Association Between Serious Hypoglycemia and Calcium-Channel Blockers Used Concomitantly With Insulin Secretagogues.
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ABSTRACT:
SUBMITTER: Nam YH
PROVIDER: S-EPMC8414188 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Association Between Serious Hypoglycemia and Calcium-Channel Blockers Used Concomitantly With Insulin Secretagogues.
Nam Young Hee YH Brensinger Colleen M CM Bilker Warren B WB Flory James H JH Leonard Charles E CE Hennessy Sean S
JAMA network open 20210901 9
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Project description:Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.
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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.
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Project description:Herbicide resistance is a worldwide problem in weed control. This prompts researchers to look for new modes of action to slow down the evolution of herbicide-resistant weeds. This research aims to determine the herbicidal action of thiazolo[3,2-a]pyrimidines derivatives, which are well known as antihypertensive drugs. The phytotoxic effects of ten compounds were investigated using leaf disc discoloration test and seed germination bioassay. At concentrations of 125 to 250 mg/L, the 5-(3-Fluoro-phenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester (c) was highly active against Oldenlandia verticillata and Eleusine indica. At application rates of 1.25 to 2.5 kg ai/ha, formulated c demonstrated selective post-emergence and pre-emergence herbicidal activity against O. verticillata, E. indica and Cyperus iria. In the crop tolerance test, formulated c outperformed the commercial herbicide diuron, with aerobic Oryza sativa being the most tolerant, followed by Zea mays, and Brassica rapa. The addition of calcium chloride partially nullified compound c's inhibitory effects on weed shoot growth, indicating that it has potential as a calcium channel blocker. Compound c acted by triggering electrolyte leakage without affecting photosystem II. These findings imply that c could be explored further as a template for developing new herbicides with novel modes of action.
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Project description:There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.
| S-EPMC9170157 | biostudies-literature
Project description:Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.
| S-EPMC3314354 | biostudies-literature
Project description:ObjectiveThis study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood-brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk.MethodsWe identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blocker prescriptions 2 years before index date/PD diagnosis.ResultsEmploying logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity score, we found that subjects prescribed dihydropyridines (excludes amlodipine) between 1995 and 2 years prior to the index date were less likely to develop PD (odds ratio, 0.73; 95% confidence interval, 0.54-0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications.InterpretationOur data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-type channel blockers.
| S-EPMC2917467 | biostudies-literature
Project description:Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (CaV2.2) is a well-validated pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of N-sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of N-sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both CaV2.2 and CaV3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in CaV2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood-brain barrier. Representative N-sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported N-acyl analogues. These compounds were also found to be relatively stable in an in vitro liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the CaV2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational changes required to open and allow calcium ions to pass through.
| S-EPMC11253866 | biostudies-literature
Project description:IntroductionUse of certain antihypertensive medications has been an area of interest during the COVID-19 pandemic, and several hypotheses have been developed regarding the effects of renin-angiotensin system blockers as well as calcium channel blockers in those infected with COVID-19. We seek to determine the association between exposure to ACEI, ARB, and CCB and outcomes in those admitted to the hospital with COVID-19 infection.MethodsThis retrospective cohort study included 841 adult patients hospitalized with COVID-19 infection at the University of Chicago Medical Center between March 25 and June 22, 2020. Out of these 841, 453 patients had a personal history of hypertension. For the first part, we evaluated primary outcomes of in-hospital mortality and ICU admission in hospitalized COVID-19 patients based on their exposure to particular medications regardless of a personal history of hypertension and compared them with those who were not on these medications. For the second part, we evaluated the aforementioned outcomes in 453 patients with a personal history of hypertension based on their medication exposure. Secondary outcomes of length of stay, readmission rate, and new-onset dialysis requirement were also compared across the study groups.ResultsOut of 841 patients, 111 (13.19%) were on ACEI/ARB (median age: 66.1, SD 15.4; 52.25% females) and 730 (86.80%) were not on them (median age: 56.6, SD 20.3; 50.14% females), while 277 (32.93%) used CCB (median age: 64.6, SD 15.2; 57.04% females) and 564 (67.06%) did not use CCB (median age: 54.6, SD 21.2; 47.16% females). After adjusting for demographics and covariates, neither ACEI/ARB nor CCB exposure was associated with any effect on mortality, but ACEI/ARB exposure was associated with 42% reduction in risk of ICU admissions (OR 0.58, 95% CI [0.35, 0.95], p value 0.03). In addition, combined use of ACEI/ARB and CCB was associated with statistically significant (45%) reduction in ICU admission (OR 0.55, 95% CI [0.32, 0.94], p value 0.029). Out of 453 patients with a personal history of hypertension, 85 (18.76%) were taking ACEI/ARB (median age 65, SD 15.6; 56.47% females) and 368 (81.24%) were not on ACEI/ARB (median age 62.8, SD 16.4; 54.89% females), while 208 (45.92%) out of 453 were on CCB (median age 65; SD 14.8; 60.1% females) and 245 (54.08%) were not on CCB (median age 61.7, SD 17.3; 51.02% females). In the fully adjusted model in this group, ACEI use was associated with 71% reduction in in-house mortality (OR 0.29, 95% CI [0.09, 0.93], p value 0.03).Discussion/conclusionAmong all hospitalized patients with COVID-19 infection, exposure to ACEI/ARB, as well as combined exposure to ACEI/ARB and CCB, were associated with reduced incidence of ICU admissions. In those admitted patients who had a personal history of hypertension, there was a trend towards reduced in-hospital mortality in those exposed to ACEI.
| S-EPMC8089461 | biostudies-literature
Project description:PurposeWe investigated the impact of four types of antihypertensive medications, angiotensin receptor blockers (ARBs), beta blockers (BBs; both selective and non-selective), calcium channel blockers (CCBs), and thiazide diuretics (TDs) on survival outcomes in epithelial ovarian cancer (EOC).Materials and methodsA single-institutional retrospective chart review of 878 patients with EOC was performed. Survival was compared according to use of the four antihypertensive medications during primary treatment. Propensity score matching (ratio 1:3) was performed to control possible associated covariates, such as age, International Federation of Gynecology and Obstetrics stage, residual status after primary debulking surgery, and co-morbidity.ResultsAmong 878 patients, 56 patients (6.4%) were ARB users, 62 (7.1%) were BB users, 107 (12.2%) were CCBs users and 32 (3.6%) used TDs. Median progression-free survival (PFS) for ARB, BB, and CCB users was 37.8, 27.2, and 23.6 months compared with 33.6 months for non-users. ARB was associated with 35% decreased risk of disease progression (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.42 to 0.99; p=0.046) in multivariate analysis. After propensity score matching, median PFS for ARB users was 37.8 months and ARB use remained to be associated with lower recurrence rate in univariate (p=0.035) and multivariate analysis (HR, 0.60; 95% CI, 0.39 to 0.93; p=0.022).ConclusionIn this study, ARBs use during primary treatment is associated with lower recurrence in EOC patients. However, CCBs, BBs, and TDs did not show beneficial impact.
| S-EPMC7176948 | biostudies-literature