Calcium Channel Research Articles

Risk Factors for Inadequate Bowel Preparation in Colonoscopy: A Comprehensive Systematic Review and Meta-Analysis.

Inadequate bowel preparation (IBP) before colonoscopy remains a common problem. This meta-analysis aimed to assess the risk factors associated with IBP. We searched multiple databases for studies that assessed risk factors for IBP after adjustment and reported the data as adjusted odds ratios with 95% confidence intervals. Meta-analyses were conducted using a random-effects model, and pooled adjusted odds ratios for risk factors reported in ≥ 3 studies were constructed. One hundred fifty-four studies with 358,257 participants were included. We analyzed 48 unique risk factors. Sociodemographic predictors of IBP were Medicaid insurance, obesity, current tobacco use, age ≥ 65 years, Black race, low education level, male sex, and unmarried status. Comorbidity-related predictors of IBP were any psychiatric disease, cirrhosis, American Society of Anesthesiologists (ASA) class ≥ 3, poor functional status, constipation, diabetes, previous abdominopelvic surgery, and hematochezia. Medication-related predictors of IBP were tricyclic antidepressants, antidepressants, opioids, nontricyclic antidepressants, and calcium channel blockers. Preparation/procedure-related predictors of IBP were brown liquid rectal effluent, any incomplete bowel preparation (BP) intake, lack of split-dose BP, increased BP-to-defecation interval, any nonadherence to dietary instructions, increased BP-to-colonoscopy interval, any BP intolerance, previous IBP, and inpatient status. Although afternoon colonoscopy was a predictor of IBP, subgroup analysis of prospective studies revealed no significant association. Our meta-analysis focused on adjusted risk factors to provide precise estimates of the most important risk factors for IBP. Our findings could help develop a validated prediction model to identify high-risk patients for IBP, improve colonoscopy outcomes, reduce the need for repeat colonoscopies, and reduce associated healthcare costs.

Differential serum levels of CACNA1C, circadian rhythm and stress response molecules in subjects with bipolar disorder: Associations with genetic and clinical factors

BackgroundMany patients with bipolar disorder (BD) do not respond to or have difficulties tolerating lithium and/or other mood stabilizing agents. There is a need for personalized treatments based on biomarkers in guiding treatment options. The calcium voltage-gated channel CACNA1C is a promising candidate for developing personalized treatments. CACNA1C is implicated in BD by genome-wide association studies and several lines of evidence suggest that targeting L-type calcium channels could be an effective treatment strategy. However, before such individualized treatments can be pursued, biomarkers predicting treatment response need to be developed. MethodsAs a first step in testing the hypothesis that CACNA1C genotype is associated with serum levels of CACNA1C, we conducted ELISA measures on serum samples from 100 subjects with BD and 100 control subjects. ResultsWe observed significantly higher CACNA1C (p < 0.01) protein levels in subjects with BD. The risk single nucleotide polymorpshism (SNP) (rs11062170) showed functional significance as subjects homozygous for the risk allele (CC) had significantly greater CACNA1C protein levels compared to subjects with one (p = 0.013) or no copies (p = 0.009). We observed higher somatostatin (SST) (p < 0.003) protein levels and lower levels of the clock protein aryl hydrocarbon receptor nuclear translocator-like (ARTNL) (p < 0.03) and stress signaling factor corticotrophin releasing hormone (CRH) (p < 0.001) in BD. SST and period 2 (PER2) protein levels were associated with both alcohol dependence and lithium response. ConclusionsOur findings represent the first evidence for increased serum levels of CACNA1C in BD. Along with altered levels of SST, ARNTL, and CRH our findings suggest CACNA1C is associated with circadian rhythm and stress response disturbances in BD.

Antihypertensive drug-associated adverse events in osteoarthritis: a study of a large real-world sample based on the FAERS database.

