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Oncogenesis Aug 2022Migration and metastasis commonly happen to triple-negative breast cancer (TNBC) patients with advanced diseases. In many studies, it has been suggested that...
Migration and metastasis commonly happen to triple-negative breast cancer (TNBC) patients with advanced diseases. In many studies, it has been suggested that epithelial-mesenchymal transition (EMT) is one of the key mechanisms triggering cancer metastasis. Accumulating evidence has proven that calcium channel blockers mediate cell motility. Therefore, we attempt to investigate the effects of diltiazem, which has been selected from several FDA-approved clinical calcium channel blockers, on EMT in TNBC. By using both mouse and human TNBC cell lines, we found that diltiazem decreases colony formation and cell migration in breast cancer cells. The expression of epithelial markers such as E-cadherin and ZO-1 were increased dose-dependently by diltiazem, while mesenchymal markers such as Snail and Twist were decreased. In addition, we found that the expression of growth differentiation factor-15 (GDF-15) was also increased by diltiazem. Administering recombinant GDF-15 also reverses EMT, inhibits colony formation and migration in breast cancer cells. Moreover, treatment with diltiazem in tumor-bearing mice also decreases cancer metastasis and nodule formation, with more GDF-15 expression in diltiazem-treated mice than saline-treated mice, respectively. These findings suggest that diltiazem regulates EMT and cell motility through elevating GDF-15 expression in breast cancers in vitro and in vivo.
PubMed: 35963873
DOI: 10.1038/s41389-022-00423-5 -
Cureus Jun 2023Photosensitivity is a condition of heightened skin sensitivity to sunlight or other forms of ultraviolet light. The case presented here highlights a rare occurrence of...
Photosensitivity is a condition of heightened skin sensitivity to sunlight or other forms of ultraviolet light. The case presented here highlights a rare occurrence of diltiazem-induced photosensitivity in an 87-year-old female patient with a history of atrial fibrillation and multiple comorbidities. The patient developed a distinctive erythematous rash limited to the sun-exposed area of the left side of her face during her hospital stay for respiratory failure and pneumonia. The localized distribution of the rash, along with its resolution upon reducing sun exposure, strongly suggested a photosensitivity reaction induced by diltiazem. Prompt discontinuation of the medication and transitioning to verapamil led to the resolution of the cutaneous manifestations. This case emphasizes the importance of recognizing and managing photosensitivity reactions as potential adverse effects of medications, such as diltiazem. Further research is needed to better understand the pathophysiology and risk factors associated with photosensitivity reactions to calcium channel blockers. Through this case report, we aim to contribute to the existing knowledge in this field and emphasize the significance of vigilance in clinical practice.
PubMed: 37456398
DOI: 10.7759/cureus.40376 -
The Mental Health Clinician Aug 2023Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of...
BACKGROUND
Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of clozapine's significant anticholinergic activity.
CASE REPORT
A 34-year-old female developed clozapine-induced nocturnal, generalized hyperhidrosis following initial titration to 400 mg/day. Dose reduction did not decrease the side effect. Treatment with an anticholinergic medication could not be initiated because of constipation. Treatment with a beta blocker resulted in worsening of asthma. Treatment with a calcium channel blocker, diltiazem CD 180 mg/day, resulted in a significant reduction in hyperhidrosis.
CONCLUSION
This case supports the use of calcium channel blockers to reduce clozapine-induced hyperhidrosis and offers an alternative to anticholinergic medications that may negatively impact clozapine tolerability.
PubMed: 37860588
DOI: 10.9740/mhc.2023.08.193 -
Antiviral Research Jul 2019The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13-15,... (Review)
Review
The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13-15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Coronavirus Infections; Humans; Influenza, Human; Pandemics; Respiratory Syncytial Virus, Human; Respiratory Tract Infections
PubMed: 30974127
DOI: 10.1016/j.antiviral.2019.04.006 -
Clinical and Translational Science Dec 2023Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer....
Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUC ) and maximum plasma concentration (C ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t ) of encorafenib increased from 4.3 to 7.3 h. The AUC and C geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.
