Preclinical mitigation of 5-HT2B agonism-related cardiac valvulopathy revisited.

Cardiac valvulopathy (Cardiac Valve Disease; CVD) associated with off-target activation of the 5-hydroxytryptamine (5-HT) 2B receptor has been well recognized, but is still poorly predicted during drug development. The regulatory guidance proposes the use of 5-HT2B binding data (i.e., Ki values) and free maximum therapeutic exposure (Cmax) to calculate safety margins as a threshold of detection (>10) for eliminating the risk of drug-induced cardiac valvulopathy. In this paper, we provide additional recommendations for preclinical prediction of CVD risk based on clinical pharmacodynamic and pharmacokinetic data obtained from drugs with or without 5-HT2B receptor activation. Our investigations showed that 5-HT2B agonist affinity of molecules tested in an in vitro 5-HT2B cell-based functional assay, placed in perspective to their sustained plasma exposure (AUCs) and not to their peak plasma exposure, Cmax (i.e., maximum therapeutic exposure) provide a solid basis for interpreting 5-HT2B data, for calculating safety margins and then, accurately differentiate drugs associated with a clinical risk of CVD from those which are not (despite having some agonist 5-HT2B activity). In addition, we discuss the risk of multi-organ fibrosis linked to 5-HT2B receptor activation, often underestimated, however well reported in FAERS for 5-HT2B agonists. We believe that our recommendations have the potential to mitigate the risk for the clinical development of CVD and fibrosis.

Use of methylphenidate and reporting of valvular heart disease: Global pharmacovigilance analysis in children and adults.

INTRODUCTION: Methylphenidate (MPH) is a common treatment of attention-deficit/hyperactivity disorder (ADHD). Concern has been raised regarding its cardiovascular safety, partly in relation with its micromolar affinity for the 5-HT2B receptor, whose activation may result in valvular heart disease (VHD). METHODS: To explore the association between the use of MPH and VHD reporting, we performed a disproportionality analysis within the WHO global safety database (VigiBase) using data, since inception until March 6th 2024, from: (i) the full database and (ii) different age groups (children/adolescents 6-17 years; adults 18-64 years). To avoid competition bias, safety reports with amphetamine-like appetite suppressants were excluded. Disproportionality was expressed using reporting odds-ratio (ROR) and its 95% confidence interval (CI). RESULTS: Of 29 129 spontaneous reports with MPH, 23 VHD cases (7.9 per 10 000 reports) were identified, including 13 adults and 10 children. Most cases concerned injury on the mitral valve. A disproportionate reporting was observed overall (ROR 1.6, 95% CI 1.1-2.4). Analysis according to age group found that disproportionality in VHD reporting was found in adults only (ROR 2.7, 95% CI 1.6-4.7) but not in children/adolescents (ROR 1.7, 95% CI 0.9-3.2). Furthermore, amongst MPH users only, VHD reporting was higher in adults compared to children (ROR 2.7, 95% CI 1.2-6.3). CONCLUSION: VHD reporting appears rare with MPH compared to other adverse events and is increased in adults only. Our findings support a potential safety signal of VHD in adults exposed to MPH. A risk in that population cannot be excluded and requires further assessment.

Cumulative incidence of cardiac surgery associated with exposure to benfluorex: A retrospective analysis based on compensation claims data.

Data on retrospective compensation claims for injuries caused by pharmaceutical drugs are prone to selection and reporting biases. Nevertheless, this case study of the antidiabetic drug benfluorex shows that such data can be used to estimate the cumulative incidence of drug-related injury, and to provide insights into its epidemiology. To this end, we develop a modelling framework for under-reporting of retrospective claims for compensation arising from drug damage. The model involves a longitudinal component related to attrition of cases over time, and a cross-sectional component related to incomplete reporting. We apply this model to cardiac valve surgery necessitated by exposure to benfluorex. Benfluorex was marketed in France between 1976 and 2009, when it was withdrawn because it caused valvular heart disease. A scandal erupted in 2010 over the scale of the damage caused by the drug. Since then, no further estimates of cumulative incidence have been published, though thousands of claims for compensation have been processed. The analysis combines compensation claims data and sociological survey data on benfluorex users, together with data on benfluorex sales and duration of treatment. We find a threshold of toxicity at about 6 months' exposure, and that at least 1690 individuals (95% CI 1290 to 2320) needed heart surgery to replace or repair valves damaged by exposure to benfluorex in France: a cumulative incidence of 3.68 per 10,000 (95% CI 2.68 to 5.34) benfluorex users or 3.22 per 10,000 (95% CI 2.48 to 4.39) person-years at risk above the exposure threshold. While these findings are tentative, they are consistent with those obtained previously using very different methods.