Hypertension is a common complication in patients with osteoarthritis (OA). There is increasing interest in the relationship between hypertension and OA. However, hypertension has been reported to negatively affect symptoms and quality of life in patients with OA. Therefore, treating hypertension is crucial for patients with OA. However, there is a lack of real-world studies on the effects of medications for treating hypertension on OA. Data from the FAERS database from January 2004 to December 2023 were extracted for disproportionality analyses, and proportional reporting ratios (PRRs) were used to assess the association between medications for hypertension and all types of arthritis. Adverse event signals were identified and determined using reporting odds ratios (RORs) Adverse event signals were considered to have occurred if a drug-induced adverse event was recorded more than or equal to 3 and the lower limit of the ROR confidence interval was more than 1. We selected five classes of drugs including, calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics and β-blockers and representative drugs were analysed for osteoarthritis-related adverse reactions, and age and gender subgroups were analysed for drugs of significance. We also analysed the occurrence of AEs in relation to time using the Weibull distribution. In terms of overall data, we found significant OA adverse reaction signals only for ARBs among the five drug classes.ARB AEs for spinal osteoarthritis (ROR 4.64, 95% CI 3.62-5.94), osteoarthritis (ROR 3.24 95% CI 2.82-3.72) and gouty arthritis (ROR 3.27 95% CI 1.22-8.75) were the three adverse reactions with the loudest signals. Next, we found that valsartan had strong osteoarthritis adverse reaction signals among the three ARBs, namely, irbesartan, cloxartan, and valsartan. We also analysed age and gender subgroups and found that osteoarthritis signals were strongest in the 18-65 and 65+ population, while females seem to be more prone to valsartan-related OA AEs. ARBs, especially valsartan, have significant positive signals for OA AEs. Therefore, ARB drugs, especially valsartan, should be used with caution when treating patients with OA combined with hypertension.

L-DOPA ELICITATION THROUGH CALCIUM ION MEDIATED CHANNEL IN CALLUS CULTURES OF MUCUNA PRURIENS

Objective: The production of L-Dopa in callus cultures of Mucuna pruriens is influenced by substances that regulate calcium channels. Methods: M. pruriens seeds were gathered from the Western Ghats area in Tamil Nadu. L-Dopa was obtained by the Brain (1976) method, A. niger cultures were used for fungal elicitor preparation, and the assay of Ca2+ATPase was studied. Results: The use of fungal triggers resulted in increased L-Dopa levels on the 9th day but reduced levels on the 24th day of culture. When calcium channel modulators like verapamil and chlorpromazine were added, it decreased the growth of calli and L-Dopa production, suggesting the role played by calcium ion channels in L-Dopa synthesis. The calcium ionophore A23187 enhanced calli growth and L-Dopa production, increasing Ca2+ATPase activity. Particularly on the 12th d, Ca2+ATPase was notably active, while the presence of calcium ionophore boosted L-Dopa biosynthesis. Conclusion: The use of fungal elicitors in in vitro cultures of Mucuna pruriens is recommended as a potential method to increase the production of secondary metabolites.

Abstract P439: An Uncommon and Missed Diagnosis of Hypertension: Fibromuscular Dysplasia

Introduction: Fibromuscular dysplasia is a noninflammatory vascular disease most commonly affecting carotid and renal arteries, especially in young to middle aged women. Renal artery stenosis may cause refractory and severe hypertension in these patients without traditional risk factors. Case: A 58-year-old woman with uncontrolled hypertension on calcium channel and angiotensin receptor blocker and history of left carotid artery stenosis, and carotid endarterectomy at the age of 48 years, was referred cardiac evaluation. Patient’s twin sister had a diagnosis of fibromuscular dysplasia (FMD). Her blood pressure was 190/90 mmHg at presentation. Computed Tomography Angiography (CTA) of the abdomen/pelvis showed a typical nodular stenosis of the mid renal artery consistent with FMD. Patient underwent renal angiogram and successful percutaneous transluminal angioplasty. She still required medical therapy but her BP significantly improved. Discussion: Our patient had severe hypertension, carotid artery stenosis and even surgery but had missed FMD diagnosis for &gt; 10 years. Physicians should have a high level of clinical suspicion for young and middle aged women with refractory hypertension and/or artery stenosis, aneurysm, or dissection in any vascular bed. CTA should be performed for renal and carotid artery imaging looking for typical “string of beads” appearance. Cerebral artery aneurysm should also be evaluated. The inheritance pattern for FMD such as PHACTR1 is most consistent with an autosomal dominant trait with variable penetrance. Renal artery angioplasty may lessen the degree of refractory or severe hypertension.

