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Cardiology and Therapy Sep 2022Modulation of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation with the potential to improve the risk-benefit profile observed with existing...
INTRODUCTION
Modulation of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation with the potential to improve the risk-benefit profile observed with existing anticoagulants through greater efficacy or a safer bleeding profile. This study assessed the effects of co-administration with strong and moderate CYP3A inhibitors itraconazole and diltiazem, respectively, on the pharmacokinetic and pharmacodynamic properties of milvexian, a Factor XIa inhibitor.
METHODS
This was an open-label, non-randomized, two-period crossover study in healthy participants. In period 1, participants received a single oral dose of milvexian (30 mg) on day 1, followed by a washout on days 2 and 3. In period 2, participants received multiple oral doses of itraconazole (200 mg) or diltiazem (240 mg) with a single dose of milvexian.
RESULTS
A total of 28 participants entered the treatment period. Following itraconazole co-administration, milvexian exposure was increased; AUC, AUC, and C were 2.5-, 2.5-, and 3.8-fold higher, while mean C was 28% higher versus milvexian alone. Diltiazem co-administration also increased milvexian exposure; AUC, AUC, and C were 38, 38, and 64% higher, and mean C was 9.6% higher versus milvexian alone. Prolongation of activated partial thromboplastin time was observed with milvexian in a concentration-dependent fashion irrespective of co-administration with itraconazole or diltiazem. Administration of a single dose of milvexian, alone or in combination with itraconazole or diltiazem, was generally safe and well tolerated; there were no deaths or serious adverse events.
CONCLUSIONS
A moderate increase in milvexian exposure was observed following co-administration of itraconazole while a minimal increase was seen with diltiazem, consistent with the involvement of CYP3A metabolism and P-glycoprotein in drug absorption/elimination. Milvexian was generally safe and well tolerated in healthy participants.
TRIAL REGISTRATION
The study was registered with ClinicalTrials.gov (NCT02807909; submitted June 17, 2016).
PubMed: 35641780
DOI: 10.1007/s40119-022-00266-6 -
Iranian Journal of Basic Medical... Dec 2018Wound healing is a natural response to restore the injured tissue to normal. Wound healing is also complicated process involving different cellular, molecular and...
Wound healing is a natural response to restore the injured tissue to normal. Wound healing is also complicated process involving different cellular, molecular and biochemical mechanisms and various types of cytokines and growth factors. Calcium channel blockers belong to cardiovascular medicine and administrated to treatment of hypertension, angina and cardiac arrhythmia because of vasodilatory effect. Calcium channel blockers is divided to dihydropyridine and non-dihydropyrine. The potential of both dihydropyridine and non-dihydropyrine calcium channel blockers in wound healing have been reported in different animal models and previously. Amlodipine, verapamil, diltiazem, nifedipine, and azelnidipine are calcium channel blockers that indicated wound healing property. The various mechanisms that involve in wound healing effect of calcium channel blockers are discussed in this article.
PubMed: 30627361
DOI: 10.22038/ijbms.2018.29753.7182 -
Open Heart Jan 2023Coronary artery vasospasm is an abnormal spasm of coronary arteries that cause transient or complete occlusion without exertion. It causes stable angina to ACS. However,...
BACKGROUND
Coronary artery vasospasm is an abnormal spasm of coronary arteries that cause transient or complete occlusion without exertion. It causes stable angina to ACS. However, this can be prevented by calcium channel blockers (CCBs) which suppress Ca influx into the vascular muscle cells. Nevertheless, several CCBs adverse effects are harmful for these patients. Selecting the right CCBs would give the best clinical practice.
METHOD
The studies were obtained from four major medical databases by various keywords. Inclusion and exclusion criteria were implemented as adult >18 years, observational study, English language and drug of interest. Duplicates were eliminated, and the remaining studies were reviewed. Final full-texts assessment was conducted independently by Newcastle-Ottawa Scale and Revised Cochrane.
RESULTS
The search found 1378 articles. However, six studies were selected after implementing the study criteria. Diltiazem was found to decrease angina and increase quality of life until 12th week of treatment; however, some adverse effects include atrioventricular block and recurrent angina up till 4th week were found. Meanwhile, nifedipine was found to decrease vasospastic angina (VSA) by the fourth and eighth weeks of treatment. Nevertheless, it caused excessive drop in BP and increase heart rate by eighth week. In addition, slow-release preparation of both CCBs were found to increase efficacy and compliance. Lastly amlodipine was also found to decrease VSA by 17%±140% and 33% after 6 weeks, but further studies needed.