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease.

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.

Long-term Cardiovascular Adverse Events Induced by Fluoroquinolones: A Retrospective Case-control Study.

ABSTRACT: A correlation is already established between fluoroquinolones (FQs) use and cardiovascular events (CVEs), such as QT prolongation; however, serious events such as aortic aneurysm and valve regurgitation have also been reported with FQs. Several unstudied factors could contribute to the development of different CVEs that were not previously evaluated with FQ therapy. Therefore, we aimed to assess the incidence of different serious CVEs after completion of FQ therapy and potential associating factors. This was a retrospective case-control study of inpatients who received ciprofloxacin, levofloxacin, or moxifloxacin for ≥3 days. Patients' echocardiograms were evaluated for the development of aortic or valvular disease or worsening of an existing condition after completion of therapy. Of 373 included patients, 83 developed new valvular disease or worsening of an existing disease, where tricuspid valve regurgitation was the most common CVE (50/83; 60.2%), followed by mitral valve diseases (48/83; 57.8%). Aortic valve regurgitation occurred more commonly with moxifloxacin compared with ciprofloxacin and levofloxacin (17.8% vs. 6.7% and 10.7%, respectively; P = 0.01). Median time to CVE detection ranged 93-166 days for all FQs. The receipt of moxifloxacin and elevated baseline QT interval were associated with an increased CVEs risk (adjusted odds ratio 3.26; 95% confidence interval, 1.31-8.11 and adjusted odds ratio 1.02; 95% confidence interval, 1.00-1.04, respectively). Other factors did not show such association. The lack of association of different factors with the occurrence of CVEs indicates that all patients receiving FQ therapy, especially moxifloxacin, should be monitored during the first-year after therapy. Alternatively, other antibiotics with a better safety profile may be considered.

Cardiac valvular surgery and history of anorectic drug intake: A retrospective study of a large population of benfluorex-exposed patients.

BACKGROUND: Anorectic drugs are overlooked as a cause of valvular heart disease (VHD). AIM: To describe the characteristics of a large population of patients with severe VHD who underwent cardiac surgery and had a history of benfluorex intake. METHODS: Retrospective observational and cross-sectional study of patients from a large French database (Office National d'Indemnisation des Accidents Médicaux). Clinical, echocardiographic, surgical and pathology findings were comprehensively collected from medical files. RESULTS: From a chart review of 9584 subjects, 1031 patients with VHD underwent cardiac surgery; 453 surgical patients were excluded because of VHD obviously unrelated to benfluorex exposure, six because of missing data and eight declined to participate. The final study population comprised 564 patients who had surgery between 1987 and 2019. Median age was 58 (interquartile range 50-65) years; 85% were female. Median duration of preoperative benfluorex exposure was 5.8 (3.3-10) years. Most patients had aortic and mitral valve disease. Pure or predominant aortic and/or mitral regurgitation were found in 84% of patients (n=471), and aortic or mitral stenosis (pure or combined with regurgitation) in 12% (n=67) and 15% (n=84), respectively. Overall, 403 aortic, 402 mitral and 64 tricuspid valve surgical procedures were collected. Aortic and mitral valves were found to be thickened, rigid and/or restrictive in most cases; restrictive tricuspid valve disease was seldom documented. Pathology was available in half of the population (276 patients); valvular fibrosis suggestive of drug-induced VHD was found in 222 patients, including 146 with expert examination. Mixed VHD aetiologies were discussed in 107 patients, including 54 with available pathology. CONCLUSIONS: Drug-induced VHD features are miscellaneous, including well-known restrictive valvular regurgitation, but also stenosis or combined regurgitation and stenosis. Besides a history of drug taking, thorough echocardiography and comprehensive surgical reports, pathology is key in the diagnostic procedure.

Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments.

OBJECTIVE: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. METHODS: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. RESULTS: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. SIGNIFICANCE/INTERPRETATION: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.

Incidence of heart valve disease in women treated with the ergot-derived dopamine agonist bromocriptine.

BACKGROUND: Ergot-derived dopamine agonists are thought to induce fibrotic changes in cardiac valve leaflets. We sought to determine the incidence of heart valve disease in women treated with bromocriptine compared with age and sex matched controls from the background population. METHODS: In nationwide Danish registries we identified female patients treated with bromocriptine in the period 1995-2018. Patients were included at date of second redeemed prescription and were matched 1:5 with controls from the background population based on age, sex and year of inclusion by use of incidence density sampling. The outcomes were hospital admission for or outpatient diagnosis of heart valve disease, and death as competing risk. Incidence rates, cumulative incidence curves, and adjusted cox-proportional hazard models adjusted for cardiovascular risk factors were used to assess outcomes in bromocriptine users versus controls. RESULTS: A total of 3035 female bromocriptine users and 15,175 matched controls were included. Median age at inclusion was 32 years (Q1-Q3, 28-37 years). Both bromocriptine users and controls had few comorbidities and low use of concomitant pharmacotherapy. Within 10 years of follow-up, 11 patients (0.34%, 95% CI 0.13-0.55%) and 44 controls (0.29%, 95% CI 0.20-0.37) met the primary endpoint of heart valve disease, p = 0.63. The adjusted cox regression analysis yielded a hazard ratio of 0.96 (95% confidence interval (CI) 0.55-1.69, p = 0.89). CONCLUSIONS: Treatment initiation with ergot-derived dopamine agonist bromocriptine in younger women with few comorbidities, was associated with a low absolute long-term risk of heart valve disease, not significantly different from the risk in age and sex matched population controls. Thus, indicating a low clinical yield of pre-treatment echocardiographic screening in this patient population in accordance with current guidelines.

Ginkgo Biloba Extract EGB761 Alleviates Warfarin-induced Aortic Valve Calcification Through the BMP2/Smad1/5/Runx2 Signaling Pathway.

ABSTRACT: Calcific aortic valve disease is a common heart disease that contributes to increased cardiovascular morbidity and mortality. There is a lack of effective pharmaceutical therapy because its mechanisms are not yet fully known. Ginkgo biloba extract (EGB761) is reported to alleviate vascular calcification. However, whether EGB761 protects against aortic valve calcification, a disease whose pathogenesis shares many similarities with vascular calcification, and potential molecular mechanisms remain unknown. In this study, porcine aortic valve interstitial cell (pAVIC) calcification was induced by warfarin with or without the presence of EGB761. Immunostaining was performed to establish and characterize the pAVIC phenotype. Calcium deposition and calcium content were examined by Alizarin Red S staining and an intracellular calcium content assay. Alkaline phosphatase activity was detected by the p-nitrophenyl phosphate method. The expression levels of bone morphogenetic protein-2 (BMP2), Runt-related transcription factor 2 (Runx2), homeobox protein MSX-2, and phosphorylated (p)-Smad1/5 were detected by reverse transcription-quantitative polymerase chain reaction (PCR) and Western blot analysis. Consistent with these in vitro data, we also confirmed the suppression of in vivo calcification by EGB761 in the warfarin-induced C57/Bl6 mice. The results indicated that both pAVICs and aortic valves tissue of mice stimulated with warfarin showed increased calcium deposition and expression of osteogenic markers (alkaline phosphatase, BMP2, homeobox protein MSX-2, and Runx2) and promoted p-Smad1/5 translocation from the cytoplasm to the nucleus. The addition of EGB761 significantly inhibited p-Smad1/5 translocation from the cytoplasm to the nucleus, thus suppressing calcification. In conclusion, EGB761 could ameliorate warfarin-induced aortic valve calcification through the inhibition of the BMP2-medicated Smad1/5/Runx2 signaling pathway.

