Drug Interactions Research Articles

Adverse cardiovascular outcomes due to potential drug-drug interactions in statin therapy: a population-based study

Abstract Background Statins have been proven to reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in primary prevention. Given their unique role in ASCVD, concomitant use of statins and other medications are inevitable. Our clinicians’ duty is to identify clinically important drug-drug interactions (DDI) with statins and to minimize potential life-threatening adverse drug reactions. Purpose To understand the clinical relevance of statin related DDI, we aimed to analyse the prevalence and level of severity of potential statin DDI in a real-world territory-wide population-based study. Methods We retrospectively analysed 95278 patients (mean age 64.3±11.4, female 45.0%) prescribed simvastatin (N=56111, 59%), atorvastatin (N=33902, 36%), or rosuvastatin (N=5265, 5%) from 2013-2022 among 16 public hospitals. Covariates were balanced with 1:1 propensity score matching for patients with and without potential DDI, resulting in 35907 patients in each arm. A composite 4-point MACE (major adverse cardiovascular events) was used as the primary outcome, which included coronary revascularisation, stroke, myocardial infarction (MI), and cardiovascular-related death (CV death). Cox proportional-hazard model with competing risk regression was performed to estimate adjusted hazards ratio (aHR) with corresponding 95% confidence intervals (CI). Secondary analyses would be focusing on adverse drug reactions in these three different statin subgroups. Results At 1-year follow up, subjects with potential statin related DDI have higher propensities of deranged liver function (ALT>=3x ULN, 4.9% vs 3.4%; p<0.001), elevated creatine kinase (CK>=5x ULN, 0.9% vs 0.5%, p<0.001) and deranged renal function (creatinine level >=2X ULN, 0.3% vs 0.2%, p<0.001) than non-DDI group. At 5-year follow up, the statin DDI group had higher incidences of MI (2.9% vs 1.9%, p<0.01), stroke (4.0% vs 2.3%, p<0.001) and CV death (1.7 % vs 1.5%, p=0.038). Potential DDI had most significant effect seen on simvastatin compared to other statins. Simvastatin DDI cohort had strong association with subsequent coronary vascularization (aHR 1.41, 95% CI 1.21–1.64, p<0.005), MI (aHR 1.66, 95% CI 1.46–1.88, p<0.005), stroke (aHR 1.95, 95% CI 1.76–2.16, p<0.005), and CV-related death (aHR 1.18, 95% 1.00–1.38, p=0.05) as compared to control. Atorvastatin DDI cohort was associated with higher rates of MI (aHR 1.81, 95% CI 1.54–2.12, p<0.005) and stroke (aHR 1.64, 95% CI 0.39–1.94, p<0.005) than control. Rosuvastatin DDI cohort was weakly associated with higher rates of MI (aHR 1.75, 95% CI 1.02–3.01, p=0.04). Conclusion Potential statin related drug-drug interactions are prevalent and were associated with major adverse cardiovascular events. Our real-world data demonstrated that simvastatin related drug-drug interaction pose a significant threat to our patients with association with CV death, myocardial infarction, stroke and future coronary revascularization.4-point MACE

