Comparison between beta-blockers and calcium channel blockers in patients with atrial fibrillation according to renal function.

BACKGROUND: Rate control is the most commonly employed first-line management strategy for atrial fibrillation (AF) in patients with chronic kidney disease (CKD). Principal agents used to control heart rate (HR) include beta-blockers (BB) and nondihydropyridine calcium channel blockers (ND-CCB). However, there is a paucity of published studies of the differences between those drugs in CKD patients. HYPOTHESIS: The present study aimed to investigate the differences, in terms of hospitalizations due to a poor HR control, in patients with AF under a rate-control strategy according to glomerular filtration rate (GFR). METHODS: The study cohort included 2804 AF patients under rate-control regime (BB or ND-CCB) between January 2014 and April 2020. The end point, determined by competing risk regression, was hospitalizations for AF with rapid ventricular response (RVR), slow ventricular response (SVR), and need for pacemaker. RESULTS: On multivariate analysis, there were no statistical differences between ND-CCB and BB for subjects with GFR > 60 mL/min/1.73 m2 (subdistribution heart rate [sHR] 0.850, 95% confidence interval [CI]: 0.61-1.19; p = .442) and GFR 30-59 mL/min/1.73 m2 (sHR 1.242, 95% CI: 0.80-1.63; p = .333), while in patients with GFR < 30 mL/min/1.73 m2, ND-CCB therapy was associated with increased hospitalizations due to poor HR control (sHR 4.53, 95% CI: 1.19-17.18; p = .026). CONCLUSION: In patients with GFR ≥ 30 mL/min/1.73 m2, the choice of ND-CCB or BB had no impact on hospitalizations due to poor HR control, while in GFR < 30 mL/min/1.73 m2, a possible association was detected. The effects of these drugs on GFR < 30 mL/min/1.73 m2 would require further investigation.

Chinese patent medicine combined with calcium channel blockers in the treatment of essential hypertension:a Bayes network meta-analysis and systematic review.

Backgroud: The co-administration of Chinese patent medicine with calcium channel blockers (CCBs) is a prevalent practice in China for treating essential hypertension (EH). However, robust evidence supporting the efficacy and safety of tailored combinations of different Chinese patent medicines with CCBs, according to individual patient conditions, is still limited. This study sought to elucidate the efficacy and safety of these combinations using a systematic review and network meta-analysis. Materials and methods: Relevant studies were sourced from established databases, incorporating randomized controlled trials published up to 1 February 2023. The ROB2 tool from the Cochrane Collaborative Network was employed to independently assess and cross-verify the quality of the included literature. A network meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 and PRISMA-Network Meta-Analyses (PRISMA-NMA) guidelines. A Bayesian network meta-analysis was utilized to gauge the efficacy and safety of distinct integrations of Chinese patent medicine and CCBs. Primary outcomes were interpreted using a paired fixed-effect meta-analysis. Publication bias was appraised through Egger's test and represented with funnel plots. All statistical analyses were executed within the R statistical framework. Results: Following rigorous selection, data extraction, and bias evaluation, 36 articles were incorporated. Tianma Gouteng Granule, when combined with CCBs, displayed superior efficacy in reducing systolic blood pressure (SBP). In terms of diastolic blood pressure (DBP) reduction, Songling Xuemaikang Capsule combined with CCBs emerged as the most effective. Regarding enhancement of antihypertensive effective rates, Qinggan Jiangya Capsule paired with CCBs demonstrated optimal results. For diminishing Traditional Chinese Medicine syndrome scores, the Qiangli Dingxuan Tablet and CCBs combination proved most beneficial. When aiming to reduce total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, Tianma Gouteng Granule and CCBs showcased superior results. In contrast, the combination of Songling Xuemaikang Capsule and CCBs was more effective in reducing LDL-C, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Conclusion: This study underscores variability in outcomes from combining Chinese patent medicine and CCBs for hypertension, emphasizing the importance of personalized medicinal combinations, especially Tianma Gouteng Granule and Songling Xuemaikang Capsule. The results offer robust evidence to inform clinical guidelines for essential hypertention and significantly aid clinician in seleting appropriate Chinese patent medicines for treatment.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.

Calcium channel blockers in patients with pulmonary arterial hypertension receiving PAH-specific treatment.