CONCLUSION
Diltiazem, nifedipine and amlodipine are potent in decreasing VSA, however, tailoring specific CCBs adverse reactions to patient condition and the drug preparation would be substantially beneficial for the outcome.
Topics: Adult; Humans; Calcium Channel Blockers; Diltiazem; Coronary Vasospasm; Nifedipine; Calcium; Quality of Life; Amlodipine; Observational Studies as Topic
PubMed: 36634997
DOI: 10.1136/openhrt-2022-002179 -
International Journal of Analytical... 2018Hypertension or high blood pressure is a harbinger of cardiovascular diseases. There are several classes of drugs used to treat hypertension. This review discusses the... (Review)
Review
Hypertension or high blood pressure is a harbinger of cardiovascular diseases. There are several classes of drugs used to treat hypertension. This review discusses the use of dried blood spots (DBSs) for the quantification by mass spectrometry (MS), tandem mass spectrometry (MS/MS), or, in some cases, by fluorescence detection methods the following antihypertensive medications: angiotensin-converting enzyme inhibitors (ramipril, ramiprilat, captopril, and lisinopril); angiotensin II receptor antagonists (valsartan, irbesartan, losartan, and losartan carboxylic acid); calcium channel blockers (verapamil, amlodipine, nifedipine, pregabalin, and diltiazem); blockers (guanfacine, doxazosin, and prazosin); blockers (propranolol, bisoprolol, atenolol, and metoprolol); endothelin receptor antagonists (bosentan and ambrisentan); and statins (simvastatin, atorvastatin, and rosuvastatin).
PubMed: 30154849
DOI: 10.1155/2018/3235072 -
Frontiers in Physiology 2018Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with... (Review)
Review
Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na) in diabetic cardiomyopathy and provides unique data on the linkage between Na flux and energy metabolism, studied with non-invasive Na, and P-NMR spectroscopy, polarography, and mass spectroscopy. Na NMR studies allow determination of the intracellular and extracellular Na pools by splitting the total Na peak into two resonances after the addition of a shift reagent to the perfusate. Using this technology, we found that intracellular Na is approximately two times higher in diabetic cardiomyocytes than in control possibly due to combined changes in the activity of Na-K pump, Na/H exchanger 1 (NHE1) and Na-glucose cotransporter. We hypothesized that the increase in Na activates the mitochondrial membrane Na/Ca exchanger, which leads to a loss of intramitochondrial Ca, with a subsequent alteration in mitochondrial bioenergetics and function. Using isolated mitochondria, we showed that the addition of Na (1-10 mM) led to a dose-dependent decrease in oxidative phosphorylation and that this effect was reversed by providing extramitochondrial Ca or by inhibiting the mitochondrial Na/Ca exchanger with diltiazem. Similar experiments with P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na (3-30 mM) led to significantly decreased ATP levels and that this effect was stronger in diabetic rats. These data suggest that in diabetic cardiomyocytes, increased Na leads to abnormalities in oxidative phosphorylation and a subsequent decrease in ATP levels. In support of these data, using P-NMR, we showed that the baseline β-ATP and phosphocreatine (PCr) were lower in diabetic cardiomyocytes than in control, suggesting that diabetic cardiomyocytes have depressed bioenergetic function. Thus, both altered intracellular Na levels and bioenergetics and their interactions may significantly contribute to the pathology of diabetic cardiomyopathy.
PubMed: 30405433
DOI: 10.3389/fphys.2018.01473 -
The American Journal of Cardiology Jun 2023Heart failure (HF) with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are interrelated and often coexisting conditions in older adults. Although...
