Evaluation of the prevalence and clinical-laboratory characteristics of Intolerance to single and multiple drug classes in hypertensive subject (MDI-TO)

Multiple Drug Intolerance (MDI) is a clinical condition where adverse drug reactions (ADRs) occur in at least three drug classes without an immunological mechanism. MDI pathogenesis mechanism has not been clarified yet and no in-vitro tests are available for its diagnosis, often carried out through an exclusion process. There are few studies in literature focused on identifying the mechanisms and clinical determinants of MDI. In the context of Arterial Hypertension, the use of combination therapy is recommended by guideline, increasing the risk for MDI events and poor medication adherence. Concerning ADRs, it is possible to distinguish common side effects (e.g. cough in ACE inhibitors) and unpredictable hypersensitivity reactions which lead to the possible involvement of the MDI if these symptoms occur for multiple drug classes. For this reason, the aim of this to evaluate the prevalence, to investigate on contributors and factors associated of MDI. In order to reach these objectives: drugs with higher incidence of intolerance events was assessed; the evaluation of therapeutic adherence (Therapeutic Drug Monitoring/Questionnaires) was performed; diet and microbiota-related metabolites were characterized; and psychological and socio-economical profile were investigated. The research was conducted over three years, beginning with a comprehensive literature review on the etiopathogenesis of MDI. A multidisciplinary study approach was designed, incorporating pharmacological factors, psychological influences, gut microbiota, and clinical aspects. Patient recruitment and methodology development for drugs and biomarker quantification were carried out during the second year. Three quantification methods, using Ultra High-Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (HPLC-MS/MS) were validated, resulting in methodological articles: two on the simultaneous quantification of antihypertensive drugs and the other on the quantitation of Trimethylamine N-oxide (TMAO) in plasma. In course of the final year, psychological tests and database structuring for the statistical analysis were assessed in order to identifying contributors associated among measured parameters and collected data. At enrolment, each patient, with a confirmed diagnosis of hypertension under antihypertensive therapy who manifest or develop intolerance to one or more antihypertensive drugs, underwent: the collection of anthropometric and clinical data; administration of a questionnaires (adherence, psychological profiling and socioeconomic status); blood sample collection for quantitative measurement of drugs and TMAO. Among 576 patients, 18 resulted poli-intolerants. Intolerances to antihypertensive medications were prevalent in older, women and leaner patients. The study found associations with psychiatric conditions like depression and anxiety, which can worsen patients' overall health and lead to poor blood pressure management and poor adherence. The evaluation of questionnaires compared to direct drug monitoring analysis highlighted the disconnection between self-reported adherence and real medication use. Examining the mean TMAO levels in the study population, was found to be higher than those in previous studies, confirming the involvement of microbiota in cardiovascular diseases. Moreover, gender-related factors were found to be associated to MDI conditions and therapeutic adherence. Further research with larger patient cohorts is needed to confirm findings and refine the study. This work could help to clarify the pharmacological mechanisms of ADRs and improve diagnostic tools for MDI. A multidisciplinary approach, could enhance patient outcomes and management, promoting tailored treatments and better compliance.