Topics: Humans; Antineoplastic Agents; Colorectal Neoplasms; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Drug Interactions; Headache; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 37837178
DOI: 10.1111/cts.13662 -
Emergency Medicine International 2023Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in the emergency department (ED) and when patients present in acute AF with rapid ventricular... (Review)
Review
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in the emergency department (ED) and when patients present in acute AF with rapid ventricular rate (RVR), it can result in significant morbidity and mortality. Primary treatment modalities are aimed at rate control with the two most common agents being intravenous metoprolol and diltiazem. Some evidence suggests that diltiazem may be more effective at controlling rate in these patients; however, the dosing strategies, pharmacologic differences, and study designs may play a role in the observation of these differences. The purpose of this article is to review the evidence for using weight-based metoprolol in the treatment of AF with RVR. The vast majority of studies comparing metoprolol and diltiazem for the treatment of acute AF with RVR compare a flat dose of metoprolol to a weight-based dose of diltiazem. Following a comprehensive review, only two studies have compared a weight-based dosing strategy of intravenous (IV) metoprolol versus IV diltiazem for this disease state. Overall, the two studies only contained 94 patients and failed to meet power. Beyond differing dosing strategies, differences in pharmacokinetics between the two medications (like the onset of action and metabolism) could have played a role in the differences observed in the studies. Further studies are warranted to provide better guidance on which agent should be used in the treatment of acute AF with RVR.
PubMed: 37096182
DOI: 10.1155/2023/3138064 -
Journal of Pharmacy & Pharmaceutical... 2021Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of...
PURPOSE
Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration's recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19.
METHODS
The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities.
RESULTS
Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir.
CONCLUSIONS
GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities.
Topics: Adenosine; Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Computer Simulation; Databases, Chemical; Drug Interactions; Furans; Humans; Prodrugs; Pyrroles; Risk Assessment; Risk Factors; SARS-CoV-2; Triazines; COVID-19 Drug Treatment
PubMed: 34107241
DOI: 10.18433/jpps32011 -
JACC. Cardiovascular Imaging Aug 2022Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive coronary artery disease (ANOCA), suspected of coronary vasomotor... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive coronary artery disease (ANOCA), suspected of coronary vasomotor dysfunction (CVDys). However, studies substantiating its effect is this patient group are lacking.
OBJECTIVES
The randomized, placebo-controlled EDIT-CMD (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial) evaluated the effect of diltiazem on CVDys, as assessed by repeated coronary function testing (CFT), angina, and quality of life.
METHODS
A total of 126 patients with ANOCA were included and underwent CFT. CVDys, defined as the presence of vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction (coronary flow reserve: <2.0, index of microvascular resistance: ≥25), was confirmed in 99 patients, of whom 85 were randomized to receive either oral diltiazem or placebo up to 360 mg/d. After 6 weeks, a second CFT was performed. The primary end point was the proportion of patients having a successful treatment, defined as normalization of 1 abnormal parameter of CVDys and no normal parameter becoming abnormal. Secondary end points were changes from baseline to 6-week follow-up in vasospasm, index of microvascular resistance, coronary flow reserve, symptoms (Seattle Angina Questionnaire), or quality of life (Research and Development Questionnaire 36).
RESULTS
In total, 73 patients (38 diltiazem vs 35 placebo) underwent the second CFT. Improvement of the CFT did not differ between the groups (diltiazem vs placebo: 21% vs 29%; P = 0.46). However, more patients on diltiazem treatment progressed from epicardial spasm to microvascular or no spasm (47% vs 6%; P = 0.006). No significant differences were observed between the diltiazem and placebo group in microvascular dysfunction, Seattle Angina Questionnaire, or Research and Development Questionnaire 36.
CONCLUSIONS
This first performed randomized, placebo-controlled trial in patients with ANOCA showed that 6 weeks of therapy with diltiazem, when compared with placebo, did not substantially improve CVDys, symptoms, or quality of life, but diltiazem therapy did reduce prevalence of epicardial spasm. (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial [EDIT-CMD]; NCT04777045).
