Project description:Cardiovascular disease (CVD) is the number one cause of death worldwide, with hypertension as the leading risk factor for both sexes. As sex may affect responsiveness to antihypertensive compounds, guidelines for CVD prevention might necessitate divergence between females and males. To this end, we studied the effectiveness of calcium channel blockers (CCB) on blood pressure (BP), heart rate (HR) and cardiac function between sexes. We performed a systematic review and meta-analysis on studies on CCB from inception to May 2020. Studies had to present both baseline and follow-up measurements of the outcome variables of interest and present data in a sex-stratified manner. Mean differences were calculated using a random-effects model. In total, 38 studies with 8202 participants were used for this review. In females as compared to males, systolic BP decreased by -27.6 mmHg (95%CI -36.4; -18.8) (-17.1% (95%CI -22.5;-11.6)) versus -14.4 mmHg (95%CI -19.0; -9.9) (-9.8% (95%CI -12.9;-6.7)) (between-sex difference p < 0.01), diastolic BP decreased by -14.1 (95%CI -18.8; -9.3) (-15.2%(95%CI -20.3;-10.1)) versus -10.6 mmHg (95%CI -14.0; -7.3) (-11.2% (95%CI -14.8;-7.7)) (between-sex difference p = 0.24). HR decreased by -1.8 bpm (95%CI -2.5; -1.2) (-2.5% (95%CI -3.4; -1.6)) in females compared to no change in males (0.3 bpm (95% CI -1.2; 1.8)) (between-sex difference p = 0.01). In conclusion, CCB lowers BP in both sexes, but the observed effect is larger in females as compared to males.
Project description:PurposeStudies on the association between the use of calcium channel blockers (CCBs) and breast cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis based on the evidence from observational studies.MethodsWe searched PubMed, MEDLINE, EMBASE and the Cochrane Library for relevant studies published up to and including December 31, 2013. We calculated pooled risk ratios (RRs) for cancer risk.ResultsA total of 17 studies (9 cohort studies, 8 case-control studies) were selected for further study. These studies included 149,607 female subjects, of which 53,812 were CCBs users, who were followed for 2-16 years. The risks of breast cancer among patients receiving CCBs were significantly different for the pooled RRs (95% confidence interval) of cohort studies 1.08 (0.95, 1.20) and case-control studies 0.98 (0.86, 1.09). Differences were also noted for cancer risk, for CCBs use of <5 years 0.96 (0.78, 1.15), and for >5 years 1.01 (0.74, 1.28), as well as for ever used 1.08 (0.95, 1.20), and for current use 1.13 (0.83, 1.42). The RR for studies longer than 10 years was 1.71 (1.01, 2.42), and for studies evaluating nifedipine was 1.10 (0.87, 1.33) and diltiazem was 0.75 (0.40, 1.10).ConclusionsThe long-term use of CCBs appears to have a significant relationship with breast cancer. Well-designed clinical trials are needed to optimize the doses and types of these drugs needed to minimize their carcinogenic potential.
Project description:Dihydropyridine calcium channel blockers (DHPCCBs) are widely used to treat hypertension and chronic coronary artery disease. One common adverse effect of DHPCCBs is peripheral edema, particularly of the lower limbs. The side effect could lead to dose reduction or discontinuation of the medication. The combination of DHPCCBs and renin-angiotensin system blockers has shown to reduce the risk of DHPCCBs-associated peripheral edema compared with DHPCCBs monotherapy. We performed the current systematic review and network meta-analysis of randomized controlled trials (RCTs) to estimate the rate of peripheral edema with DHPCCBs as a class and with individual DHPCCBs and the ranking of the reduction of peripheral edema. The effects of renin-angiotensin system blockers on DHPCCBs network meta-analysis were created to analyze the ranking of the reduction of peripheral edema. A total of 3312 publications were identified and 71 studies with 56,283 patients were included. Nifedipine ranked highest in inducing peripheral edema (SUCRA 81.8%) and lacidipine (SUCRA 12.8%) ranked the least. All DHPCCBs except lacidipine resulted in higher relative risk (RR) of peripheral edema compared with placebo. Nifedipine plus angiotensin receptor blocker (SUCRA: 92.3%) did not mitigate peripheral edema and amlodipine plus angiotensin-converting enzyme inhibitors (SUCRA: 16%) reduced peripheral edema the most. Nifedipine ranked the highest and lacidipine ranked the lowest amongst DHPCCBs for developing peripheral edema when used for cardiovascular indications. The second or higher generation of DHPCCBs combination with ACEIs or ARBs or diuretics lowered the chance of peripheral edema development compared to single DHPCCB treatment.
Project description:Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).