Drug-drug interactions of empagliflozin and dapagliflozin

Abstract Introduction The sodium glucose co-transporter2-inhibitors dapagliflozin (Dapa) and empagliflozin (Empa), initially developed as antihyperglycemic agents, are increasingly also prescribed for non-diabetic patients with heart failure (HF). Glucuronidation by uridine-diphosphate glucuronosyltransferase (UGT)1A9 is the main mechanism of metabolism of Dapa, whereas Empa is eliminated mainly by excretion. Both Dapa and Empa are substrates of P-glycoprotein. The risk for drug-drug interactions (DDI) of Empa and Dapa is assumed to be low. Aim of this study was to summarize reports of DDI of Empa and Dapa from the literature. Methods Search-terms in PubMed were "drug-drug interaction" and AND "sodium glucose co-transporter2-inhibitors" OR "SGLT2" OR "dapagliflozin" OR "empagliflozin". The drugs were classified according the Anatomical Therapeutic Chemical (ATC) system. Included were randomized trials, pharmacovigilance studies, case series, case reports, studies in healthy subjects and in vivo data. The funding of the study and the disclosures of the authors were registered. Results In 45 reports DDI of Empa and Dapa with 29 drugs were described (Table). According to the ATC system, these were drugs for the alimentary tract and metabolism (n=5), blood and blood forming organs (n=2), cardiovascular system (n=11), genitourinary system and sex hormones (n=2), antiinfectives (n=2), antineoplastic and immunomodulating agents (n=3), musculo-skeletal system (n=2) and nervous system (n=2). The reports comprised studies in healthy subjects (n=28), case reports (n=7), case series (n=6), pharmacovigilance studies (n=2), a subgroup analysis of a randomized trial (n=1) and in vivo data (n=1). Most of the reports found no clinically relevant DDI (n=32). Dapa and Empa both had a synergistic diuretic effect with bumetanide, and led to severe infections when combined with the interleukin-17-inhibitors secukinumab or ixekizumab. Empa administered with intravenous iron was reported to increase cell-iron availability, with lithium to reduce lithium exposure and with valproate to increase valproate exposure. Dapa administered with sacubitril-valsartan was reported to lead to severe hypotension, with linezolid to pancytopenia, with donafenib to an increased exposure to donafenib, with rifampicin to a reduction and mefenamic acid to an increase in Dapa exposure. Of the 45 reports, 33 were funded by a pharmaceutical company marketing Dapa or Empa and 33 had authors with conflicts of interest with pharmaceutical companies marketing Dapa or Empa. Conclusions Most data about DDI of Empa and Dapa derive from studies in healthy subjects and from the marketing companies. The clinical relevance DDI of Empa and Dapa in polymorbid patients with polymedication is largely unknown. There is an urgent need for independent studies on DDI of these drugs in diabetic and non-diabetic patients with HF.Table

Sulcardine, an investigational multichannel blocker for atrial fibrillation with uniquely intense JTp inhibition to enhance safety

Abstract Background Sulcardine is a multi-ion channel blocker for treating atrial fibrillation (AF) with similar inhibitory potency on peak/late sodium, L-type calcium, and rapidly activating delayed-rectifier potassium (IKr) currents. The therapeutic effect of inhibiting IKr includes QT prolongation (accompanied by a proportional J to T peak [JTp] interval prolongation), which, when excessive, may cause malignant arrhythmias. As previously reported, sulcardine strongly mitigates the JTp increase that may contribute to excessive QT prolongation by inhibiting late sodium and L-type calcium currents, an intrinsic mechanism to protect from excessive IKr block. Purpose We explored the JTp mechanism, pharmacokinetics (PK), electrocardiogram (ECG) changes, safety, and drug-drug interaction (DDI) of a single sulcardine (as HBI-3000) intravenous (IV) infusion in healthy subjects. Methods An open-label Phase 1 study evaluated the PK interaction between sulcardine, dosed as a 350 mg 30-minute infusion of the sulfate salt HBI-3000, and a cytochrome P450 CYP2D6 enzyme inhibitor (paroxetine). Triplicate ECGs were extracted from continuous 12-lead Holter ECG recordings at baseline and 10 time points thereafter. Mean baseline-subtracted and heart rate-corrected QTcF (dQTcF), JTpc (dJTpc), and other ECG changes were calculated at each time point. Left ventricular ejection fraction (LVEF) was assessed at baseline, 30-, and 120-minutes post-infusion start by transthoracic echocardiography (TTE). Results 39 subjects received HBI-3000, 33 in the paired PK population. Expected ECG parameter changes proportional to sulcardine plasma concentrations were observed in the HBI-3000-alone portion of the study, including modest QTcF prolongation (Fig 1, blue slope, confidence band) and JTpc inhibition (Fig 1, red). The usual JTpc increase associated with IKr blockers, even those with mitigating channel block (such as the late sodium current), was not only reduced but actually reversed. We calculated the dQTcF change that would have been observed in the absence of JTpc reduction by sulcardine (Fig 1, green). Sulcardine reduced the QTcF increase that might have occurred by about 21 msec at the highest concentrations, and this mitigating effect was observed at all concentrations. No clinically significant safety findings or arrhythmias were observed. The most frequent TEAEs were nausea and headache (n=2 each [5.1%]). No LVEF changes were clinically significant. Sulcardine had minimal metabolic interactions. Conclusion Acute IV HBI-3000 administration resulted in no clinically significant safety findings, LVEF depression, or DDI with CYP2D6. Sulcardine facilitates QT prolongation, which has a therapeutic benefit in terminating AF, with simultaneous uncoupling and reversing of the JTpc interval increase, a potential mechanism for reducing proarrhythmic risk due to excessive QT prolongation.Figure 1.ECG Intervals vs Sulcardine Conc

Patients with dementia: prevalence and type of drug-drug interactions.

