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Clinical Cardiology Sep 1994Amlodipine, a third-generation dihydropyridine calcium antagonist, has a mode of action and pharmacodynamic profile which are comparable to those of conventional... (Review)
Review
Amlodipine, a third-generation dihydropyridine calcium antagonist, has a mode of action and pharmacodynamic profile which are comparable to those of conventional compounds in this series, such as nifedipine. Its physicochemical behavior, however, appears to be somewhat different. A pKa value of 8.7 means that amlodipine is predominantly present in the ionized form at a physiologic pH. It possesses, therefore, a strong affinity for cell membranes. These phenomena apparently contribute to amlodipine's unique pharmacokinetic profile, which is characterized by almost complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic biodegradation. This profile translates into potential clinical benefits by virtue of a slow onset of action and long duration of effect. The slow onset of action may explain why there seems to be very little reflex tachycardia and a lower incidence of vasodilator side effects when comparing amlodipine with conventional dihydropyridines. The slow elimination of amlodipine explains the long duration of action, which allows a convenient once-daily dosage schedule.
Topics: Amlodipine; Angina Pectoris; Animals; Humans; Hypertension; In Vitro Techniques
PubMed: 9156957
DOI: No ID Found -
Journal of Clinical Hypertension... Oct 2020Single risk factors, such as hypertension and dyslipidemia, can combine to exacerbate the development and severity of cardiovascular disease. Treatment goals may be more... (Randomized Controlled Trial)
Randomized Controlled Trial
Single risk factors, such as hypertension and dyslipidemia, can combine to exacerbate the development and severity of cardiovascular disease. Treatment goals may be more effectively achieved if multiple disease factors are targeted with combination treatment. We enrolled 202 patients who were randomly divided into the following three groups: telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg, telmisartan 80 mg + rosuvastatin 20 mg, and telmisartan/amlodipine 80/5 mg. The primary efficacy variables were changes from baseline in mean sitting systolic blood pressure (MSSBP) between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg at 8 weeks, and the percent changes from baseline in low-density lipoprotein (LDL) cholesterol between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg at 8 weeks. The secondary efficacy variables were changes in MSSBP, mean sitting diastolic blood pressure (MSDBP), LDL cholesterol and other lipid levels at 4 weeks and 8 weeks, as well as observed adverse events during follow-up. There were no significant differences between the three groups in demographic characteristics and no significant difference among the three groups in terms of baseline characteristics for the validity evaluation variables. The mean overall treatment compliance in the three groups was, respectively, 98.42%, 96.68%, and 98.12%, indicating strong compliance for all patients. The Least-Square (LS) mean (SE) for changes in MSSBP in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg) groups were -19.3 (2.68) mm Hg and -6.69 (2.76) mm Hg. The difference between the two groups was significant (-12.60 (2.77) mm Hg, 95% CI -18.06 to -7.14, P < .0001). The LS Mean for the percent changes from baseline in LDL cholesterol in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg) groups were -52.45 (3.23) % and 2.68 (3.15) %. The difference between the two groups was significant (-55.13 (3.20) %, 95% CI -61.45 to -48.81, P < .0001). There were no adverse events leading to discontinuation or death. Combined administration of telmisartan/amlodipine 80/5 mg and rosuvastatin 20 mg for the treatment of hypertensive patients with dyslipidemia significantly reduces blood pressure and improves lipid control. ClinicalTrials.gov identifier: NCT03067688.
Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Rosuvastatin Calcium; Telmisartan
PubMed: 32937023
DOI: 10.1111/jch.13893 -
Journal of Clinical Hypertension... Sep 2023Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which... (Review)
Review
Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which amlodipine, a dihydropyridine, has unique characteristics that distinguish it from other drugs within this class. This review aims to provide an updated overview of the evidence supporting the use of amlodipine over the past 30 years and highlights its cardiovascular benefits in current hypertension management. Amlodipine has low renal clearance (7 mL/min/mg) and long half-life (35-50 h) and duration of action, which allows it to sustain its anti-hypertensive effect for more than 24 h following a single dose. Additionally, blood pressure (BP) control is maintained even when a dose has been missed, providing continuous protection in case of incidental noncompliance. It has proven to reduce BP variability and successfully lower BP. Amlodipine also controls BP in patients with a systolic/diastolic BP of 130/80 mm Hg or higher, diabetes, or chronic kidney disease without worsening glycemic or kidney function. Additionally, amlodipine is a wise choice for older adults due to its ability to control BP and protect against stroke and myocardial infarction. Side effects of amlodipine include edema, palpitations, dizziness, and flushing, which are more common with the higher dose of 10 mg. Amlodipine is cost effective and predicted to be cost saving when compared with usual care.
