was well tolerated with no adverse events reported. Mean decreases of 36%, 46%, 54%, and 60% in MASI scores were observed at weeks 4, 8, 12, and 16, respectively, which were further corroborated by standardized photography showing visible reduction in the appearance of melasma. Results suggest that the brightening system consisting of 0.01% decapeptide-12 cream, an antioxidant cleanser, 20% buffered glycolic acid lotion, and broad spectrum SPF 30 sunscreen is safe and efficacious for the treatment of mild-to-moderate melasma in Hispanic females.

Prescription of oral antidiabetics in Mexico. A cross-sectional study.

In 2016 diabetes was declared an epidemic and a health emergency in Mexico. As the rationale of the treatment is to achieve target glycemia levels, the appropriateness of the medications used is important. The aim of this study is to learn the pattern of antidiabetic drug prescription and factors associated with inappropriate prescription in Mexico. A retrospective cross-sectional drug utilization study has been conducted. A randomly selected sample was carefully examined. Out of 3600 clinical records of patients diagnosed with type 2 diabetes mellitus (T2DM), 196 records were revised. As far as control is concerned, 36.7% had their glycemia values in the recommended range. A combination of different antidiabetics was the most common pattern observed (60.7%); the most frequent was that of the association of metformin with whatever oral antidiabetics. Prescriptions were considered as inappropriate in 149 cases (76.0%); younger age and lack of nutritional assessment was significantly related to inappropriate prescription. A trend to use more drugs for treating T2DM has been consistently observed. Despite using so many drugs, most of the patients are not controlled. Avoiding inappropriate prescription by following current guidelines may contribute to a better control and, in turn, decrease morbidity and mortality for this cause.

Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.

BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Trends in the consumption of attention deficit hyperactivity disorder medications in Castilla y León (Spain): changes in the consumption pattern following the introduction of extended release methylphenidate.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most diagnosed behavioural disorder in children and adolescents; prevalence has been estimated around 5%. Studies have shown an increase in the use of ADHD medications during the last years. The aim of the present study was to learn the pattern and the evolution of ADHD medication consumption in Castilla y León (Spain). METHOD: Consumption data for the period 1992-2009 were obtained from databases containing information upon consumption and cost of medications dispensed by pharmacies at the expense of the Spanish National Health System. The data were expressed in defined daily doses (DDDs) per 1000 inhabitants per day (DDD/1000 inhabitants/day). A model to forecast consumption was built. RESULTS: Attention deficit hyperactivity disorder medication consumption increased in Castilla y León from 0.1 DDD/1000 inhabitants/day in 1992 to 1.5 DDD/1000 inhabitants/day in 2009; expected consumption will reach 2.5 DDD/1000 inhabitants/day by 2013. The drugs accounting for this increase were mainly made up of methylphenidate preparations (1.4 DDD/1000 inhabitants/day in 2009). From 1992 to 1999, there was a slight reduction in methylphenidate use; following amphetamine withdrawal, the consumption of stimulants began to increase, and figures showed a sharp rise after marketing of extended-release formulations in 2003. CONCLUSIONS: There has been an enormous increase in ADHD medication consumption in Castilla y León in the last few years; increase rocketed when extended-release methylphenidate was marketed. A rapid increase in the consumption is a warning on possible overdiagnosis and inappropriate prescription.

Hepatic disorders associated with the use of Ivermectin for SARS-CoV-2 infection in adults: a pharmacovigilance study in VigiBase.

Aim: The aim of the present study was to review in VigiBase the reports of serious hepatic disorders associated with the use of ivermectin for COVID-19 in adults. Background: In the face of the global health emergency caused by SARS-CoV-2, ivermectin, among other drugs, has been repurposed in some Latin American countries to treat COVID-19. Studies are needed on the safety of ivermectin for this new indication. VigiBase is the WHO pharmacovigilance database that registers all individual case safety reports (ICSRs) from more than 130 countries. Methods: We extracted the ICSRs of men or women aged ≥ 18 years and dated between 1 January 2020 and 7 March 2021 which included an association with the use of ivermectin. Results: Of 1393 ICSRs associated with ivermectin, 60 (4.3%) were registered as "serious." Ivermectin had been used for COVID-19 in 25 of those cases. Among the latter, 6 experienced hepatic disorders (hepatitis, hepatocellular injury, cholestasis, increased alanine aminotransferase and/or aspartate aminotransferase levels, abnormal liver function tests). Conclusion: The safety of the use of ivermectin should be studied more exhaustively, especially as regards the possibility of hepatic disorders developing when the drug is used for COVID-19.

[Amoxicillin-induced cholestatic hepatitis]. / Hepatitis colestásica por amoxicilina.

Drug-induced hepatotoxicity is a challenge in daily clinical practice. One of the most frequent causes is antibiotics. However, amoxicillin-induced liver injury is uncommon. We report the case of an 87-year-old man who developed cholestatic hepatitis after ingesting amoxicillin 500 mg/8 hours for dental disease. A review of the literature on this topic is provided.

Association of CNR1 and INSIG2 polymorphisms with antipsychotics-induced weight gain: a prospective nested case-control study.