BACKGROUND: Calcium channel blockers (CCB) are the first effective therapy for vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH). However, the advent of modern PAH-specific drugs may undermine the role of vasoreactivity tests and CCB treatment. We aimed to clarify the effect of acute vasoreactivity testing and CCB on patients with IPAH receiving PAH-specific treatment. METHODS: We retrospectively investigated consecutive patients with IPAH (n = 136) diagnosed between 2000 and 2020 and collected data from patients who underwent acute vasoreactivity testing using inhaled nitric oxide (NO). The effects of vasoreactivity testing and CCB therapy were reviewed. Long-term survival was analysed using the Kaplan-Meier method. RESULTS: Acute vasoreactivity testing was performed in 49% of patients with IPAH (n = 67), including 23 patients (34%) receiving PAH-specific therapy without vasoreactivity testing. Eight patients (12%), including three patients (4.4%) receiving PAH-specific therapy, presented acute responses at vasoreactivity testing. They received high-dose CCB therapy (CCB monotherapy for five patients [7.5%] and CCB therapy and PAH-specific therapy for three patients [4.4%]). They presented a significant improvement in clinical parameters and near-normalisation of haemodynamics (mean pulmonary arterial pressure decreased from 46 [interquartile range: 40-49] to 19.5 [interquartile range: 18-23] mmHg [P < .001] at 1-year follow-up). All eight vasoreactive responders receiving CCB therapy showed better long-term survival than non-responders treated with PAH-specific therapy (P < .001). CONCLUSIONS: CCB therapy benefited patients with IPAH who showed acute response to vasoreactivity testing using inhaled NO, even when receiving modern PAH-specific therapy. Acute vasoreactive responders may benefit more from CCB than from PAH-specific therapy.

Novel protocol for multiple-dose oral administration of the L-type Ca2+ channel blocker isradipine in mice: A dose-finding pharmacokinetic study.

Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca2+ channels in human disease. Therefore, the inhibition of L-type Ca2+ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca2+ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca2+ channel blockers.

Effect of nifedipine administration before embryo transfer on reproductive outcome in ICSI cycles, a double-blind control trial study.

PURPOSE: Nifedipine is a calcium channel blocker with smooth muscle relaxing properties. This study set out to investigate the efficacy of nifedipine administered orally before embryo transfer (ET) on the improvement of the intracytoplasmic sperm injection (ICSI) outcome. This randomized, double-blind, comparator-controlled, was carried out between 2019 and 2020 in the infertility center of Babol, Iran. 200 women candidates for ICSI and recipients of frozen-thawed ET aged 18-40 years were randomly assigned in the ratio 1:1 to an intervention group that received nifedipine 20 mg tablets orally 30 min before ET (n = 100) or to a group of placebo (n = 100). A randomization center in Babol University of Medical Science used computer-generated numbers to allocate treatments. The allocation treatment was blind to the participants, the sonographer of endometer monitoring, the staff of the ICSI laboratory, and the outcome assessor. The primary analysis was based on the intention-to-treat principle done on 200 participants, (n = 100), comparing chemical pregnancy rates in the two comparing groups at 14 days' follow-up after ET. Implantation rate and clinical pregnancy were considered secondary outcomes. RESULT: 200 participants were analyzed. There is no significant difference in the number of oocytes and the quality of embryos in the nifedipine and placebo groups. Despite a numerical increase in the rate of chemical pregnancy, there were no statistical differences in the study group versus the comparison group (24% vs 14%, P = 0.1, rate ratio 0.88, 95% CI 0.77 to 1.01), respectively. Also, no significant increase in clinical pregnancy was found compared with the placebo (17% vs 8%, P = 0.26, rate ratio 0.90, 0.81 to 1.00). CONCLUSION: Nifedipine administered orally 30 min before embryo transfer did not improve the chemical pregnancy rate, and clinical pregnancy rate in infertile women undergoing ICSI. This trial has been registered on the Iranian Clinical Trials Registration Site (IRCT) with the number IRCT20180417039338N3.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional classification I/II or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, hereditary, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

The Use of Methylene Blue in Conjunction With Hydroxocobalamin and Multiple Pressors to Treat Severe Vasoplegia in a Patient Due to Calcium Channel Blocker Toxicity: A Case Report.