O51 EXPLORING GENETIC BASIS OF RESISTANT HYPERTENSION IN EUROPEAN AND AFRICAN POPULATIONS

Background: Approximately 15% of hypertensive (HTN) patients experience resistant hypertension (RHTN) despite the use of ≥ 3 antihypertensive agents (diuretic and blockers of calcium channels and the renin-angiotensin system) at maximum tolerated doses. Intriguingly, genetic variation and alterations in gene content may contribute to RHTN developing. Aim: To comprehend the genetic determinants of RHTN across diverse ethnicities, this study has compared the gene content and presence of single nucleotide variants (SNVs) in RHTN versus controlled-HTN and normotensive participants within European (EU) and South African (SA) populations. Methods: Blood-isolated DNA was collected from 6 participants from EU and 15 from SA. Patients were categorized into 3 groups: RHTN (SA; n=5 and EU; n=6), controlled-HTN (n=5), and normotensive (n=5). DNA was used for Whole Exome Sequencing (WES) analysis. Library preparation and exome capture were done using the MGIEasy Universal DNA library prep and exome capture v5 probe set. Mapping was done using GATK, and the variant calling and annotation were performed using with the SIFT tool and R software. Results: PCA analysis and minimum spanning network showed significant genetic diversity between EU and SA populations. WES identified 16 common genes, with 207 and 220 genes associated to RHTN in EU and SA, respectively. These genes were involved in cardiac electrical conduction (K+/Ca++ channels) and lipid storage (HDL deficiency). In addition, SNV within pharmacogenes in SA (CYP2D6, CYP3A5, APOE) and EU (ADD1) cohorts alongside genes linked to disease susceptibility (RyR1 and PPP1CA) were also identified. RyR1 and PPP1CA are both implicated in HTN development through their roles in calcium signaling and vascular smooth muscle cell function. Noteworthy, two SNVs, rs121918006 and rs61732908, within RyR1 were previously linked to HTN. Conclusions: The large genetic differences observed between EU and SA subjects highlight the diverse genetic landscape surrounding RHTN. Notably, specific genes and their related SNV that associated to cardiac calcium channels and lipid storage could show potential targets for personalized therapeutic intervention. Scientific Session 15: Exploring Novel Therapeutic Approaches to Kidney Disease

Role of Cav2.3 (R-type) Calcium Channel in Pain and Analgesia: A Scoping Review.

Voltage-gated calcium channels (VGCCs) play an important role in pain development and maintenance. As Cav2.2 and Cav3.2 channels have been identified as potential drug targets for analgesics, the participation of Cav2.3 (that gives rise to R-type calcium currents) in pain and analgesia remains incompletely understood. Identify the participation of Cav2.3 in pain and analgesia. To map research in this area as well as to identify any existing gaps in knowledge on the potential role of Cav2.3 in pain signalling, we conducted this scoping review. We searched PubMed and SCOPUS databases, and 40 articles were included in this study. Besides, we organized the studies into 5 types of categories within the broader context of the role of Cav2.3 in pain and analgesia. Some studies revealed the expression of Cav2.3 in pain pathways, especially in nociceptive neurons at the sensory ganglia. Other studies demonstrated that Cav2.3-mediated currents could be inhibited by analgesic/antinociceptive drugs either indirectly or directly. Some articles indicated that Cav2.3 modulates nociceptive transmission, especially at the pre-synaptic level at spinal sites. There are studies using different rodent pain models and approaches to reduce Cav2.3 activity or expression and mostly demonstrated a pro-nociceptive role of Cav2.3, despite some contradictory findings and deficiencies in the description of study design quality. There are three studies that reported the association of single-nucleotide polymorphisms in the Cav2.3 gene (CACNA1E) with postoperative pain and opioid consumption as well as with the prevalence of migraine in patients. Cav2.3 is a target for some analgesic drugs and has a pro-nociceptive role in pain.