Topics: Humans; Aged; Amlodipine; Hypertension; Antihypertensive Agents; Calcium Channel Blockers; Blood Pressure
PubMed: 37551050
DOI: 10.1111/jch.14709 -
British Journal of Pharmacology May 2022Non-alcoholic fatty liver disease (NAFLD) represents a severe public health problem. It often coexists with hypertension in the context of metabolic syndrome. We...
BACKGROUND AND PURPOSE
Non-alcoholic fatty liver disease (NAFLD) represents a severe public health problem. It often coexists with hypertension in the context of metabolic syndrome. We investigated the effects of amlodipine on NAFLD combined with hypertension and investigated the underlying mechanism/s.
EXPERIMENTAL APPROACH
Mice were fed with high-fat diet (HFD) and 0.05% N-nitro-L-arginine methylester sterile water to induce NAFLD with hypertension. Gut microbiota composition and function were assessed by 16S ribosomal DNA and metagenomic sequencing. Untargeted metabolome profiles were applied to identify differential metabolites in mice caecum.
KEY RESULTS
Amlodipine besylate and amlodipine aspartate significantly decreased liver injury and hepatic steatosis, and improved lipid metabolism with a concomitant reduction in the expression of lipogenic genes in mice with NAFLD and hypertension. Mechanistically, amlodipine besylate and amlodipine aspartate have potential to restore intestinal barrier integrity and improve antimicrobial defence, along with the elevated abundances of Akkermansia, Bacteroides and Lactobacillus. Noteworthily, the gut microbiota in amlodipine besylate- and amlodipine aspartate-treated mice had higher abundance of functional genes involved in taurine and hypotaurine metabolism. Consistently, the strengthened taurine and hypotaurine metabolism was confirmed by untargeted metabolome analysis. Based on the correlation and causal analysis, the altered gut microbiota composition and the enhancement of taurine and hypotaurine metabolism may synergistically decreased alanine aminotransferase, liver triglycerides, lipogenic genes and plasma cholesterol in HFD-fed hypertensive mice.
CONCLUSION AND IMPLICATIONS
Amlodipine besylate and amlodipine aspartate exert multifactorial improvements in NAFLD and hypertension by modulating gut microbiota. They may serve as promising therapeutic agents for treating these diseases.
Topics: Amlodipine; Animals; Antihypertensive Agents; Diet, High-Fat; Gastrointestinal Microbiome; Mice; Non-alcoholic Fatty Liver Disease
PubMed: 34862599
DOI: 10.1111/bph.15768 -
Ugeskrift For Laeger Apr 2023Pedal oedema is a well-known adverse effect of amlodipine, but significantly less frequent if only half of the maximum recommended dosage is used. Diuretics are... (Review)
Review
Pedal oedema is a well-known adverse effect of amlodipine, but significantly less frequent if only half of the maximum recommended dosage is used. Diuretics are ineffective. To cause as few side effects as possible, options for managing are prioritised in this review: Reduce dosage, switch to lercanidipine/lacidipine, switch to another group, add/increase dosage of an ACE-inhibitor/angiotensin II-receptor blocker, administer at night, or switch to verapamil/diltiazem. Non-pharmacologic actions or observation may be considered when the oedemas are mild and not bothersome.
