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Cureus Dec 2023Taxanes, in combination with platinum-based drugs, are considered the initial treatment option for certain types of cancer, including ovarian cancer. Here, we report the...
Taxanes, in combination with platinum-based drugs, are considered the initial treatment option for certain types of cancer, including ovarian cancer. Here, we report the case of a 59-year-old woman who developed a malar rash on her face, a maculopapular rash on her forearms, and bluish discoloration on her fingers immediately following the end of the third cycle of chemotherapy. After discontinuing paclitaxel and using oral and topical steroids for rash and diltiazem and topical minoxidil for the treatment of Raynaud's phenomenon, the symptoms completely resolved. While taxanes are known to cause drug-induced lupus, there has never been any information on taxanes causing isolated Raynaud's phenomenon. This is the first case report that suggests paclitaxel-induced Raynaud's phenomenon along with paclitaxel-induced lupus.
PubMed: 38259408
DOI: 10.7759/cureus.50974 -
European Heart Journal. Cardiovascular... Dec 2023The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of...
Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.
AIMS
The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.
METHODS AND RESULTS
AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality.
CONCLUSION
Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.
Topics: Humans; Administration, Oral; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Cohort Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Hemorrhage; Stroke
PubMed: 37791408
DOI: 10.1093/ehjcvp/pvad070 -
CPT: Pharmacometrics & Systems... Apr 2024Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies...
Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.
Topics: Humans; Rifampin; Cytochrome P-450 CYP3A Inhibitors; Itraconazole; Cytochrome P-450 CYP3A; Carcinoma, Non-Small-Cell Lung; ATP Binding Cassette Transporter, Subfamily G, Member 2; Lung Neoplasms; Neoplasm Proteins; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Membrane Transport Proteins; Receptor Protein-Tyrosine Kinases; Models, Biological; Organophosphorus Compounds; Pyrimidines
PubMed: 38288787
DOI: 10.1002/psp4.13106 -
Veterinary Microbiology May 2024Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen for swine, resulting in substantial economic losses to the swine industry. However, there has...
Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen for swine, resulting in substantial economic losses to the swine industry. However, there has been little success in developing effective vaccines or drugs for PRRSV control. In the present study, we discovered that Diltiazem HCl, an inhibitor of L-type Ca channel, effectively suppresses PRRSV replication in MARC-145, PK-15 and PAM cells in dose-dependent manner. Furthermore, it demonstrates a broad-spectrum activity against both PRRSV-1 and PRRSV-2 strains. Additionally, we explored the underlying mechanisms and found that Diltiazem HCl -induced inhibition of PRRSV associated with regulation of calcium ion homeostasis in susceptible cells. Moreover, we evaluated the antiviral effects of Diltiazem HCl in PRRSV-challenged piglets, assessing rectal temperature, viremia, and gross and microscopic lung lesions. Our results indicate that Diltiazem HCl treatment alleviates PRRSV-induced rectal temperature spikes, pulmonary pathological changes, and serum viral load. In conclusion, our data suggest that Diltiazem HCl could serve as a novel therapeutic drug against PRRSV infection.
Topics: Animals; Swine; Porcine respiratory and reproductive syndrome virus; Diltiazem; Cell Line; Virus Replication; Macrophages, Alveolar; Porcine Reproductive and Respiratory Syndrome; Swine Diseases
PubMed: 38507832
DOI: 10.1016/j.vetmic.2024.110054 -
Cureus Mar 2024This study aims to assess the association between intravenous diltiazem and metoprolol in rate control for atrial fibrillation (AF) patients with rapid ventricular rate,... (Review)
Review
This study aims to assess the association between intravenous diltiazem and metoprolol in rate control for atrial fibrillation (AF) patients with rapid ventricular rate, focusing on rate control efficacy and hemodynamic adverse events. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, electronic searches were conducted in Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) until February 20, 2024. The primary outcome was achieving ventricular rate control < 110/min. Secondary outcomes included new hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (heart rate < 60/min). Nineteen studies (three randomized controlled trials and 16 observational studies) were included in this meta-analysis. Pooled analysis showed intravenous metoprolol resulted in a 39% lower rate control attainment compared to diltiazem (OR: 0.61; 95% CI: 0.44 to 0.84; p = 0.002). There were no significant differences in bradycardia (OR: 0.51; 95% CI: 0.22 to 1.22; p = 0.13) or hypotension risk (OR: 1.08; 95% CI: 0.72 to 1.61; p = 0.72) between the two groups. Intravenous diltiazem demonstrated superior rate control efficacy compared to metoprolol in AF patients with rapid ventricular rate. However, no significant differences were observed in safety outcomes, namely, bradycardia and hypotension.