Abstract P153: The Role of Lipoprotein Lipase Activation in Vascular Aging

Lipoprotein metabolism plays a role in cardiovascular diseases and becomes impaired with aging. Angiopoietin-like proteins (ANGPTLs) regulate lipoprotein lipase (LPL) and endothelial lipase (EL), key hydrolases in triglyceride catabolism. We hypothesized that ANGPTL3 and ANGPTL4 would be elevated in aging and that the response to LPL activation would be impaired in mesenteric resistance arteries (MRAs) from old rats. To assess this, MRAs were isolated from 3 and 16-month-old male and female Fischer344 rats and mounted on wire myographs. Concentration-response curves (CRC) to phenylephrine (PE, 10nM-100μM), Ca 2+ channel agonist Bay-K8644 (10nM-30nM), and acetylcholine (ACh, 0.1nM-100uM) were performed with or without LPL activator, NO-1886 (10uM and 50uM). Protein expression was assessed by Western blot. We show for the first time that circulating ANGPTL3 (young: 1.5±0.8 vs old: 5±0.7) and ANGPTL4 (young: 1.7±0.3 vs old: 2.5±0.5) are increased in aging. In MRAs from young rats, NO-1886 attenuated PE-induced contraction in males (Emax; vehicle: 106±3 vs NO-1886 10uM: 86 ± 5* vs NO-1886 50uM: 69±8*, p&lt;0.05) and females (Emax; vehicle: 104±4 vs NO-1886 10uM: 91±5* vs NO-1886 50uM: 75±8*, p&lt;0.05). While 16-month-old males presented a similar reduction in contraction (Emax; vehicle: 105±6 vs NO-1886 10uM: 88±11* vs NO-1886 50uM: 73±17*, p&lt;0.05), in females only 50uM showed a significant anti-contractile effect in a sex-dependent manner (Emax; vehicle: 100±7 vs NO-1886 10uM: 95±7 vs NO-1886 50uM: 83±22*, p&lt;0.05). CRC to bay-K8644 showed decreased contraction after NO-1886 incubation (Emax; vehicle: 16±8 vs NO-1886 50uM: 5±3) indicating that L-type Ca 2+ channel Ca 2+ influx isn’t involved in NO-1886’s anti-contractile effect. NO-1886 incubation did not change the maximal ACh response in young rat MRAs, but a rightward shift in the curve was seen in both sexes. As expected, MRAs from old males (Emax; young: 97±2 vs old: 86±7) and females (Emax; young: 95±2 vs old: 92±6) had decreased maximal relaxation to ACh, compared to young rats. Interestingly, in old rats NO-1886 induced further impaired relaxation to ACh in males (Emax; vehicle: 86±7 vs NO-1886 10uM: 78±14) and females (Emax; vehicle: 92±6 vs NO-1886 10uM: 77±22). Together, this data suggests (1) ANGPTL3 and ANGPTL4 are increased in old rats, (2) LPL/EL activity diminished with age in females, but not males, and (3) while NO-1886 exerts an anti-contractile effect, it can also induce endothelial dysfunction.

P082 HOW LONG DO BLOOD PRESSURE LOWERING DRUGS TAKE TO WORK? A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS

Background: Evidence on the time course of antihypertensive drug (AHTD) efficacy is crucial to guide the frequency of visits recommended in guidelines and when it is appropriate to wait for further effects to accrue. Objective: To assess how quickly AHTD therapy works to lower blood pressure (BP). Methods: We systematically searched multiple electronic databases for relevant randomized, double-blind, placebo-controlled trials of untreated adults. These trials compared fixed doses of AHTDs from the five major classes to a placebo for a minimum of four weeks and reported BP data at baseline, and at least at weeks 2 and 4. Primary outcomes were systolic and diastolic BP reduction at weeks 2, 4, and 8. A fixed-effect meta-analysis was conducted, and a best-fit exponential association model was used to evaluate BP-lowering efficacy over time. Results: A total of 94 trials (25,637 participants) were included. Trial duration ranged from 4-16 (median 8) weeks. The best-fit exponential association model predicted that the reductions in systolic BP (SBP) at weeks 1, 2 and 3 were 64%, 79%, 85% of the reductions seen at week 4. There was no evidence of additional BP reduction after week 4. In absolute terms, after week 2 the additional reduction in BP averaged only 1.8/0.8 mmHg by week 4 and 0.4/0.2 mmHg between week 4 and week 8. This finding was consistent across trials by drug class, with no evidence that renin-angiotensin-aldosterone system inhibitors, diuretics, beta-blockers, calcium channel blockers, diuretics or combinations took longer to work. Baseline BP did appear to modify the effect, but still there was no additional benefit after 4 weeks. Conclusion: BP lowering drugs work quickly, with little additional BP lowering occurring after 2 weeks. These findings have relevance for guidelines and for addressing treatment inertia related to expectation of time needed for drugs to work fully.

Psoriasiform drug eruption: A case series with a review of the literature.