Patients with Alzheimer's disease (AD) and other dementias are more frequently exposed to polymedication, mainly due to the presence of comorbidities, are particularly vulnerable to drug-related problems, and present greater risk of adverse effects due to drug-drug interactions (DDIs). To assess the prevalence of clinically relevant interactions in dementia patients using a routine database, we describe the most frequent interactions and risk factors associated with them to facilitate specific interventions and programs to prevent and minimize them. An observational, descriptive, and cross-sectional study that included patients with AD and other types of dementia (n = 100, 64% female) was conducted to identify potential DDI in their treatment using the Lexi-Interact/Lexicomp® database. A total of 769 drugs were prescribed, involving 190 different active ingredients; 83% of the treatments included five or more drugs. DDI occurred in 87% of the patients, of which 63.2% were female. A total of 689 DDIs were found, grouped in 448 drug pairs, with a mean of 6.9 ± 7.1 (range, 0-31) DDIs per patient, and 680 DDIs were considered clinically relevant. It was observed that 89.8% of the DDIs had a moderate level of severity, 23.5% had a good level of relevance, and pharmacodynamic-based DDIs accounted for 89.5%. The drugs most frequently involved in DDIs were quetiapine (24.5%) and acetylsalicylic acid (10%). A total of 97 DDIs were detected between the acetylcholinesterase inhibitors (AChEIs), and the remaining drugs were administered concomitantly. One of the most frequent DDIs was between AChEIs and beta-blocking agents (n = 29, 4.3%). The most important factors that showed the strongest association with the presence of drug interactions were the use of AChEIs (p = 0.01) and the total number of drugs (p = 0.014) taken by the patient. Patients with dementia present increased risk of DDIs. Among the most common drugs are psychotropic drugs, which are involved in pharmacodynamic interactions caused by the concomitant use of CNS-targeted drugs. The results highlight the difficulty to evaluate DDIs in clinical practice due to polymedication and variety of comorbidities. Therefore, it is important to review their treatment and consider metabolism inhibition or induction, and potentially P450 substrate overlapping.

Safety and effectiveness of sodium-glucose co-transporter 2 inhibitors in active cancer patients with heart failure: results of the observational TOSCA trial

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) currently represent a pillar of heart failure (HF) treatment. However, cancer patients have not been included in landmark randomized controlled trials (RCTs), and data on safety and effectiveness in this population are lacking. Purpose Purpose of present study was to evaluate safety and effectiveness of SGLT2i in active cancer patients with HF. Methods TOSCA is a multi-centre observational trial including patients (≥ 18 years) with active cancer (diagnosis < 3 years) receiving SGLT2i for HF treatment. Patients were enrolled in two (prospective and retrospective) cohorts. The primary endpoint was safety (incidence of known and unexpected side effects). The secondary endpoint was effectiveness (ejection fraction (EF) increase, New York Heart Association (NYHA) class change, HF-related events). Exploratory endpoints included drug-drug interactions with anticancer and supportive care drugs, treatment of cancer therapy-related cardiac dysfunction (CTRCD), and changes in NT-proBNP. Results Eighty-three pts were enrolled (59 prospective - 24 retrospective). Median age was 71 (range 44-92) yrs, M/F 48/52%. The main cancer sites were breast, gastrointestinal tract, and hematological malignancies. Most cases (62%) received an active treatment (mainly chemotherapy) while on SGLT2i. Prevalent aetiology was drug-induced HF (37%) with reduced EF as the prevalent clinical presentation (39%). Prescribed agents were dapagliflozin in 60% and empagliflozin in 40% of cases on top of conventional guideline-directed medical therapy, with a median treatment duration of 3 (range 3-25) months. The incidence of urinary tract infection was 2.5%. No cases of genital infection, hypoglycemia, diabetic ketoacidosis, acute renal injury, thrombosis, and bone fractures were reported. Mean overall EF slightly increased (44.1% vs. 46.6%), and NYHA class improved (class improvement in 16%). Unplanned cardiology visits (1.2%), i.v. diuretics (1.2%), coronary angiography (5%), emergency access (2.5%), and new HF episodes (3.7%) rates were low. SGLT2i appeared effective in 31 cases of CTRCD. A relative reduction in mean NT-proBNP levels (2748 vs 1125pg/mL) was observed. No drug-drug interactions were reported. Conclusions SGLT2i appear to be safe and effective in active cancer patients with HF, with potential cardioprotective effect. No new safety warnings were recorded.