Heart failure (HF) with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are interrelated and often coexisting conditions in older adults. Although equally recommended, nondihydropyridine calcium channel blockers (non-DHP CCBs), such as diltiazem and verapamil, are less often used than β blockers. Because recent studies suggested that β-blocker use in both HFpEF and AF may increase the risk for HF, we tested whether non-DHP CCBs were associated with lower HF hospitalization risk than β blockers. We examined fee-for-service Medicare beneficiaries who were aged ≥66 years, had HFpEF or AF, and newly initiated a β blocker (n = 83,458) or non-DHP CCB (n = 18,924) from 2014 to 2018. The outcomes of HF hospitalization and all-cause mortality were analyzed using multivariable-adjusted Cox regression in the full cohort and, separately, in the subset without a recent hospital or skilled nursing discharge. Follow-up was analyzed using 2 frameworks: intention-to-treat and censored-at-drug-switch-or-discontinuation. There was a modestly protective association of non-DHP CCBs for the risk of HF hospitalization. Before drug switch or discontinuation, the use of diltiazem or verapamil was associated with decreased risk of HF hospitalization in the full cohort (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.81 to 1.00, p = 0.05) and in the subgroup (HR 0.70, 95% CI 0.56 to 0.89, p = 0.003). However, the association with all-cause mortality tended to favor β blockers, including in the intention-to-treat analysis (HR 1.21, 95% CI 1.17 to 1.25, p <0.001). In conclusion, compared with β blockers, the initiation of diltiazem or verapamil in patients with HFpEF or AF may be associated with fewer HF hospitalization events but also with more all-cause deaths.
Topics: Humans; Aged; United States; Heart Failure; Calcium Channel Blockers; Diltiazem; Medicare; Stroke Volume; Hospitalization; Atrial Fibrillation; Verapamil; Receptors, Adrenergic, beta; Adrenergic beta-Antagonists
PubMed: 37150720
DOI: 10.1016/j.amjcard.2023.04.013 -
BMJ Clinical Evidence Nov 2014Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of recent onset. Various definitions of acute atrial fibrillation have been used in the... (Review)
Review
INTRODUCTION
Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of recent onset. Various definitions of acute atrial fibrillation have been used in the literature, but for the purposes of this review we have included studies where atrial fibrillation may have occurred up to 7 days previously. Risk factors for acute atrial fibrillation include increasing age, cardiovascular disease, alcohol, diabetes, and lung disease. Acute atrial fibrillation increases the risk of stroke and heart failure. The condition resolves spontaneously within 24 to 48 hours in more than 50% of people; however, many people will require interventions to control heart rate or restore sinus rhythm.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent embolism, for conversion to sinus rhythm, and to control heart rate in people with recent-onset atrial fibrillation (within 7 days) who are haemodynamically stable? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 26 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, atenolol, bisoprolol, carvedilol, digoxin, diltiazem, direct current cardioversion, flecainide, metoprolol, nebivolol, propafenone, sotalol, timolol, and verapamil.
Topics: Acute Disease; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Humans; Safety
PubMed: 25430048
DOI: No ID Found -
Indian Heart Journal 2022Intravenous calcium channel blockers or beta-blockers are the preferred rate control medications for hemodynamically stable patients with atrial fibrillation with rapid... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intravenous calcium channel blockers or beta-blockers are the preferred rate control medications for hemodynamically stable patients with atrial fibrillation with rapid ventricular rate (AF-RVR) in the emergency department.
OBJECTIVES
To compare the efficacy of intravenous diltiazem and metoprolol for rate control and safety with respect to development of hypotension and bradycardia in patients with AF-RVR.
METHODS
For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane databases, and the clinicaltrials.gov registry between database inception and 30th May 2021. Articles were included if they compared efficacy and safety of diltiazem versus metoprolol in critically ill adult patients hospitalized with AF-RVR. Outcome measures were achievement of rate control, development of new hypotension, and bradycardia after drug administration.
RESULTS
Of 86 records identified, 14 were eligible, all of which had a low to moderate risk of overall bias. The meta-analysis (Mantel-Haenszel, random-effects model) showed that diltiazem use was associated with increased achievement of rate control target compared to metoprolol [14 studies, n = 1732, Odds Ratio (OR): 1.92; 95% Confidence Intervals (CI):1.26 to 2.90; I = 61%]. In the pooled analysis, no differences were seen in hypotension using diltiazem vs metoprolol [12 studies, n = 1477, OR: 0.96; 95% CI:0.61 to 1.52; I = 35%] or bradycardia [9 studies, n = 1203, OR: 2.44; 95% CI: 0.82 to 7.31; I = 48%].
CONCLUSIONS
Intravenous diltiazem is associated with increased achievement of rate control target in patients with AF-RVR compared to metoprolol, while both medications are associated with similar incidence of hypotension and bradycardia.
Topics: Adult; Humans; Diltiazem; Atrial Fibrillation; Metoprolol; Bradycardia; Hypotension; Heart Rate
PubMed: 36334652
DOI: 10.1016/j.ihj.2022.10.195 -
The Cochrane Database of Systematic... Mar 2018Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic medications are associated with a variety of adverse effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been among these experimental treatments.