The present case series examined five instances of psoriasiform drug eruption diagnosed between 2014 and 2022 at the study site and 23 cases of drug eruption manifesting psoriasiform lesions which had been reported between 1986 and 2022. The causative drug, distribution of the skin eruptions, clinical latency to eruption, treatment course, and histopathological findings were investigated. The most common causative agents were calcium channel blockers (CCB) (64.5%). Of the 28 cases of psoriasiform drug eruption for which details of the eruption sites were reported, 46.4% occurred on the face, which was slightly higher than the usual distribution of psoriasis. CCB were responsible for 80.0% of the cases of facial skin rash. The mean time from the administration of the suspected drug to eruption onset was 25.0 months (range: 0.5-120 months; median: 13.0 months). In all the cases, the skin rash improved after the causative drug was discontinued. CCB were the most common causative agent, and the eruptions more commonly occurred on the face than in normal psoriasis, suggesting that it is especially important to confirm whether there is a history of CCB administration in psoriasis patients with extensive, facial skin eruptions.

Levosimendan as an Antidote in Experimental Calcium Channel Blocker Intoxication.

The effects of the calcium sensitizer levosimendan on hemodynamics and survival in guinea pigs intoxicated with the calcium blockers verapamil or diltiazem were evaluated in a randomized controlled study. One hundred four animals were randomized to be intoxicated with either verapamil (2.0 mg/kg) or diltiazem (4.5 mg/kg) and thereafter further randomized into 6 groups which received either saline (control), 3 different regimes of levosimendan, calcium chloride, and levosimendan combined with calcium chloride. The hemodynamics and survival of the animals were followed for 60 minutes after intoxication.The negative inotropic effect of calcium blockers was seen as a decrease by over 70% of the positive derivative of the left ventricular pressure. This was reversed by levosimendan. Moreover, both verapamil and diltiazem-induced marked hypotension (-69% and -63% of the baseline value, respectively) which was also reversed by levosimendan. The combined levosimendan and calcium chloride treatment had a synergistic effect in reversing verapamil or diltiazem-induced deterioration in hemodynamics.Both verapamil and diltiazem intoxications decreased the survival rate of guinea pigs to 13%. Levosimendan addition improved survival dose-dependently up to a survival rate of 75% and 88% in the verapamil and diltiazem groups, respectively. Low dose of levosimendan combined with calcium chloride improved survival in verapamil and diltiazem group to 88% and 100%, respectively.In conclusion, the administration of levosimendan improved hemodynamics and survival in calcium channel blocker intoxicated guinea pigs. The synergistic effect of levosimendan and calcium chloride suggests that this combination could be an effective antidote in calcium channel blocker intoxications.

P103 EFFICACY AND SAFETY OF TRIPLE VERSUS DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF DOUBLE-BLIND RANDOMIZED CLINICAL TRIALS

Background: Some patients taking two blood pressure (BP) lowering drugs do not achieve and maintain BP &lt;140/90mmHg on two drugs and substantially more do not reach &lt;130/80 mmHg targets that are increasingly recommended by guidelines. Objective: To evaluate, among adults with hypertension, triple combination of antihypertensive drugs (AHTDs) compared to dual combinations of AHTDs for BP-lowering efficacy and safety. Methods: We searched multiple databases and the USFDA website until December 2023 for randomized, double-blind trials involving adults with hypertension, that compared triple versus dual combinations of AHTDs from five major classes (angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, calcium channel blockers, beta-blockers, and diuretics) over a minimum of 4 weeks. Drugs and doses were categorized by standard daily doses based on WHO daily defined dose. Primary outcomes were reduction in BP and treatment withdrawals due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: Twenty-four trials (15,533 participants) were included. Overall, triple compared with dual combination reduced BP by 5.1/3.7 mmHg (95% CI 4.3-5.9/3.0-4.4, p&lt;0.001 for both), improved BP control by 69% versus 54% (relative risk [RR] 1.35 [95% CI: 1.25%-1.45%], p=&lt;0.001). Incidence of WDAE was 4.2% versus 2.9% (RR 1.9 [95% CI: 1.3-2.4], P=0.004). Addition of a third drug to dual combinations at 0.5, 1, 1.5 and 2 standard doses resulted in additional SBP reduction of 3.4 (95% CI: 2.2-4.6), 6.1 (95% CI: 4.8-7.0), 4.5 (95% CI: 1.7-7.6) and 7.5 (95% CI: 6.2-8.8) mmHg, respectively with no significant difference in incidence of WDAEs [RR 1.63 (95% CI: 0.84-3.18) vs 1.58 (95% CI: 1.14-2.19) vs 0.94 (95% CI: 0.44-1.98)]. Conclusion: Triple combinations of AHTDs reduce BP significantly, compared to dual combinations. Adding a third AHTD to dual combination, at 0.5 or 1 standard dose appear to produce most BP reduction and can avoid dose-related adverse effects.