Notable drug-drug interaction between omeprazole and voriconazole in CYP2C19 *1 and *2 (rs4244285, 681G>A) alleles in vitro

The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele. CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole. Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A). Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).

PCSK9 inhibitors in HIV patients with dyslipidemia

Abstract Introduction Cardiovascular disease has become increasingly prevalent in the HIV (human immunodeficiency virus) population. Antiretroviral therapy and HIV itself independently increase the risk of dyslipidemia. While statins are currently the predominant therapy to treat dyslipidemia in HIV patients, drug-drug interactions and adverse drug events can limit their use. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a naturally occurring inhibitor of the LDL-receptor pathway. PCSK9 inhibitors offer an alternative in patients who cannot tolerate or need additional therapy in addition to statin for optimal dyslipidemia management. Purpose The purpose of this study is to compare major adverse cardiovascular events in HIV patients on a PCSK9 inhibitor (evolucumab, alirocumab, inclisiran) vs patients not on a PCSK9 inhibitor. Methods A retrospective cohort study was conducted using electronic medical records from a global federated health research network. The TriNetX network was searched on February 10, 2024, including records from 2020 to 2024. Patients were included based on a diagnosis of HIV status and concomitant dyslipidemia. Patients with HIV and dyslipidemia on a PCSK9 inhibitor were propensity-score matched for age, sex, race, and comorbidities with patients who were not on a PCSK9 inhibitor. The outcomes were mortality, myocardial infarction, heart failure and stroke. Results A total of 485 patients were included in the study. PCSK9 inhibitor use associated with 9% lower odds of all-cause mortality (odds radio, .29; 95% CI, 0.18-0.48; p<.0001). PCSK9 inhibitor use was also associated with 8% lower odds of heart failure (odds radio, .63; 95% CI, 0.47-0.85; p<.0023). No significant associations were noted for myocardial infarction (odds radio, .87; 95% CI, 0.63-1.21; p=0.406) or stroke (odds radio, .67; 95% CI, 0.45-1.01; p=0.052). Conclusion The role of dyslipidemia in HIV is challenging due the complex pathophysiology of HIV. There is an apparent increased risk of cardiovascular disease from the infection itself as well current antiretroviral therapies. While current guidelines recommend the use of statins as first line therapy for dyslipidemia in this population, the drug-drug interaction of statins with ARTs, as well as their side effects, limit their use at times. PCSK9 inhibitors are associated with lower odds of all-cause mortality and heart failure. No significant association was seen for myocardial infarction or stroke. They should be considered as an early intervention alongside statins in HIV patients with dyslipidemia. Further research should be done for the long term safety and tolerance of this therapy as well as cost-effectiveness and access to PCSK9 inhibitors in this population.

Abnormally high plasma concentrations of M-4, the active metabolite of edoxaban, at the onset of acute kidney injury in a patient receiving rifampin and clarithromycin: a case report