PubMed: 38646329
DOI: 10.7759/cureus.56560 -
American Journal of Cardiovascular... Jan 2024Atrial fibrillation (AF) and/or atrial flutter (AFL) with rapid ventricular response (RVR) is a condition that often requires urgent treatment. Although guidelines have... (Meta-Analysis)
Meta-Analysis
Intravenous Diltiazem Versus Metoprolol in Acute Rate Control of Atrial Fibrillation/Flutter and Rapid Ventricular Response: A Meta-Analysis of Randomized and Observational Studies.
BACKGROUND
Atrial fibrillation (AF) and/or atrial flutter (AFL) with rapid ventricular response (RVR) is a condition that often requires urgent treatment. Although guidelines have recommendations regarding chronic rate control therapy, recommendations on the best choice for acute heart rate (HR) control in RVR are unclear.
METHODS
A systematic search across multiple databases was performed for studies evaluating the outcome of HR control (defined as HR less than 110 bpm and/or 20% decrease from baseline HR). Included studies evaluated AF and/or AFL with RVR in a hospital setting, with direct comparison between intravenous (IV) diltiazem and metoprolol and excluded cardiac surgery and catheter ablation patients. Hypotension (defined as systolic blood pressure less than 90 mmHg) was measured as a secondary outcome. Two authors performed full-text article review and extracted data, with a third author mediating disagreements. Random effects models utilizing inverse variance weighting were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the I test.
RESULTS
A total of 563 unique titles were identified through the systematic search, of which 16 studies (7 randomized and 9 observational) were included. In our primary analysis of HR control by study type, IV diltiazem was found to be more effective than IV metoprolol for HR control in randomized trials (OR 4.75, 95% CI 2.50-9.04 with I = 14%); however, this was not found for observational studies (OR 1.26, 95% CI 0.89-1.80 with I = 55%). In an analysis of observational studies, there were no significant differences between the two drugs in odds of hypotension (OR 1.12, 95% CI 0.51-2.45 with I = 18%).
CONCLUSION
While there was a trend toward improved HR control with IV diltiazem compared with IV metoprolol in randomized trials, this was not seen in observational studies, and there was no observed difference in hypotension between the two drugs.
Topics: Humans; Atrial Fibrillation; Atrial Flutter; Diltiazem; Hypotension; Metoprolol; Observational Studies as Topic
PubMed: 37856044
DOI: 10.1007/s40256-023-00615-3 -
The Korean Journal of Internal Medicine Jan 2024There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the... (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIMS
There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify all risk factors for anticoagulant-associated GIB to inform risk prediction in the management of anticoagulation- related GIB.
METHODS
A systematic review and meta-analysis were conducted to search PubMed, EMBASE, Web of Science, and Cochrane Library databases (from inception through January 21, 2022) using the following search terms: anticoagulants, heparin, warfarin, dabigatran, rivaroxaban, apixaban, DOACs, gastrointestinal hemorrhage, risk factors. According to inclusion and exclusion criteria, studies of risk factors for anticoagulation-related GIB were identified. Risk factors for anticoagulant-associated GIB were used as the outcome index of this review.
RESULTS
We included 34 studies in our analysis. For anticoagulant-associated GIB, moderate-certainty evidence showed a probable association with older age, kidney disease, concomitant use of aspirin, concomitant use of the antiplatelet agent, heart failure, myocardial infarction, hematochezia, renal failure, coronary artery disease, helicobacter pylori infection, social risk factors, alcohol use, smoking, anemia, history of sleep apnea, chronic obstructive pulmonary disease, international normalized ratio (INR), obesity et al. Some of these factors are not included in current GIB risk prediction models. such as anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction, etc.
CONCLUSION
The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.
Topics: Humans; Anemia; Anticoagulants; Diltiazem; Gastrointestinal Hemorrhage; Gemfibrozil; Heart Failure; Helicobacter Infections; Helicobacter pylori; Myocardial Infarction; Risk Factors; Verapamil
PubMed: 38062723
DOI: 10.3904/kjim.2023.098 -
Annals of Cardiac Anaesthesia 2023In this study the authors have tried to examine the role of magnesium alone or in combination with diltiazem and / or amiodarone in prevention of atrial fibrillation... (Clinical Trial)
Clinical Trial
OBJECTIVES
In this study the authors have tried to examine the role of magnesium alone or in combination with diltiazem and / or amiodarone in prevention of atrial fibrillation (AF) following off-pump coronary artery bypass grafting (CABG).