Topics: Angina Pectoris; Coronary Angiography; Coronary Artery Disease; Coronary Vasospasm; Coronary Vessels; Diltiazem; Humans; Myocardial Ischemia; Predictive Value of Tests; Quality of Life
PubMed: 35466050
DOI: 10.1016/j.jcmg.2022.03.012 -
Journal of Medical Case Reports Jun 2023Gabapentin is commonly prescribed for the treatment of neuropathic pain, restless leg syndrome, and partial-onset seizures. Although the most frequent side effects of...
BACKGROUND
Gabapentin is commonly prescribed for the treatment of neuropathic pain, restless leg syndrome, and partial-onset seizures. Although the most frequent side effects of gabapentin are associated with the central nervous system, gabapentin can also affect the cardiovascular system. Case reports and observational studies have showed that gabapentin can be associated with increased risk of atrial fibrillation. However, all the evidence is concentrated in patients older than 65 years old with comorbidities that predispose them to the development of arrhythmias.
CASE PRESENTATION
We describe a case of an African American male in his 20s that presented to our chronic pain clinic with lumbar radiculitis and developed atrial fibrillation 4 days after being started on gabapentin. Laboratory workup did not show significant abnormalities, including normal complete blood count, comprehensive metabolic panel, toxicology screen, and thyroid-stimulating hormone. Transthoracic and transesophageal echocardiography showed a patent foramen ovale with right-to-left shunt. The patient was initially treated with diltiazem for heart rate control and apixaban. Direct current cardioversion with successful conversion to sinus rhythm was performed 24 hours after admission. The patient was then discharged on apixaban and diltiazem. Apixaban was changed to low-dose aspirin 1 month after discharge.
CONCLUSION
With rapidly increasing usage of gabapentin for approved and off-label indications, it is important to identify unintended adverse effects of this drug as they are considered safe alternatives to opioids. New-onset atrial fibrillation could be induced by gabapentin in young individuals.
Topics: Humans; Male; Aged; Atrial Fibrillation; Gabapentin; Diltiazem; Echocardiography, Transesophageal; Electric Countershock
PubMed: 37291648
DOI: 10.1186/s13256-023-03975-1 -
Molecular Pharmacology Oct 2019Diltiazem is a widely prescribed Ca antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral Ca channel construct CaAb as a...
Diltiazem is a widely prescribed Ca antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral Ca channel construct CaAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca channel underneath its selectivity filter and physically blocks ion conduction. The diltiazem-binding site overlaps with the receptor site for phenylalkylamine Ca antagonist drugs such as verapamil. The dihydropyridine Ca channel blocker amlodipine binds at a distinct site and allosterically modulates the binding sites for diltiazem and Ca Our studies resolve two distinct binding poses for diltiazem in the absence and presence of amlodipine. The binding pose in the presence of amlodipine may mimic a high-affinity binding configuration induced by voltage-dependent inactivation, which is favored by dihydropyridine binding. In this binding pose, the tertiary amino group of diltiazem projects upward into the inner end of the ion selectivity filter, interacts with ion coordination Site 3 formed by the backbone carbonyls of T175, and alters binding of Ca to ion coordination Sites 1 and 2. Altogether, our results define the receptor site for diltiazem and elucidate the mechanisms for pore block and allosteric modulation by other Ca channel-blocking drugs at the atomic level. SIGNIFICANCE STATEMENT: Calcium antagonist drugs that block voltage-gated calcium channels in heart and vascular smooth muscle are widely used in the treatment of cardiovascular diseases. Our results reveal the chemical details of diltiazem binding in a blocking position in the pore of a model calcium channel and show that binding of another calcium antagonist drug alters binding of diltiazem and calcium. This structural information defines the mechanism of drug action at the atomic level and provides a molecular template for future drug discovery.
Topics: Allosteric Regulation; Amlodipine; Animals; Binding Sites; Calcium Channel Blockers; Calcium Channels; Crystallography, X-Ray; Diltiazem; Humans; Models, Molecular; Protein Conformation; Verapamil
PubMed: 31391290
DOI: 10.1124/mol.119.117531