BackgroundEdoxaban, the only factor Xa inhibitor with active metabolites, is metabolized by carboxylesterase-1 to its main active metabolite, M-4, which is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and is excreted in bile and urine. Because the area under the plasma concentration–time curve ratio of M-4 to parent compound is typically less than 10% in healthy subjects, M-4 is generally considered to exhibit negligible antithrombotic activity in patients treated with edoxaban. However, we identified a case in which drug interactions and kidney impairment led to a substantive increase in plasma M-4 concentrations.Case presentationThis case report involved a 68-year-old man with pancreatic cancer who was orally administered edoxaban tablets for prevention of thrombus formation in non-valvular atrial fibrillation, in addition to rifampin and clarithromycin (CAM) for treatment of mycobacterium avium complex lung disease. These medications were temporarily discontinued for a pancreaticoduodenectomy but were resumed 8 days post-surgery (POD8). On POD9, the patient developed acute kidney injury, and the trough concentrations of edoxaban and M-4 were 131.1 ng/mL and 115.8 ng/mL, respectively (M-4 ratio: 88.3%). On POD11, the M-4 trough concentration and M-4 ratio increased to 216.2 ng/mL and 186.2%, respectively. The plasma concentration of coproporphyrin-I, an endogenous biomarker of OATP1B1 activity, increased during this period.ConclusionsThis case suggests that in patients with impaired renal function taking edoxaban, co-administration of carboxylesterase-1 inducers such as rifampin and/or OATP1B1 inhibitors such as rifampin or clarithromycin may increase plasma concentrations of M-4 to clinically non-negligible levels.

Estimating the Prevalence of Primary Hypothyroidism in Karbala City, and Modulation of Clinical Manifestations Among Patients Receiving Levothyroxine; A Single Center Study

Background: Hypothyroidism has a wide range of clinical manifestations and general symptoms, including but not limited to obesity, tiredness, poor concentration, depression, widespread muscle soreness, menstruation abnormalities, and constipation. The administration of a daily dosage of levothyroxine is sufficient for the successful management of hypothyroidism, as it facilitates the restoration of serum thyroid stimulating hormone (TSH) levels to their normal range. Several factors can influence the absorption of levothyroxine in the human body, including age, weight, the presence of other medical problems, and dietary intake. The aim of this study was to assess the prevalence of primary hypothyroidism and alteration in clinical presentation associated with replacement therapy. Methods: This was a cross-sectional, observational study conducted over at Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) in Karbala city. The study team created a questionnaire, and data was collected from face-to-face patient interviews, which included various sociodemographic variables, TSH and ferritin levels, drug interactions, as well as signs and symptoms exhibited both prior to and following treatment. Additionally, the patient treatment regimen and the specific doses of levothyroxine administered are also recorded. Results: the total number of cases visited Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) during the study period was (10800). The prevalence of thyroid diseases was 300 (2.8%). The rate of primary hypothyroidism out of the total number of hypothyroid cases was 85.1%. (61%) of the patients had normal levels of TSH whereas (42%) of the patients were found to be undertreatment. A total of (84%) of the patients exhibited normal levels of ferritin. The patients exhibited a reduction in their signs and symptoms following the administration of therapy. Conclusion: treatment with levothyroxine improved sluggish speech, constipation, lack of appetite, cold sensitivity, weight gain, and weariness. There is no observed correlation between the dosage of levothyroxine and the manifestation of signs and symptoms.

Table 3: Some drug interactions with DAAs for HCV infection.

Table 3: Some drug interactions with DAAs for HCV infection.

Polypharmacy and associated factors in the older population in Germany: Results Gesundheit 65+ study

Abstract Background Polypharmacy, the use of 5 or more medications simultaneously, favors the risk of adverse drug events, drug interactions, potentially inappropriate medication (PIM), hospitalizations, falls, frailty, and mortality. This analysis presents the prevalence of polypharmacy and associated factors in people aged 66+ years living in Germany. Methods Data from the nationally representative Study on Health of Older People in Germany (Gesundheit 65+) conducted between 2021-2023 by the Robert Koch Institute, was analyzed. All medicines used, prescribed and over-the-counter, in the 7 days before the interview were documented and classified into anatomical therapeutic chemical codes. Weighted prevalences and associated factors for polypharmacy are presented. Results 96% of the sample (N = 1,474) took at least 1 medication in the 7 days before the interview. Of these, 39% took up to 4 medications, 39% 5-9 and 22% 10+. The overall prevalence of polypharmacy was 61% (95%CI 58-65%) and was significantly higher in women (64%) than in men (59%). Polypharmacy increased with age, from 52% in the age group 66-74 (53% in men, 51% in women), 66% in the age group 75-84 (63% in men, 69% in women) to 81% in the age group 85 + (72% in men, 86% in women). People with low educational level had a polypharmacy prevalence of 63% (58% in men, 66% in women) compared to 56% (55% in men, 58% in women) in those with high educational level. Severe difficulties in organizing daily medication intake were reported in 1% of people taking up to 4 medicines, in 4% of people taking between 5-9 medicines and in 16% of people taking 10+. The prevalence of PIM increased with the number of medicines used: 13% in 1-4 medicines, 31% in 5-9 medicines, and 53% in 10+ medicines. Conclusions Polypharmacy was more frequent in women, older age groups and in people with low educational level. It was associated with increased difficulty in organizing medication intake and with PIM use. Key messages • Polypharmacy is very common, affecting more women, older age groups, people with a low educational level and is associated with PIM use. • Strategies to promote appropriate medication use are needed.