Incidence of Cabergoline-Associated Valvulopathy in Primary Care Patients With Prolactinoma Using Hard Cardiac Endpoints.

BACKGROUND: Controversy exists as to whether low-dose cabergoline is associated with clinically significant valvulopathy. Few studies examine hard cardiac endpoint data, most relying on echocardiographic findings. OBJECTIVES: To determine the prevalence of valve surgery or heart failure in patients taking cabergoline for prolactinoma against a matched nonexposed population. DESIGN: Population-based cohort study based on North East London primary care records. METHODS: Data were drawn from ~1.5 million patients' primary care records. We identified 646 patients taking cabergoline for >6 months for prolactinoma. These were matched to up to 5 control individuals matched for age, gender, ethnicity, location, diabetes, hypertension, ischemic heart disease, and smoking status. Cumulative doses/durations of treatment were calculated. Cardiac endpoints were defined as cardiac valve surgery or heart failure diagnosis (either diagnostic code or prescription code for associated medications). RESULTS: A total of 18 (2.8%) cabergoline-treated patients and 62 (2.33%) controls reached a cardiac endpoint. Median cumulative cabergoline dose was 56 mg (interquartile range [IQR] 27-123). Median treatment duration was 27 months (IQR 15-46). Median weekly dose was 2.1 mg. Neither univariate nor multivariate analysis demonstrated a significant association between cabergoline treatment at any cumulative dosage/duration and an increased incidence of cardiac endpoints. In a matched analysis, the relative risk for cardiac complications in the cabergoline-treated group was 0.78 (95% CI, 0.41-1.48; P = 0.446). Reanalysis of echocardiograms for 6/18 affected cabergoline-treated patients showed no evidence of ergot-derived drug valvulopathy. CONCLUSIONS: The data did not support an association between clinically significant valvulopathy and low-dose cabergoline treatment and provide further evidence for a reduction in frequency of surveillance echocardiography.

The risks of medical treatment of prolactinoma.

First-line treatment of prolactinoma is usually medical, based on dopamine agonists receptors, mainly cabergoline. The classical side-effects of cabergoline (low blood pressure and nausea) have been well known since it was first introduced. Other side-effects, however, are more controversial or simply less frequent, but need to be considered during monitoring. This review will focus on these side-effects: cardiac valvular fibrosis, pleural, pericardial and retroperitoneal fibrosis, addictive/compulsive behaviors, and risks secondary to significantly decreased tumor volume. We will also describe how such side-effects should be monitored and managed. In our opinion, the low prevalence of these side-effects should not cast doubt on the role of cabergoline in the therapeutic algorithm of prolactinoma.

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study.

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.

Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling.

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-ß, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.

Cardiac valvular abnormalities associated with use and cumulative exposure of cabergoline for hyperprolactinemia: the CATCH study.