Efficacy and Safety of Intravenous Diltiazem Versus Metoprolol in the Management of Atrial Fibrillation with Rapid Ventricular Response in the Emergency Department: A Comprehensive Umbrella Review of Systematic Reviews and Meta-analyses.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States, affecting 2.7-6.1 million people. AF can cause symptoms, but when it triggers a rapid ventricular response (RVR), most patients suffer from decompensation. Therefore, we performed an umbrella review of systematic reviews and meta-analyses comparing intravenous (IV) metoprolol and diltiazem to identify discrepancies, fill in knowledge gaps, and develop standardized decision-making guidelines for physicians to manage AF with RVR. A comprehensive search was conducted in PubMed, the Cochrane Library, and Scopus to identify studies for this umbrella review. The overall certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation method, while the quality of the included reviews was evaluated using AMSTAR 2, the Cochrane Collaboration tool, and the Newcastle-Ottawa scale. This study comprehensively analyzed four meta-analyses covering 11 randomized controlled trials and 19 observational studies. The analysis showed that IV diltiazem treatment was significantly more successful in rate control for AF with rapid ventricular response (RVR) than IV metoprolol (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.09-1.56; I 2 = 0%; P = .003). IV diltiazem also led to a significantly greater reduction in ventricular rate (mean difference, -14.55; 95% CI, -16.93 to -12.16; I 2 = 72%; P < .00001), particularly at 10 min. The analysis also revealed a significantly increased risk of hypotension associated with treatment with IV diltiazem (RR, 1.43; 95% CI, 1.14-1.79; I 2 = 0%; P = .002). In conclusion, IV diltiazem therapy achieved better rate control and ventricular rate decrease than metoprolol therapy in AF with RVR. Future clinical trials should compare calcium channel blockers and β-blockers for heart rate control efficacy and safety, considering adverse events.

P026 A PRESCRIPTION TREND ANALYSIS OF ANTIHYPERTENSIVE PHARMACOTHERAPY ACROSS DIFFERENT SPECIALTIES IN INDIA

Objective: To evaluate the temporal trends in the prescription patterns of antihypertensive medications among healthcare practitioners in India. Methods: The IQVIA (formerly Quintiles and IMS Health) prescription audit data came from prescriptions of a panel of 6000 private sector primary care clinicians for the different classes of antihypertensive drugs; beta-blockers(BB), calcium channel blockers(CCB), angiotensin receptor blockers(ARB), angiotensin-converting enzyme(ACE) inhibitors, and diuretics were examined. The analysis encompassed the period from 2014 to 2022. Additionally, combinations of these drug classes involving two or three medications were also subject to analysis. Results: Cardiologists’ prescription rates for antihypertensive medications stood at 21% in 2017 and decreased to 19% by 2023. In 2023, the highest rate of prescribing antihypertensive drugs was observed among consultant physicians, with a rate of 30%, followed by general practitioners at 27%. In addition, during COVID-19, the prescription share of general practitioners was highest (31%). Among antihypertensive medications, the prescription rates for BBs were highest (32%), followed by ARBs &amp; CCBs (25% &amp; 24% respectively). Single-drug formulation of anti-hypertensive medications was the most preferred (60%) among Indian clinicians. Prescription shares of fixed-dose combinations (FDC) of two antihypertensive drugs showed a slight decline (36% in 2017 to 34% in 2023) &amp; FDCs of triple-drug exhibited an upward trend (3% in 2017 to 5% in 2023). Among the two drug FDCs, ARB &amp; diuretics were most preferred (25% prescription share) &amp; triple drug FDCs, CCB, ARB &amp; diuretics were most preferred. Conclusions: Cardiovascular medications are prominent in the Indian pharmaceutical market, with antihypertensives standing out as one of the most frequently prescribed treatments. Consultant physicians and general practitioners manage the majority of hypertension cases. Notably, there has been an observed rise in preference for triple-drug combinations of antihypertensive medications, indicating a trend toward a more aggressive approach to hypertension management among Indian clinicians. The insights gleaned from this investigation can further assist healthcare professionals in crafting tailored treatment strategies for individuals grappling with hypertension. Such personalized approaches hold promise in enhancing treatment adherence and ultimately improving the QoL.