Weight gain is a frequent and severe adverse reaction in patients taking antipsychotics. The objective was to further investigate in a natural setting influential risk factors associated with clinically significant weight gain. An observational follow-up study was conducted. Patients when initiating treatment with whatever antipsychotic were included; a structured questionnaire was applied at baseline, 3 and 6 months later; a blood sample was obtained. In a nested case-control approach, patients with an increase ≥ 7% of their initial weight were considered as cases, the remaining, as controls. The results showed that, out of 185 patients, 137 completed the 6-month follow-up (cases, 38; controls, 99). Weight gain gradually and significantly increased in cases (baseline, 65.0 kg; 6 months, 74.0 kg) but not in controls (65.6 kg and 65.8 kg, respectively). Age (adjusted OR = 0.97, 95% CI = 0.96-0.99, p = 0.004), olanzapine (adjusted OR = 2.98, 95% CI = 1.13-7.80, p = 0.027) and quetiapine (adjusted OR = 0.25, 95% = 0.07-0.92, p = 0.037) significantly associated with weight gain. An association was also found for the CNR1 (rs1049353) and INSIG2 (rs7566605) polymorphisms. In conclusion, an increased risk of antipsychotics-induced weight gain was observed for younger age and olanzapine, and a relative lower risk for quetiapine. A potential role of CNR1 rs1049353 and INSIG2 rs7566605 polymorphisms is suggested.

Trends in the consumption of antidepressants in Castilla y León (Spain). Association between suicide rates and antidepressant drug consumption.

OBJECTIVE: To learn the evolution of antidepressant and lithium use in Castilla y León (Central Spain) and its relationship with suicide rates. METHODS: A search in the ECOM (Especialidades Consumo de Medicamentos) database of the Spanish Ministry of Health for antidepressants and lithium was carried out for the period 1992-2005. Defined daily doses (DDD) per 1000 inhabitants per day were obtained as consumption data. Population and suicide rates data come from the Spanish National Statistics Institute. RESULTS: Antidepressant consumption increased 7-fold, from 6.9 DDD per 1000 inhabitants per day in 1992 to 47.3 in 2005; the corresponding increase in cost was more than 10-fold. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption. Venlafaxine consumption multiplied by 2.2. The consumption of monoamine oxidase inhibitors (MAOIs) decreased after venlafaxine and mirtazapine were marketed. Lithium consumption increased by 76% during the period studied, but it plateaued in 2000. CONCLUSIONS: The consumption of antidepressants in Castilla y León has increased remarkably and the pattern has changed; there is an increase in the consumption of the new and more expensive antidepressants such as venlafaxine and escitalopram. No association was observed between suicide rates and antidepressant consumption.

A pharmacological perspective of chloroquine in SARS-CoV-2 infection: An old drug for the fight against a new coronavirus?

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria. Moreover, their antiviral properties have been previously studied, including against coronaviruses, where evidence of efficacy has been found. In the current race against time triggered by the COVID-19 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ. These could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low-molecular-weight heparin, aimed at preventing acute respiratory distress syndrome (ARDS)-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. This review also re-examines the real information provided by some of the published alarming reports, although concluding that cardiac toxicity should in any case be stringently monitored in patients receiving CQ/HCQ.

Drug-induced parkinsonism: Revisiting the epidemiology using the WHO pharmacovigilance database.

INTRODUCTION: Drug-Induced Parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease. Little is known about DIP epidemiology. Using VigiBase®, the objective of this study was to assess the main characteristics of DIP reporting around the world. METHODS: We described reports recorded in the WHO pharmacovigilance database, Vigibase® and classified as "Parkinsonism" between 2000 and 2017. Differences of reporting between geographical locations and characteristics of reports were investigated using disproportionality analysis with calculation of Reporting Odds Ratios (ROR) and its 95% confidence interval. RESULTS: Among the 9,009,107 reports recorded in VigiBase®, 4565 (0.05%) were DIP. Co reported terms were mainly "tremor" (n = 408, 8.9%), "gait disturbance" (n = 209, 4.6%) and "extrapyramidal disorders" (n = 180, 3.9%). DIP reports were significantly more frequent in men (ROR = 1.4; 95% CI 1.3-1.5) and in patients aged 75 and over (ROR = 2.12; 95% CI 1.98-2.26). Compared to all other continents, risk of reporting drug-induced parkinsonism was higher in Europe (ROR = 2.89; 95% CI 2.73-3.07), Africa (ROR = 1.81; 95% CI 1.46-2.25) and Oceania (ROR = 1.50; 95% CI 1.27-1.77). The risk was lower in Asia (ROR = 0.55; 95% CI 0.51-0.59) and America (ROR = 0.55 95% CI 0.51-0.59). The highest risk of DIP reporting was found with sulpiride and haloperidol followed by risperidone, aripiprazole, paliperidone, metoclopramide, olanzapine, quetiapine and clozapine. CONCLUSION: Risk of DIP reports was higher in men, in people aged 75 and over and in Europe. Main drugs involved are antipsychotics not only drugs from the first generation but also those from the second one.

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.