Project description:We aimed to perform a systematic review and meta-analysis to determine the overall effect of the preadmission/prediagnosis use of calcium channel blockers (CCBs) on the clinical outcomes in hypertensive patients with COVID-19. A systematic literature search with no language restriction was conducted in electronic databases in July 2021 to identify eligible studies. A random-effects model was used to estimate the pooled summary measure for outcomes of interest with the preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs at 95% confidence intervals (CIs). The meta-analysis revealed a significant reduction in the odds of all-cause mortality with the preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs (pooled OR = 0.65; 95% CI 0.49-0.86) and a significant reduction in the odds of severe illness with preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs (pooled OR = 0.61; 95% CI 0.44-0.84), and is associated with adequate evidence to reject the model hypothesis of 'no significant difference' at the current sample size. The potential protective effects offered by CCBs in hypertensive patients with COVID-19 merit large-scale prospective investigations.
Project description:Ca(2+) influx via voltage-dependent CaV1/CaV2 channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded calcium channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into calcium channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method 'channel inactivation induced by membrane-tethering of an associated protein' (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated channel inhibition with rapamycin. The results reveal a universal method for developing novel calcium channel blockers that may be extended to develop probes for a broad cohort of unrelated ion channels.
Project description:The effect of calcium channel blockers (CCBs), beta blockers and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) on the prognosis of patients with acute myeloid leukemia (AML) is largely unknown. We collected data on the use of these medications in 1043 patients with AML, excluding promyelocytic leukemia, diagnosed and treated at M. D. Anderson Cancer Center between 2000 and 2012. Treatment with either amlodipine or diltiazem predicted a worse overall survival (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.22-2.06, p < 0.0001). There was no difference in survival depending on whether patients were taking beta blockers, ACE inhibitors or ARBs. The effect of CCBs on survival was independent from the National Comprehensive Cancer Network risk classification, age, performance status, response to treatment, year of diagnosis and CD34 levels, assessed by flow cytometry (HR 1.39, 95% CI 1.05-1.80, p = 0.02). Treatment with either amlodipine or diltiazem predicts worse survival in patients with AML independent of known prognostic factors.
Project description:ObjectiveTo determine whether outpatient exposure to calcium-channel blockers (CCBs) at the time of delivery is associated with an increased risk for postpartum haemorrhage (PPH).DesignCohort study.SettingUnited States of America.Population or sampleMedicaid beneficiaries.MethodsWe identified a cohort of 9750 patients with outpatient prescriptions for CCBs, methyldopa, or labetalol for pre-existing or gestational hypertension whose days of supply overlapped with delivery; 1226 were exposed to CCBs. The risk of PPH was compared in those exposed to CCBs to those exposed to methyldopa or labetalol. Propensity score matching and stratification were used to address potential confounding.Main outcome measuresThe occurrence of PPH during the delivery hospitalisation.ResultsThere were 27 patients exposed to CCBs (2.2%) and 232 patients exposed to methyldopa or labetalol (2.7%) who experienced PPH. After accounting for confounders, there was no meaningful association between CCB exposure and PPH in the propensity score matched (odds ratio 0.77, 95% CI 0.50-1.18) or stratified (odds ratio 0.79, 95% CI 0.53-1.19) analyses. Similar results were obtained across multiple sensitivity analyses.ConclusionsThe outpatient use of CCBs in late pregnancy for the treatment of hypertension does not increase the risk of PPH.
Project description:Giant cell arteritis (GCA) is a systemic vasculitis that may cause ischemic stroke. Rarely, GCA can present with aggressive intracranial stenoses, which are refractory to medical therapy. Endovascular treatment (EVT) is a possible rescue strategy to prevent ischemic complications in intracranial GCA but the safety and efficacy of EVT in this setting are not well-described. A systematic literature review was performed to identify case reports and series with individual patient-level data describing EVT for intracranial GCA. The clinical course, therapeutic considerations, and technique of seven endovascular treatments in a single patient from the authors' experience are presented. The literature review identified 9 reports of 19 treatments, including percutaneous transluminal angioplasty (PTA) with or without stenting, in 14 patients (mean age 69.6 ± 6.3 years). Out of 12 patients 8 (66.7%) with sufficient data had > 1 pre-existing cardiovascular risk factor. All patients had infarction on MRI while on glucocorticoids and 7/14 (50%) progressed despite adjuvant immunosuppressive agents. Treatment was PTA alone in 15/19 (78.9%) cases and PTA + stent in 4/19 (21.1%). Repeat treatments were performed in 4/14 (28.6%) of patients (PTA-only). Non-flow limiting dissection was reported in 2/19 (10.5%) of treatments. The indications, technical details, and results of PTA are discussed in a single illustrative case. We report the novel use of intra-arterial calcium channel blocker infusion (verapamil) as adjuvant to PTA and as monotherapy, resulting in immediate improvement in cerebral blood flow. Endovascular treatment, including PTA with or without stenting or calcium channel blocker infusion, may be effective therapies in medically refractory GCA with intracranial stenosis.