Mirogabalin: a novel gabapentinoid or another false dawn?

Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects. Mirogabalin's slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking. Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

Antidiarrheal and Spasmolytic activity of Calendula arvensis Linn in laboratory animal models — the potential role of calcium channel blockade

Antidiarrheal and Spasmolytic activity of Calendula arvensis Linn in laboratory animal models — the potential role of calcium channel blockade

O90 EFFICACY AND SAFETY OF DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS AS FIRST-LINE THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: Hypertension remains the primary cause of mortality worldwide, resulting in about 11 million deaths annually. Despite recent hypertension guidelines advocating for dual combination of antihypertensive drugs as the first-line therapy for most patients, many patients do not receive this therapy. Objective: To assess, among adults with hypertension, dual combinations of AHTDs compared to monotherapy as first-line treatment for blood pressure (BP)-lowering efficacy and safety. Methods: We systematically searched multiple electronic databases until December 2022 to identify relevant randomized, double-blind trials. We included trials involving adults with hypertension who were either treatment naive or untreated for at least 2 weeks, compared dual combinations of drugs with monotherapy from 5 major classes of AHTDs (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics), for a duration of at least 4 weeks and reported data on BP reduction. AHTDs and their combinations were categorized based on standard daily doses. Outcomes were reduction in BP, treatment related adverse events (TRAE) and withdrawals from the treatment due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: We included 98 trials (636 comparisons and 25892 participants). Overall, baseline mean BP was 159/102 mmHg. Overall BP reduction with dual combination compared to monotherapy was 4.4 (CI: 3.8-5.1)/3.5 (CI:3.2-3.9) mmHg. Compared with standard-dose monotherapy, dual combinations of &lt;1 + &lt;1, 1 + &lt;1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing BP by 1.4 (CI: 0.01-2.7)/2.3 (CI: 1.4-3.1), 4.4 (CI: 3.6-5.2)/ 3.3 (CI: 2.9-3.8) and 7.8 (CI: 6.2-8.9)/5.2 (CI: 4.4-5.9) mmHg, respectively. TRAEs [4.8% vs 4.9%; RR 0.92 (0.80 to 1.06)] and WDAEs [0.8% vs 0.9%; RR 1.8 (1.5 to 2.1)] were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy. Conclusion: First-line treatment with low-to-standard dose dual combination therapy is more efficacious and equally safe compared to monotherapy to reduce BP.

Abstract P400: Adherence to First Line Antihypertensive Medication Prescription Recommendations by Race

Introduction: The burden of hypertension is not felt uniformly across the population, with non-Hispanic Black (NHB) adults experiencing the highest rates of hypertension-attributable mortality. The 2017 AHA guidelines recommend calcium channel blockers (CCBs) and thiazide-like diuretics as initial medications for NHB patients, with ACE/ARBs a first line recommendation for other populations. It remains unclear to what degree providers adhere to these race-specific recommendations. Methods: We examined electronic health record data of all hypertensive adults (first blood pressure &gt;140/90 mmHg) starting antihypertensive therapy between 1/2013-12/2022. We excluded patients with a diagnosis of CAD/MI, diabetes, stroke, heart failure, or CKD. We specifically identified the order in which each antihypertensive medication class was prescribed. Results: We identified a total of n=26,862 patients, of whom n=4015 (14.95%) were NHB. CCBs were the most prescribed first line antihypertensive agent for NHBs, followed by ACE/ARBs, then diuretics. By comparison, for all other patients, ACE/ARBs were the most prescribed first agent, followed by CCBs, then beta-blockers (Figure 1A-B). Over the study period, initial use of CCBs increased and diuretic use decreased for both groups (Figure 1C-D). Conclusions: Following guidelines, the most frequently prescribed first line antihypertensive agents were CCBs and ACE/ARBs for NHB and non-NHB populations, respectively, with decreasing diuretic use. The identified patterns increased over the study period, indicating an overuse of ACE/ARB and underuse of diuretics among NHB patients.