Vasoplegia, the demonstration of persistently low systemic vascular resistance (SVR) and resistant hypotension in the presence of a normal cardiac index despite aggressive resuscitation attempts, is a serious clinical diagnosis that requires prompt treatment to prevent patient morbidity and mortality. Currently, treatment of vasoplegia involves treatment with vasopressors such as vasopressin, norepinephrine, and hydroxocobalamin. However, some evidence suggests that in addition to this treatment regimen, the addition of methylene blue may result in a reduction in overall norepinephrine equivalent vasopressor requirements, increased mean arterial pressure, and an improved clinical course. Here, we report the case of a 64-year-old male patient who presented to the ED after being found unresponsive and covered in emesis at home. The patient's presentation was complicated by worsening dyspnea, hypotension, and hemodynamic instability, requiring intubation and admission to the ICU for management of undifferentiated shock of unclear etiology and acute respiratory failure. Urine studies were consistent with a diagnosis of vasoplegia due to dihydropyridine calcium channel blocker toxicity, which was confirmed by pill counting of his home medications in the setting of recent paranoia and depression. The patient was treated aggressively with vasopressors, including vasopressin, phenylephrine, and epinephrine, as well as a combination of hydroxocobalamin and methylene blue. He was also started on a calcium and insulin drip. Upon initiation of non-catecholamine agents for vasoplegia, his clinical course quickly improved, and he was weaned from all vasopressors. He regained hemodynamic stability, was successfully extubated, evaluated by psychiatry, and discharged from the hospital in a stable condition on day 15 with the continuation of outpatient psychiatric services.

Effect of intravenous lipid therapy in critically ill pediatric patients with calcium channel blocker toxicity.

BACKGROUND: Overdose with calcium-channel blockers (CCBs) still maintain their importance with a high lethality rate after exposure. We report the intravenous lipid emulsion therapy (ILE) therapy in our CCB overdose patients. METHODS: We retrospectively analyzed the records of 6 patients with CCB intoxication from Batman Training and Research Hospital PICU between March 2021 and September 2022. Patients aged 0-18 years who received ILE treatment for CCB poisoning were included. RESULTS: All six patients ingested CCB with the intention of committing suicide and were followed up in the pediatric intensive care unit (PICU). All patients received ILE therapy due to hemodynamic instability despite intravenous fluid boluses, calcium, glucagon, insulin-dextrose, and vasoactive agents. Vasoactive-Inotropic Score (VIS) decreased after ILE treatment. All patients were transferred from the PICU after recovery. CONCLUSIONS: ILE therapy should be kept in mind as a salvage therapy in hemodynamically unstable CCB poisoning cases that do not respond to initial and advanced options.

T- and L-Type Calcium Channels Maintain Calcium Oscillations in the Murine Zona Glomerulosa.

BACKGROUND: The zona glomerulosa of the adrenal gland is responsible for the synthesis and release of the mineralocorticoid aldosterone. This steroid hormone regulates salt reabsorption in the kidney and blood pressure. The most important stimuli of aldosterone synthesis are the serum concentrations of angiotensin II and potassium. In response to these stimuli, voltage and intracellular calcium levels in the zona glomerulosa oscillate, providing the signal for aldosterone synthesis. It was proposed that the voltage-gated T-type calcium channel CaV3.2 is necessary for the generation of these oscillations. However, Cacna1h knock-out mice have normal plasma aldosterone levels, suggesting additional calcium entry pathways. METHODS: We used a combination of calcium imaging, patch clamp, and RNA sequencing to investigate calcium influx pathways in the murine zona glomerulosa. RESULTS: Cacna1h-/- glomerulosa cells still showed calcium oscillations with similar concentrations as wild-type mice. No calcium channels or transporters were upregulated to compensate for the loss of CaV3.2. The calcium oscillations observed were instead dependent on L-type voltage-gated calcium channels. Furthermore, we found that L-type channels can also partially compensate for an acute inhibition of CaV3.2 in wild-type mice. Only inhibition of both T- and L-type calcium channels abolished the increase of intracellular calcium caused by angiotensin II in wild-type. CONCLUSIONS: Our study demonstrates that T-type calcium channels are not strictly required to maintain glomerulosa calcium oscillations and aldosterone production. Pharmacological inhibition of T-type channels alone will likely not significantly impact aldosterone production in the long term.

Anti-inflammatory activity of benidipine hydrochloride in LPS-activated mammalian macrophages.

Benidipine hydrochloride (BH), a medication frequently used by the hypertension patients, acts as a calcium channel blocker. However, its effects on the macrophages have not been investigated thus far. Our goal was investigating the effect of the benidipine hydrochloride to modulate the J774.2 murine macrophage cells inflammatory activity. Our results suggest that in the absence of a standard stimulating agent (LPS) BH did not stimulate the macrophages to produce pro-inflammatory IL-12p40, TNF-α, GM-CSF and IL-6 cytokines. However, when BH was administrated to the cells in the presence of LPS as stimulating agent, it reduced the production of these pro-inflammatory cytokines. Therefore, it had anti-inflammatory activity. At the clinical setting this study suggests that BH can be utilized as hypertension drug that can suppress the inflammation associated with it.

Effect of calcium-channel blockers on the risk of active tuberculosis and mortality: systematic review and meta-analysis.