BACKGROUND
AF after CABG is common and contributes to morbidity and mortality. Various pharmacological preventive measures including magnesium, amiodarone, diltiazem, and combination therapy among others have been tried to lower the incidence of AF. Most of the studies have been performed in patients undergoing conventional on-pump CABG. In this uncontrolled trial, efficacy of magnesium alone or in combination with amiodarone and / or diltiazem has been studied in patients undergoing off-pump CABG.
METHODS
One hundred and fifty patients undergoing off-pump CABG were divided into 3 groups, Group M (n=21) received intraoperative magnesium infusion at 30mg/ kg over 1 hour after midline sternotomy; Group MD (n=78) received magnesium infusion in similar manner with diltiazem infusion at 0.05 μg/kg/hr throughout the intraoperative period; Group AMD (n=51) received preoperative oral amiodarone at a dose of 200 mg three times a day for 3 days followed by 200 mg twice daily for another 3 days followed by 200 mg once daily till the day of surgery along with magnesium and diltiazem infusion as in other groups. AF lasting more than 10 min or requiring medical intervention was considered as AF.
RESULTS
The overall incidence of postoperative AF was 12.6% with 11.7% in group AMD, 19% in group M, and 11.5% in group MD, which was not statistically significant.
CONCLUSIONS
It is concluded that the use of amiodarone and/or diltiazem in addition to magnesium did not result in additional benefit of lowering the incidence of AF.
Topics: Humans; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Coronary Artery Bypass; Diltiazem; Magnesium; Postoperative Complications; Treatment Outcome
PubMed: 37861573
DOI: 10.4103/aca.aca_35_23 -
The American Journal of Emergency... Sep 2023Diltiazem is an antiarrhythmic drug widely used in the treatment of atrial fibrillation (AFib) with rapid ventricular response (RVR). It reveals its effect by blocking...
INTRODUCTION
Diltiazem is an antiarrhythmic drug widely used in the treatment of atrial fibrillation (AFib) with rapid ventricular response (RVR). It reveals its effect by blocking L-type calcium channels. Thus, it inhibits the extracellular calcium influx into the cytosol. The relationship between serum calcium level and the efficacy of intravenous (IV) diltiazem used in the treatment of AFib with RVR has not been investigated in vivo. The aim of this study is to investigate the mentioned relationship.
METHODS
This study was planned as a single-center retrospective study. The data of 349 patients who presented to the emergency department with AFib with RVR and treated with diltiazem were retrospectively analyzed. A patient was considered to have responded to diltiazem treatment if the existing heart rhythm returned to sinus rhythm, or the heart rate decreased below 100 beats/min, or the heart rate decreased >20% provided that it was below 120 beats/min. The ionized calcium levels were recorded. The relationship between serum calcium level and the success of diltiazem treatment was examined.
RESULTS
Fifty five percent of the patients were female. The median age was 75 years. The rate of response to diltiazem treatment was 67.3%. The median of ionized calcium levels in the group which responded to diltiazem treatment (n = 235) was 1.14 mmol/L (IQR: 0.12), and the group which did not respond to diltiazem treatment (n = 114) was 1.11 mmol/L (IQR: 0.12) (p = 0.322). The patients were divided into three groups as low, normal, and high calcium levels according to the calcium reference levels determined by the hospital laboratory. The rate of response to diltiazem treatment was 61.4% in patients with low ionized calcium levels, 76.1% in patients with normal ionized calcium levels, and 40.0% in patients with high ionized calcium levels. The rate of response to diltiazem treatment was higher in patients with normal ionized calcium levels compared to patients with low or high ionized calcium levels (p = 0.004, p = 0.003).
CONCLUSION
The success rate of diltiazem used in the treatment of AFib with RVR was highest in physiological calcium levels. The current study may provide the clinician with awareness about the consideration of serum ionized calcium levels when choosing drugs in patients with AFib with RVR.
Topics: Humans; Female; Aged; Male; Diltiazem; Atrial Fibrillation; Retrospective Studies; Calcium; Treatment Outcome; Heart Rate
PubMed: 37343339
DOI: 10.1016/j.ajem.2023.06.007 -
The American Journal of Emergency... Nov 2023
PubMed: 37689491
DOI: 10.1016/j.ajem.2023.09.001