BACKGROUND: Whether lower dose cabergoline therapy for hyperprolactinemia increases risk of valvular dysfunction remains controversial. We examined valvular abnormalities among asymptomatic adults with hyperprolactinemia treated with dopamine agonists. METHODS: This cross-sectional study was conducted among adults receiving cabergoline or bromocriptine for > 12 months for hyperprolactinemia and had no cardiac-related symptoms. Cardiac valve morphology and function were assessed from transthoracic echocardiograms at the study visit (except for two participants) with evaluation performed blinded to type and duration of dopamine agonist received. RESULTS: Among 174 participants (mean age 49 ± 13 years, 63% women) without known structural heart disease before starting therapy, 62 received only cabergoline, 63 received only bromocriptine, and 49 received both. Median cabergoline use was 2.8 years in cabergoline only users and 3.2 years for those exposed to both cabergoline and bromocriptine; median bromocriptine use was 5.5 years in bromocriptine only users and 1.1 years for those exposed to both cabergoline and bromocriptine. Compared with bromocriptine only users (17.5%), regurgitation of ≥1 valve was more common for cabergoline only (37.1%, P = 0.02) but not for combined exposure (26.5%, P = 0.26). Compared with bromocriptine only exposure (1.6%), regurgitation of ≥2 valves was more common for cabergoline only (11.3%, P = 0.03) and combined exposure (12.2%, P = 0.04). Cabergoline only users had higher age-sex-adjusted odds for ≥1 valve with grade 2+ regurgitation compared to bromocriptine only users (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI]:1.3-7.5, P = 0.008), but the association for combined exposure to cabergoline and bromocriptine was not significant (aOR 1.7, 95%CI:0.7-4.3, P = 0.26). Compared to bromocriptine only, age-sex-adjusted odds of ≥2 valves with grade 2+ regurgitation were higher for both cabergoline only (aOR 8.4, 95% CI:1.0-72.2, P = 0.05) and combined exposure (aOR 8.8, 95% CI:1.0-75.8, P = 0.05). Cumulative cabergoline exposure > 115 mg was associated with a higher age-sex adjusted odds of ≥2 valves with grade 2+ regurgitation (aOR 9.6, 95%CI:1.1-81.3, P = 0.04) compared to bromocriptine only. CONCLUSIONS: Among community-based adults treated for hyperprolactinemia, cabergoline use and greater cumulative cabergoline exposure were associated with a higher prevalence of primarily mild valvular regurgitation compared with bromocriptine. Research is needed to clarify which patients treated with dopamine agonists may benefit from echocardiographic screening and surveillance.

Induction of aortic valve calcification by celecoxib and its COX-2 independent derivatives is glucocorticoid-dependent.

BACKGROUND: Celecoxib, a selective cyclooxygenase-2 inhibitor, was recently associated with increased incidence of aortic stenosis and found to produce a valvular calcification risk in vitro. Several cyclooxygenase-2 independent celecoxib derivatives have been developed and identified as possible therapies for inflammatory diseases due to their cadherin-11 inhibitory functions. Potential cardiovascular toxicities associated with these cyclooxygenase-2 independent celecoxib derivatives have not yet been investigated. Furthermore, the mechanism by which celecoxib produces valvular toxicity is not known. METHODS AND RESULTS: Celecoxib treatment produces a 2.8-fold increase in calcification in ex vivo porcine aortic valve leaflets and a more than 2-fold increase in calcification in porcine aortic valve interstitial cells cultured in osteogenic media. Its cyclooxygenase-2 independent derivative, 2,5-dimethylcelecoxib, produces a similar 2.5-fold increase in calcification in ex vivo leaflets and a 13-fold increase in porcine aortic valve interstitial cells cultured in osteogenic media. We elucidate that this offtarget effect depends on the presence of either of the two media components: dexamethasone, a synthetic glucocorticoid used for osteogenic induction, or cortisol, a natural glucocorticoid present at basal levels in the fetal bovine serum. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. By adding glucocorticoids or hydrocortisone to a serum substitute lacking endogenous glucocorticoids, we show that dimethylcelecoxib conditionally induces a 3.5-fold increase in aortic valve calcification and osteogenic expression. Treatment with the Mitogen-activated protein kinase kinase inhibitor, U0126, rescues the offtarget effect, suggesting that celecoxib and dimethylcelecoxib conditionally augment Mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase activity in the presence of glucocorticoids. CONCLUSION: Here we identify glucocorticoids as a possible source of the increased valvular calcification risk associated with celecoxib and its cyclooxygenase-2 independent derivatives. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. Furthermore, the offtarget effects are not due to the drug's intrinsic properties as dual cyclooxygenase-2 and cadherin-11 inhibitors. These findings inform future design and development of celecoxib derivatives for potential clinical therapy.

Use of methylphenidate and risk for valvular heart disease: A case-control study nested in the BIFAP cohort.