Introduction: Recent studies suggest that calcium channel blockers (CCBs) could reduce the risk of active tuberculosis and improve clinical outcomes. We aimed to synthesize the evidence regarding the effect of CCBs on the risk of developing active tuberculosis and mortality. Methods: We systematically searched for observational studies and clinical trials published in six databases until 31 August 2023, following a PECO/PICO strategy. Results: We included eight observational studies, 4,020,830 patients, among whom 241,761 had diabetes mellitus and 30,397 had active tuberculosis. According to our results, CCBs reduce the risk of developing active tuberculosis by 29% (RR 0.71; 95% CI 0.67-0.75) in patients with and without diabetes mellitus. However, CCBs do not show any benefit in terms of tuberculosis-related mortality (RR 1.00; 95% CI 0.98-1.02). For both outcomes, no statistical heterogeneity was found (I2 = 0, p > 0.10). This protective effect of CCBs on the risk of active tuberculosis remained independent of the type of patient (with diabetes mellitus vs. general population) or the class of CCB administered (DHP-CCB vs. non-DHP-CCB) (test for subgroup differences I2 = 0, p > 0.10). However, this beneficial effect was more significant among the general population (RR 0.70; 95% CI 0.66-0.74) compared to patients with diabetes mellitus (RR 0.72; 95% CI 0.61-0.86) and among those patients treated with DHP-CCBs (RR 0.69; 95% CI 0.63-0.74) compared to patients treated with non-DHP-CCBs (RR 0.72; 95% CI 0.67-0.78). Conclusion: CCBs may reduce the risk of active TB in patients with diabetes and the general population. On the contrary, CCBs do not seem to have a protective effect on tuberculosis-related mortality. However, more evidence is still needed. We recommend developing clinical trials to verify these findings, including more diverse populations. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352129].

The Management of Drug-Induced Gingival Enlargement in a Patient With Preexisting Periodontitis.

Antihypertensives such as amlodipine, which is a family of calcium channel blockers (CCBs), possess a limitation by causing gingival enlargement on long-term use. Gingival enlargement hinders the patient's oral hygiene maintenance and causes more plaque accumulation and inflammation. The severity of the condition is dependent on dose and duration. When untreated, this leads to functional and esthetic disabilities. This is a case report of amlodipine-induced gingival enlargement in a young, chronic periodontitis patient who was under 5 mg of amlodipine for six months. Upon diagnosis, the patient underwent periodontal surgery and supportive periodontal therapy, which significantly improved her periodontal health in a one-year follow-up period.

Multivariate Approaches in Quantitative Structure-Property Relationships Study for the Photostability Assessment of 1,4-Dihydropyridine Derivatives.

1,4-dihydropyridines (1,4-DHPs) are widely recognized as highly effective L-type calcium channel blockers with significant therapeutic benefits in the treatment of cardiovascular disorders. 1,4-DHPs can also target T-type calcium channels, making them promising drug candidates for neurological conditions. When exposed to light, all 1,4-DHPs tend to easily degrade, leading to an oxidation product derived from the aromatization of the dihydropyridine ring. Herein, the elaboration of a quantitative structure-property relationships (QSPR) model was carried out by correlating the light sensitivity of structurally different 1,4-DHPs with theoretical molecular descriptors. Photodegradation experiments were performed by exposing the drugs to a Xenon lamp following the ICH rules. The degradation was monitored by spectrophotometry, and experimental data were elaborated by Multivariate Curve Resolution (MCR) methodologies to assess the kinetic rates. The results were confirmed by the HPLC-DAD method. PaDEL-Descriptor software was used to calculate molecular descriptors and fingerprints related to the chemical structures. Seventeen of the 1875 molecular descriptors were selected and correlated to the photodegradation rate by means of the Ordinary Least Squares (OLS) algorithm. The chemometric model is useful to predict the photosensitivity of other 1,4-DHP derivatives with a very low relative error percentage of 5.03% and represents an effective tool to design new analogs characterized by higher photostability.

Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage-gated calcium channel ligand drugs.

AIMS: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Cav ). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants. METHODS: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method. RESULTS: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses. CONCLUSIONS: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

The effect of calcium channel blockers on digital ulcers in systemic sclerosis: data from a prospective cohort study.

Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p < 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p < 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p < 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU.

Extract of Chenopodium album lowers blood pressure in rats through endothelium-dependent and -independent vasorelaxation.