OBJECTIVES
To determine the effects of calcium channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA
We selected randomised controlled trials comparing calcium channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness who remained on their antipsychotic medication.
DATA COLLECTION AND ANALYSIS
We independently extracted data and estimated risk ratios of dichotomous data or mean differences (MD) of continuous data, with 95% confidence intervals (CI). We assumed that people who left the trials early had no improvement. We also created a 'Summary of findings' table using GRADE.
MAIN RESULTS
Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients.
AUTHORS' CONCLUSIONS
Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.
Topics: Antipsychotic Agents; Calcium Channel Blockers; Diltiazem; Dyskinesia, Drug-Induced; Flunarizine; Humans; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 29578611
DOI: 10.1002/14651858.CD000206.pub4 -
Journal of Education & Teaching in... Jan 2024Emergency medicine residents and medical students on emergency medicine rotation.
AUDIENCE
Emergency medicine residents and medical students on emergency medicine rotation.
BACKGROUND
Calcium channel blocker (CCB) overdoses can be severe with potentially serious adverse outcomes. CCBs work by blocking the calcium channels on smooth and cardiac muscle tissue. At low dose ranges, dihydropyridine CCBs (such as nifedipine, amlodipine, and nicardipine) block the L-type calcium receptors in the peripheral vasculature, whereas non-dihydropyridine CCBs (such as: verapamil and diltiazem) affect the L-type calcium receptors in the myocardium.1 Because of this distinction, dihydropyridine CCB toxicity manifests as arterial vasodilation and non-dihydropyridine CCB toxicity is associated with cardiac manifestations such as bradycardia and negative inotropy.2 It is important to note that in high concentrations (such as in overdoses), CCBs lose specificity for their specific receptors and can show all the manifestations of toxicity such as bradycardia, peripheral vasodilation, and hypotension. Patients can develop both vasoplegic shock from peripheral vasodilation and cardiogenic shock. This is a high acuity low occurrence case with infrequently used but specific treatments, and thus this case provides educational value.
EDUCATIONAL OBJECTIVES
At the end of this oral board session, examinees will: (1) demonstrate ability to evaluate a patient with undifferentiated shock with bradycardia and discuss the differential diagnosis, (2) recognize the signs and symptoms of calcium channel blocker overdose, (3) demonstrate ability to manage treatment of a patient with calcium channel overdose.
EDUCATIONAL METHODS
This oral board case followed the standard American Board of Emergency Medicine-style case in a tertiary care hospital with access to all specialists and resources needed. This case was tested using 12 resident volunteers ranging from PGY 1-2 in an ACGME (Accreditation Council for Graduate Medical Education) accredited emergency medicine residency program.
RESEARCH METHODS
Immediate feedback was solicited both from the learners and from the evaluators following the debriefing session. Residents were asked to evaluate the educational value of the case using a 1-5 Likert scale (5 being excellent). Evaluators were asked to score the residents using the ACGME core competencies with a scale of 1-8, 1-4 being unacceptable and 5-8 being acceptable.
RESULTS
Seven PGY1 residents and five PGY2 residents, thus twelve residents in total, completed the case. The average score was 5.10/8. Three residents missed zero critical actions. The most common critical action missed was consulting cardiology or cardiothoracic surgery for circulatory support options. Many residents failed to recognize that the patient did not have a perfusing blood pressure at the beginning of the case and did not start CPR. Although most residents recognized the patient's hemodynamic collapse was from a calcium channel blocker overdose, most did not know the treatment for this beyond atropine and intravenous fluids.The learners rated the educational value of the case as 4.9/5. Seven residents reported that the case definitely increased their medical knowledge; five residents reported that it somewhat increased their medical knowledge. All residents rated the case as helpful in preparing to manage this medical condition.
DISCUSSION
The educational content from this case was effective. This is a high acuity low occurrence case that has unique treatments that are not commonly used. This makes this case excellent for practice and discussion. We learned during implementation that this case has a high degree of difficulty compared to other cases, and junior learners will need more prompting. It is also important for the proctor to keep the case moving because there is a lot to cover in the allotted amount of time.
TOPICS
Calcium channel blocker overdose, toxicology.
PubMed: 38344049
DOI: 10.21980/J8CQ07