Abstract P116: Hypertension Treatment and Control in Canadians with Diabetes

Introduction: 3 million Canadians and 23 million Americans have concurrent hypertension and diabetes. Blood pressure (BP) control reduces the risk of heart attacks, strokes, retinopathy, and kidney disease. We investigated hypertension control rates in patients with diabetes, responses to uncontrolled BP measurements, and use of antihypertensive drug classes. Methods: We performed an observational study of adults with diabetes and hypertension drawing from the IQIVA primary care database (contains data on 1.2 million Canadians). Our first outcome was mean BP at 3, 6, 12, and 24 months after inclusion. Our second outcome was the number of uncontrolled BP measurements (≥130/80) followed by a physician BP check, medication dose/frequency increase, or new medication in the subsequent 6 weeks. Our third outcome (for a subset of individuals with medication data available) was the number of individuals prescribed renin-angiotensin-aldosterone-system inhibitors (RAASi), dihydropyridine calcium channel blockers (DHP-CCBs), or thiazide/thiazide-like diuretics. Results: We identified 10,814 individuals identified with both diabetes and hypertension. Mean BP (in mmHg) remained largely unchanged over 24 months: 136.7/78.6 at 3 months, 135.5/82.2 at 6 months, 137.2/82.8 at 12 months, and 136.6/82.3 at 24 months. Over the two years of follow-up there were 55,381 uncontrolled BP events, and in the subsequent 6 weeks only 27,877 (50.3%) were followed by ≥1 physician BP checks. Among individuals with medication data, there were 16,364 uncontrolled BP events, 33.4% followed by a new antihypertensive medication and 18.2% followed by an antihypertensive dose/frequency change. Of the 6,919 individuals for whom we had medication data, 6,216 (89.8%) were prescribed a RAASi, 2,371 (34.3%) were prescribed a DHP-CCB, and 1,672 (24.2%) were prescribed thiazide/thiazide like diuretic. Conclusion: Over two-thirds (68.8%) of people with diabetes and hypertension had uncontrolled blood pressure that persisted over 2 years during which half of uncontrolled BPs were followed by a physician BP check in 6 weeks, and one-fifth by a antihypertensive dose/frequency change. While almost 90% were treated with RAASi, over a third were on a DHP-CCB and less than one quarter were treated with a thiazide/thiazide like diuretic. Therapeutic inertia and under-prescribing of dual and triple therapy contribute to persistently high BP thus represent opportunities for improvement.

Abstract P309: Vasodilating Effects of Macrolides: ex vivo and in vivo study

Background: Anecdotal reports showed a decrease in blood pressure (BP) values in subjects assuming macrolide antibiotics when co-administered with calcium channel blockers. Recently, in the MAPA study, in patients with primary hypertension given a single dose of macrolide a decrease in BP was observed. However, whether macrolides induce per se vasorelaxation remains unknown. Aim: To investigate if macrolides induce vasorelaxation and to identify the underlying mechanisms. Methods: The effects of 3 macrolides (roxithromycin, azithromycin, clarithromycin) were investigated in a wire myograph in aortas isolated from C57BL/6J mice, following standard protocols. Relaxation/contraction was evaluated in phenylephrine pre-contracted aorta segments exposed to different macrolide concentrations [10 -10 M to 10 -5 M]. Longer-term effects of azithromycin (50 mg/Kg/d intraperitoneally for 14 days) were investigated in vivo in a mouse model of Ang II-induced hypertension. BP was measured with the tail-cuff method; functional and structural/mechanical properties of the aorta and mesenteric arteries were evaluated with wire or pressure myograph, as appropriate. Results: After exposure to macrolides, phenylephrine pre-contracted mice aorta segments showed relaxation (maximum effect: -15-20% vs DMSO). The vasodilating effect was abolished by the removal of the endothelium, and was blunted by L-NAME. In the vivo studies treatment with azithromycin lowered BP values and prevented Ang II-induced endothelial dysfunction. Conclusions: Macrolides exert a vasodilatory action that involves endothelium-dependent NO release. In a model of Ang II-mediated hypertension, azithromycin exerted a BP-lowering effect.