Challenges posed by climate hazards to cardiovascular health and cardiac intensive care: implications for mitigation and adaptation.

Global warming, driven by increased greenhouse gas emissions, has led to unprecedented extreme weather events, contributing to higher morbidity and mortality rates from a variety of health conditions, including cardiovascular disease (CVD). The disruption of multiple planetary boundaries has increased the probability of connected, cascading, and catastrophic disasters with magnified health impacts on vulnerable populations. While the impact of climate change can be manifold, non-optimal air temperatures (NOTs) pose significant health risks from cardiovascular events. Vulnerable populations, especially those with pre-existing CVD, face increased risks of acute cardiovascular events during NOT. Factors such as age, socio-economic status, minority populations, and environmental conditions (especially air pollution) amplify these risks. With rising global surface temperatures, the frequency and intensity of heatwaves and cold spells are expected to increase, emphasizing the need to address their health impacts. The World Health Organization recommends implementing heat-health action plans, which include early warning systems, public education on recognizing heat-related symptoms, and guidelines for adjusting medications during heatwaves. Additionally, intensive care units must be prepared to handle increased patient loads and the specific challenges posed by extreme heat. Comprehensive and proactive adaptation and mitigation strategies with health as a primary consideration and measures to enhance resilience are essential to protect vulnerable populations and reduce the health burden associated with NOTs. The current educational review will explore the impact on cardiovascular events, future health projections, pathophysiology, drug interactions, and intensive care challenges and recommend actions for effective patient care.

Proton pump inhibitors and cardiovascular risk: a critical review.

Proton pump inhibitors (PPI) are widely used medications for gastrointestinal disorders. Recent research suggests a potential association between long-term PPI use and increased cardiovascular (CV) risk, creating a complex clinical dilemma. This review critically evaluates the current evidence for this association, considering the limitations of observational studies and the lack of definitive confirmation from randomized controlled trials.This review delves into the reported association between PPIs and adverse CV events, examining proposed mechanisms such as drug interactions, electrolyte imbalances induced by PPIs and their potential impact on cardiac and vascular function. Evidence suggests these mechanisms converge, with varying influence depending on patient populations.Clinicians require a risk-benefit analysis for each patient considering their CV risk profile. Alternative gastrointestinal therapies should be explored for high-bleeding risk patients. Medications with lower cytochrome-P450 interaction potential may be preferable among essential PPI users. Elucidating the specific mechanisms by which PPIs might influence CV health, assessing long-term vascular effects and investigating interactions with newer anticoagulant medications are crucial for future research.