PURPOSE: To examine the association between use of methylphenidate and the risk for valvular heart disease (VHD) in the Spanish primary care database BIFAP. METHODS: Case-control study nested in a cohort of patients aged 5 to 25 years between 2002 and 2014, based in a general practice research database. Cases were people with a validated diagnosis of VHD. Ten controls per case were matched on age, sex, and calendar year. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) of VHD comparing patients ever treated with methylphenidate vs never users, as well as by time since last use, treatment duration, and variations in case inclusion criteria. RESULTS: From a cohort of 1 596 284 patients, we identified 262 valid cases of VHD. No difference in the incidence of VHD was observed when comparing "ever users" of methylphenidate with "never users" (adjusted OR 0.52, 95%CI 0.16-1.69). A similar result was found comparing current, recent, or past users of methylphenidate. Differences were not significant when both valid and probable cases were included as events of interest (adjusted OR 0.59, 95%CI 0.22-1.63). CONCLUSIONS: In this first-ever population-based study on this issue, association between methylphenidate and the incidence of VHD among persons in the 5 to 25 years age range was neither confirmed nor excluded. Additional studies may be required to clarify the presence or absence of this relationship.

Drug-associated valvular heart diseases and serotonin-related pathways: a meta-analysis.

OBJECTIVE: Serotonergic appetite suppressants and ergot-derived dopamine agonists have been associated with drug-induced valvular heart disease. The purpose of this meta-analysis is to synthesise the current evidence of a link between several medications affecting sertonergic pathways and valvular heart disease. METHODS: PubMed was searched to identify studies evaluating an association between medications with serotonergic activity and cardiac valvular pathology. Case reports, uncontrolled studies and in vitro studies were excluded. Relevant studies were assessed for quality and potential bias; those of adequate quality were included in a quantitative synthesis. Sensitivity analyses were conducted, and potential publication bias was examined. RESULTS: There was a consistent, significant relationship between certain medications and heart valve disease, including serotonergic medications (OR 3.30, 95% CI 1.99 to 5.49) and dopaminergic medications (OR 2.56, 95% CI 1.68 to 3.91). Subanalyses, including analyses that limited exposure to a single medication or effects to a single heart valve were also consistently significant. Most studies were retrospective or observational in nature, with a higher risk of selection and presentation biases. There was significant heterogeneity and variability between studies, particularly when it came to dose and duration of exposure. CONCLUSIONS: There was a consistent, significant association between many medications that affect serotonergic pathways and valvular heart disease. Although many of these medications have been withdrawn from the market, some small studies suggest that recreational drug 3,4-methylenedioxy​methamphetamine and widely prescribed selective serotonin reuptake inhibitors may affect similar pathways.

Group A streptococcal M-protein specific antibodies and T-cells drive the pathology observed in the rat autoimmune valvulitis model.

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune mediated diseases triggered by group A streptococcal (GAS) infections. Molecular mimicry between GAS M-proteins and host tissue proteins has been proposed as the mechanism that initiates autoreactive immune responses in ARF/RHD. However, the individual role of antibodies and T-cells specific for GAS M-proteins in the pathogenesis of autoimmune carditis remains under-explored. The current study investigated the role of antibodies and T-cells in the development of carditis in the Lewis rat autoimmune valvultis (RAV) model by transferring serum and/or splenic T-cells from rats previously injected with GAS recombinant M5 protein. Here we report that serum antibodies alone and serum plus in vitro expanded rM5-specific T-cells from hyperimmune rats were capable of transferring carditis to naïve syngeneic animals. Moreover, the rats that received combined serum and T-cells developed more severe carditis. Recipient rats developed mitral valvulitis and myocarditis and showed prolongation of P-R intervals in electrocardiography. GAS M5 protein-specific IgG reactivity and T-cell recall response were also demonstrated in recipient rats indicating long-term persistence of antibodies and T-cells following transfer. The results suggest that both anti-GAS M5 antibodies and T-cells have differential propensity to induce autoimmune mediated carditis in syngeneic rats following transfer. The results highlight that antibodies and effector T-cells generated by GAS M protein injection can also independently home into cardiac tissue to cross-react with tissue proteins causing autoimmune mediated immunopathology.