OBJECTIVES: To investigate the antihypertensive effect of crude extract of Chenopodium album (Ca.Cr), based on its medicinal use in hypertension. METHODS: Ca.Cr and its fractions were tested in-vivo in normotensive anesthetized rats for blood pressure-lowering effect. In-vitro experiments were performed on isolated rat aortae to explore the vascular mechanism(s). RESULTS: In normotensive anesthetized rats, Ca.Cr produced a dose-dependent (1-300mg/kg) fall (30%mmHg) in mean arterial pressure (MAP). Among the fractions, nHexane was the most potent (46% fall). In rat aortic rings precontracted with phenylephrine (PE), Ca.Cr and its fractions (except Ca.Aq) produced endothelium-dependent vasorelaxation, which was partially reversed with endothelium removal and by pretreating intact aortic rings with L-NAME (10µM) and atropine (1µM). This relaxation to Ca.Cr and fractions (nHexane, ethylacetate and chloroform) was also eliminated with indomethacin pretreatment, however, it unmasked a vasoconstriction effect with Ca.Cr only. Surprisingly, the aqueous fraction produced a calcium sensitive strong vasoconstriction instead of vasorelaxation. The crude extract and its fractions (except Ca.Aq) also antagonized vasoconstriction induced with high K+ (80mM), suggesting calcium antagonistic effect. The aqueous fraction produced mild vasorelaxation against high K+. This effect was further confirmed when pretreatment of the aortic rings with different concentrations of crude extract and fractions suppressed CaCl2 concentration response curves, similar to verapamil. In acute toxicity test, Ca.Cr extract was found safe up to 5g/kg body weight in mice. CONCLUSION: These findings suggest that crude extract and fractions of C. album produced vasorelaxant effect through muscarinic receptors linked-NO pathway, prostaglandin (endothelium-dependent) and calcium antagonism (endothelium-independent), which explains the blood pressure lowering effect of C. album in rats.

Thiazide Diuretics and Risk of Colorectal Cancer: A Population-Based Cohort Study.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Environmental fate and risk evolution of calcium channel blockers from chlorine-based disinfection to sunlit surface waters.

Organic micropollutants present in disinfected wastewater and discharged to sunlit surface waters may be transformed by multiple processes, such as chlorination due to the presence of chlorine residuals, solar irradiation as well as solar-irradiated chlorine residues. This study reports, for the first time, the multi-scenario degradation kinetics, transformation products, and risk evolution of calcium channel blockers (CCBs), a class of emerging pharmaceutical contaminants with worldwide prevalence in natural waters and wastewater. It was found that the chlorination of the studied CCBs (amlodipine (AML) and verapamil (VER)) was dominated by the reaction of HOCl with their neutral species, with second-order rate constants of 6.15×104 M-1 s-1 (AML) and 7.93×103 M-1 s-1 (VER) at pH 5.0-11.0. Bromination is much faster than chlorination, with the measured kapp,HOBr values of 2.94×105 M-1 s-1 and 6.58×103 M-1 s-1 for AML and VER, respectively, at pH 7.0. Furthermore, both CCBs would undergo photolytic attenuations with hydroxyl and carbonate radicals as the dominant reactive species in water. Notably, free chlorine mainly contributed to their abatement during the solar/chlorine treatment. Additionally, the halogen addition on the aromatic ring was observed during chlorination and bromination of the two CCBs. Cyclization was observed under solar irradiation only, while the aromatic ring was opened in the solar/chlorine system. Some products generated by the three transformation processes exhibited non-negligible risks of high biodegradation recalcitrance and toxicity, potentially threatening the aquatic environment and public health. Overall, this study elucidated the environmental fate of typical CCBs under different transformation processes to better understand the resulting ecological risks in these environmental scenarios.

Recent Developments in Drug Targets and Combination Therapy for the Clinical Management of Hypertension.

Raised blood pressure is the most common complication worldwide that may lead to atherosclerosis and ischemic heart disease. Unhealthy lifestyles, smoking, alcohol consumption, junk food, and genetic disorders are some of the causes of hypertension. To treat this condition, numerous antihypertensive medications are available, either alone or in combination, that work via various mechanisms of action. Combinational therapy provides a certain advantage over monotherapy in the sense that it acts in multi mechanism mode and minimal drug amount is required to elicit the desired therapeutic effect. Such therapy is given to patients with systolic blood pressure greater than 20 mmHg and/or diastolic blood pressure exceeding 10 mmHg beyond the normal range, as well as those suffering from severe cardiovascular disease. The selection of antihypertensive medications, such as calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and low-dose diuretics, hinges on their ability to manage blood pressure effectively and reduce cardiovascular disease risks. This review provides insights into the diverse monotherapy and combination therapy approaches used for elevated blood pressure management. In addition, it offers an analysis of combination therapy versus monotherapy and discusses the current status of these therapies, from researchbased findings to clinical trials.