Drug interactions in incident NOACs users and risk of bleeding

Abstract Introduction Oral anticoagulants (NOACs) are known to have a better safety profile than Vitamin K antagonists, but their metabolism largely depends on the P-glycoprotein and CYP3A4. All drugs inhibiting those proteins may affect NOACs’ bioavailability, by increasing the risk of drug interactions, particularly the risk of bleeding. Purpose The objective was to describe the pattern of polypharmacy in a large cohort of NOAC users, at baseline and within one year after starting anticoagulant treatment. Materials and Methods All persons residing in the catchment areas of Caserta LHU during the years 2012–2020 were considered. From the source population, all patients with at least 1 year of database history and receiving at least one NOAC dispensing during the observation period were identified. Of these, incident (i.e. no NOAC dispensing within one year prior to the first dispensing date, Index Date) NOAC users were included into the cohort and represented the majority of the patients enrolled (97,4%). The comparison of the distribution of interacting drugs number dispensed Pre-ID (within three months before the Index date) and Post-ID (within 12 months after Index date) was explored stratified by high/low dose of anticoagulant. 20.491 incident NOAC users were identified from Caserta LHU and 16,367 (79.9%) NOAC incident users with at least one year of follow-up after ID were included in the analysis. NVAF was the main indication for use of the study cohort (64.3%) and almost 60% of incident NOAC users treated for NVAF received high-dose NOAC. The frequency of incident NOAC users with at least one hospitalization for major bleeding within one year after ID was calculated and stratified by high/low dose of NOACs and the number of drug interactions. A statistically significant test result was considered if p ≤ 0.05. Results The number of interacting drugs dispensed within one year after ID increased from pre-ID to post-ID. 2,077 (12.7%) incident NOAC users without any interacting drugs within 3 months pre-ID received 1 interacting drug within one year after ID. 11.3% and 8.4% of incident NOAC users increased from 1 interacting drug (Pre-ID) to 2 interacting drugs (Post-ID) and from 2 interacting drugs (Pre-ID) to 3-5 interacting drugs (Post-ID) (Table 1). The proportion of NOAC users with a major bleeding increased with the increasing number of interacting drugs, reaching 2.9% and 2.1% among low-dose and high-dose NOAC users with more than 9 interacting drugs (Table 2). Conclusions The results of the current analysis suggest that independently from the type and the dose of NOAC, the number of interacting drugs prescribed with NOACs tends to increase after the first administration of NOACs. Hemorrhagic events are more related to the number of interacting drugs instead of dose of anticoagulant.Table 1 Table 2

Deep dermatophyte infections

Deep dermatophytosis is a rare condition in which dermatophytes invade deep into the skin. Predisposing factors include chronic superficial dermatophytosis, immunosuppression or the use of topical steroids. Clinical, mycological, and histological examination are crucial for accurate diagnosis. Microscopy and culture or molecular diagnostic are useful tools when identifying the causative dermatophyte species. Species-directed systemic antimycotic treatment is golden standard and require careful consideration of potential drug-drug interactions and monitoring for both efficacy and side effects, as argued in this review.

Efficacy of pitavastatin in patients with HIV: a systematic review and meta-analysis of randomized controlled trials

Abstract Background People with HIV (PWH) experience elevated cardiovascular disease (CVD) risk, exacerbated by antiretroviral therapy-induced dyslipidemia. Managing CVD risks in PWH presents significant challenges, notably due to the potential drug interactions. Pitavastatin is a statin with minimal interactions with antiretrovirals. Methods A systematic literature search of PubMed, Cochrane Library, and Embase databases was conducted up to March 1st, 2024, for studies comparing pitavastatin in PWH. Statistical software RStudio version 4.1.2 was used. Results Three studies with a total of 8045 participants were included in this analysis. Of these 4026 (50.04%) received pitavastatin. The mean age was 49.98 years and 69.38% were male. In the pooled analysis of studies, pitavastatin significantly reduced LDL cholesterol (MD -25.47; 95% CI -35.26 to -15.69; p<0.01; I² = 91%; Figure 1A) and non-HDL cholesterol (MD -27.53; 95% CI -41.19 to -13.87; p<0.01; I² = 91%; Figure 1B). Recently, the randomized trial to prevent vascular events in HIV study showed a reduction in adverse cardiovascular events and noncalcified plaque volume, as well as a reduction in inflammatory markers including oxidized LDL. Conclusions Pitavastatin offers a promising strategy for managing dyslipidemia and reducing CVD risk in PWH by reducing cholesterol, improving coronary plaque characteristics and inflammatory markers.

A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M-5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.

Pharmacological Pain Treatment in Older Persons.