Topics: Humans; Amlodipine; Calcium Channel Blockers; Hypertension; Ankle; Edema; Drug-Related Side Effects and Adverse Reactions
PubMed: 37114573
DOI: No ID Found -
Journal of Clinical Hypertension... May 2019In a multicenter, randomized trial, we investigated whether the long half-time dihydropyridine calcium channel blocker amlodipine was more efficacious than the... (Randomized Controlled Trial)
Randomized Controlled Trial
In a multicenter, randomized trial, we investigated whether the long half-time dihydropyridine calcium channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering ambulatory blood pressure (BP) in sustained hypertension (clinic systolic/diastolic BP 140-179/90-109 mm Hg and 24-hour systolic/diastolic BP ≥ 130/80 mm Hg). Eligible patients were randomly assigned to amlodipine 5-10 mg/day or nifedipine-GITS 30-60 mg/day. Ambulatory BP monitoring was performed for 24 hours at baseline and 4-week treatment and for 48 hours at 8-week treatment with a dose of medication missed on the second day. After 8-week treatment, BP was similarly reduced in the amlodipine (n = 257) and nifedipine-GITS groups (n = 248) for both clinic and ambulatory (24-hour systolic/diastolic BP 10.3/6.5 vs 10.9/6.3 mm Hg, P ≥ 0.24) measurements. However, after missing a dose of medication, ambulatory BP reductions were greater in the amlodipine than nifedipine-GITS group, with a significant (P ≤ 0.04) between-group difference in 24-hour (-1.2 mm Hg) and daytime diastolic BP (-1.5 mm Hg). In conclusion, amlodipine and nifedipine-GITS were efficacious in reducing 24-hour BP. When a dose of medication was missed, amlodipine became more efficacious than nifedipine-GITS.
Topics: Amlodipine; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Case-Control Studies; China; Circadian Rhythm; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Safety; Treatment Outcome
PubMed: 30973207
DOI: 10.1111/jch.13543 -
The New England Journal of Medicine Sep 2001It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure.
METHODS
We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point.
RESULTS
The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point.
CONCLUSIONS
The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.
Topics: Adult; Aged; Amlodipine; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hypertension; Irbesartan; Kidney Failure, Chronic; Male; Middle Aged; Proportional Hazards Models; Tetrazoles
PubMed: 11565517
DOI: 10.1056/NEJMoa011303 -
The New England Journal of Medicine Dec 2008The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic.
METHODS
In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.
RESULTS
The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs.
CONCLUSIONS
The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)
Topics: Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Kaplan-Meier Estimate; Male; Middle Aged; Risk
PubMed: 19052124
DOI: 10.1056/NEJMoa0806182 -
Proceedings of the National Academy of... May 2022There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly...
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.
Topics: Amlodipine; Animals; Antineoplastic Agents; Calcium Channel Blockers; Calmodulin; Deoxycytidine; Humans; Pancreatic Neoplasms; United States; Gemcitabine
PubMed: 35476525
DOI: 10.1073/pnas.2200143119 -
Hypertension (Dallas, Tex. : 1979) May 2023Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and...
Improved Persistence to Medication, Decreased Cardiovascular Events and Reduced All-Cause Mortality in Hypertensive Patients With Use of Single-Pill Combinations: Results From the START-Study.
BACKGROUND
Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and all-cause mortality. We analyzed whether single-pill combinations are superior to identical multiple pills on persistence to medication, cardiovascular outcomes, and all-cause mortality.
METHODS
This was a retrospective claims data (German AOK PLUS) analysis. Data from hypertensive patients ≥18 years treated with renin-angiotensin system combinations given as single pill or identical multipills covering the years 2012 to 2018 were analyzed and followed up to at least 1 year. After 1:1 propensity score matching, persistence to medication, cardiovascular events, and all-cause mortality were compared using non-parametric tests. Results were reported as incidence rate ratios and hazard ratios.
RESULTS
After propensity score matching data from 57 998 patients were analyzed: 10 801 patients received valsartan/amlodipine, 1026 candesartan/amlodipine, 15 349 ramipril/amlodipine, and 1823 amlodipine/valsartan/hydrochlorothiazide as single pill or identical multipill. No relevant differences in patient characteristics were observed within the 4 groups. In all groups, a significant lower all-cause mortality, a significant a higher persistence to medication, a significant lower event rate in 15 out of 20 comparisons, and a tendency in the remaining 5 comparisons was observed under single pills compared with multipill combinations.
CONCLUSIONS
Antihypertensive combination therapy reduces all-cause mortality and cardiovascular events when provided as single pill compared to identical drugs as multipills. This strongly supports the European Society of Cardiology/European Society of Hypertension and International Society of Hypertension guidelines recommending the use of a single-pill combination and thus should be more rigorously implemented into daily clinical practice.
Topics: Humans; Retrospective Studies; Drug Combinations; Hypertension; Antihypertensive Agents; Amlodipine; Valsartan; Tetrazoles; Medication Adherence; Blood Pressure
PubMed: 36987918
DOI: 10.1161/HYPERTENSIONAHA.122.20810