Pharmacological pain treatment in older persons is presented by a multi-disciplinary group of European pain experts. Drugs recommended for acute or chronic nociceptive pain, also for neuropathic pain and the routes of administration of choice are the same as those prescribed for younger persons but comorbidities and polypharmacy in older persons increase the risk of adverse effects and drug interactions. Not all drugs are available or authorised in all European countries. For mild-to-moderate pain, non-opioids including paracetamol and non-steroidal anti-inflammatory drugs are first-line treatments, followed by nefopam and metamizole. Codeine, dihydrocodeine and tramadol are prescribed for moderate to severe pain and 'strong' opioids, including morphine, hydromorphone, oxycodone, fentanyl, buprenorphine, methadone and tapentadol, for severe pain. Chronic neuropathic pain treatment relies on coanalgesics, including anti-epileptics (gabapentinoids) and anti-depressants with additional option of topical lidocaine and capsaicine. The choice of analgesic(s) and the route of administration should be guided by the pain characteristics, as well as by the patient's comorbidities, organ function and medications. Several directions have been highlighted to optimise pharmacological pain management in older individuals: (1) before starting pain treatment adequately detect and assess pain and always perform a full geriatric assessment, (2) consider kidney function systematically to adjust the doses of analgesics and avoid the risks of overdose, (3) start with the lowest dose of an analgesic and increase it gradually under the control of the effect, (4) involve the older persons and family in their treatment, (5) reevaluate pain regularly during treatment and (6) combine pharmacological treatment with non-pharmacological approaches.

Challenges for Family Caregivers of Persons With Mild Cognitive Impairment: A Qualitative Longitudinal Study.

Family caregivers of persons with mild cognitive impairment attempt to understand the behavioural and functional changes exhibited by their relative. However, how caregivers respond to initial changes and changes over time has not been explored. The purpose of this qualitative study was to explore the experience of family caregivers responding to changes in their relative's memory, behaviours, and physical functions over 2 years. Eleven family caregivers of a relative with mild cognitive impairment were purposively recruited from neurological clinics in Taiwan. Face-to-face semi-structured interviews were conducted within 6-months of referral; three follow-ups were conducted at 6-month intervals. Content analysis of 41 transcribed audio-recorded interviews revealed the longitudinal changes in their relative with cognitive impairment was made caregiving challenging. Three themes described the challenges: (1) Changes related to their relative's cognitive impairment, which included increases in mood fluctuations, erratic behaviours, and reductions in physical abilities; (2) changes in their relative's comorbidities, which included adapting to new symptoms and treatments for a chronic disease, monitoring medication adherence and drug interactions; and (3) changes in caregiver burden, which increased levels of stress, uncertainty, and anxiety resulting in greater role strain. Caregiving became more challenging with time, especially caregivers whose relative developed dementia during the study period. These findings offer insight into the trajectory of the experience of family caregivers attempting to understand changes in cognition, behaviours, and physical functions for their relative with mild cognitive impairment over 2 years, which could help mental healthcare providers develop support services to reduce caregiver role strain.

O IMPACTO DA REGULAÇÃO DO SISTEMA ENDOCANABINOIDE NA FARMACOTERAPIA DA ANSIEDADE E DO ESTRESSE

This article addresses the impact of regulation of the endocannabinoid system on the pharmacotherapy of anxiety and stress, topics of increasing relevance in neuroscience and pharmacology. The endocannabinoid system, composed of receptors, endocannabinoids and enzymes responsible for their synthesis and degradation, plays a fundamental role in modulating several physiological functions, including the regulation of stress and anxiety. Cannabidiol (CBD), a phytocannabinoid, has stood out for its anxiolytic and modulating effects on the endocannabinoid system, presenting itself as a promising therapeutic alternative for anxiety disorders. The objective of the study was to analyze the therapeutic effects of regulating the endocannabinoid system in the treatment of anxiety and stress, focusing on the benefits and limitations of using CBD. To this end, a bibliographic review of studies published between 2010 and 2024 was carried out, using databases such as PubMed, SciELO and Google Scholar. Inclusion criteria involved peer-reviewed studies that addressed the relationship between the endocannabinoid system and anxiety disorders. The results showed that CBD can significantly reduce symptoms of anxiety and stress, with few side effects. However, there are still gaps regarding optimal dosage and drug interactions, which limits its widespread clinical adoption. Regulation of the medicinal use of cannabis has also proven to be an obstacle in several countries. It is concluded that, despite the challenges, the use of cannabinoids such as CBD represents a promising approach, requiring greater investment in clinical research and adequate regulation.