Since 3D printing technology is an emerging field in pharmaceutical technology, the present study aimed at the development of a mixed-mode liquid chromatographic method for the separation and determination of hydrochlorothiazide, diltiazem, and propranolol to investigate their in-vitro release performance from 3D printed tablets. Due to the unique properties of the mixed-mode stationary phase, the three drugs were separated in less than 8 min under isocratic elution. Method development was accomplished following the Analytical Quality by Design principles and was evaluated using risk assessment and multivariate analysis. The influences of critical method parameters on critical method attributes (were screened using a 2-level fractional factorial design and subsequently optimized through a central composite design. The method operable design region was approved by the establishment of a robust zone using Monte Carlo simulation and capability analysis. The validation of the HPLC method was performed based on the total error concept. The relative bias was varied between ─ 11.6 % and 10.5 % and the RSD values for repeatability and intermediate precision were below 4.4 % in all cases. The limits of detection (LOD) ranged between 0.17 - 0.90 μg/mL and were adequate for the specific application. The developed method was successfully applied to the analysis of the studied drugs in in-vitro drug release samples obtained from 3D-printed tablets combining the above-mentioned active pharmaceutical ingredients (APIs).

BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with amiodarone/diltiazem/verapamil, but whether there is a drug interaction between these drugs is unclear.
OBJECTIVE: To investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil.
METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from 1/1/2011-31/12/2019. We used a cohort design to estimate hazard ratios for Ischaemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality comparing DOACs+amiodarone/diltiazem/verapamil users, respectively and DOACs+beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window versus referent window within an individual was also conducted.
RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs+amiodarone/diltiazem/verapamil users, respectively versus DOACs+beta-blocker users in cohort design. However, in case-crossover design, we observed an odds ratio (OR) of 2.09 (99%CI: 1.37-3.18) for all-cause mortality associated with an initiation of a DOAC while taking amiodarone; which was greater than that observed for DOAC monotherapy (OR: 1.30; 99%CI: 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem.
CONCLUSIONS: Our study shows no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem or verapamil respectively. The elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.

This study introduces a practical and cost-effective method for tracking diltiazem (DLZ) analytically. It utilizes a fluorimetric approach that relies on the modulation of fluorescence intensity of a dye called erythrosine B. Through a one-pot experiment performed in an acidic environment, a complex is rapidly formed between DLZ and erythrosine B. By observing the decrease in erythrosine B emission, a linear calibration plot is established, enabling the detection and quantification of DLZ concentrations ranging from 40 to 850 ng/ml. The estimated limits of detection and quantitation were 10.5 and 32.1 ng/ml, respectively. The variables affecting the DLZ-dye complex system were carefully adjusted. The validity of the approach was confirmed through a thorough evaluation based on the criteria set by ICH guidelines. The accuracy and precision of the methodology were evaluated, and the standard deviation and relative standard deviation were below 2. The strategy was successfully employed to analyze DLZ in tablets and capsules, and no significant variation between the proposed and reported methods as the values of the estimated t-test and F-test at five determinations were below 2.306 and 6.338, respectively. Notably, the method adheres to the principle of green chemistry by utilizing distilled water as the dispersing medium.

暂无摘要。

UNASSIGNED: The prehospital treatment for stable patients with atrial fibrillation with rapid ventricular response is rate-controlling agents such as calcium channel blockers, often diltiazem given as a bolus. At our agency we encourage the use of a bolus given via the infusion pump over two to four minutes immediately followed by a maintenance infusion, given concerns of recurrent tachycardia or hypotension secondary to rapid bolus administration. We examined if administering a bolus and infusion via an infusion pump shows better heart rate (HR) control at arrival to the emergency department (ED) compared with administration of a bolus only, while maintaining hemodynamic stability during transport. We also analyzed if a patient received a second bolus within 60 min of arrival to the ED.
UNASSIGNED: We used a retrospective propensity-matched cohort of prehospital patients with atrial fibrillation for whom diltiazem was administered, from 1/1/2018 to 12/31/2021, in our system of 10 New Jersey paramedic units. We analyzed the age, gender, and initial HR and used it to match groups. We analyzed the mode and time of administration, dosage of the bolus, and presence of hypotension prehospitally.
UNASSIGNED: The matched groups contained 145 patients who received a prehospital diltiazem bolus only (BO) and 146 patients who received a diltiazem bolus and infusion (BI). There was no significant difference between the mean change in HR from initial paramedic arrival to ED arrival between the two groups (BO 38 vs. BI 34, p = 0.16). There was no significant difference in the need for a second bolus within the first 60 min of arrival to the ED (BO 9.7% vs. BI 11.6%, p = 0.30). Patients in the BO group were more likely to experience prehospital hypotension then in the BI group (BO 17.2% vs BI 8.2%, p = 0.01), despite receiving smaller initial bolus doses (BO 14.2 mg vs. BI 17.4 mg, p < 0.001).
UNASSIGNED: Our results show no significant differences in HR control or need for repeat bolus at the ED with the use of a diltiazem infusion following a diltiazem bolus. However, even when administering larger boluses, the use of an infusion pump resulted in less hypotension.

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.

This study investigates the efficacy of modified Albizia procera gum as a release-retardant polymer in Diltiazem hydrochloride (DIL) matrix tablets. Carboxymethylated Albizia procera gum (CAP) and ionically crosslinked carboxymethylated Albizia procera gum (Ca-CAP) were utilized, with Ca-CAP synthesized via crosslinking CAP with calcium ions (Ca2+) using calcium chloride (CaCl2). Fourier Transform (FT) IR analysis affirmed polymer compatibility, while differential scanning calorimetry (DSC) and X-ray diffraction (XRD) assessed thermal behavior and crystallinity, respectively. Zeta potential analysis explored surface charge and electrostatic interactions, while rheology examined flow and viscoelastic properties. Swelling and erosion kinetics provided insights into water penetration and stability. CAP\'s carboxymethyl groups (-CH2-COO-) heightened divalent cation reactivity, and crosslinking with CaCl2 produced Ca-CAP through -CH2-COO- and Ca2+ interactions. Structural similarities between the polymers were revealed by FTIR, with slight differences. DSC indicated modified thermal behavior in Ca-CAP, while Zeta potential analysis showcased negative charges, with Ca-CAP exhibiting lower negativity. XRD highlighted increased crystallinity in Ca-CAP due to calcium crosslinking. Minimal impact on RBC properties was observed with both polymers compared to the positive control as water for injection (WFI). Ca-CAP exhibited improved viscosity, strength, controlled swelling, and erosion, allowing prolonged drug release compared to CAP. Stability studies confirmed consistent six-month drug release, emphasizing Ca-CAP\'s potential as a stable, sustained drug delivery system over CAP. Robustness and accelerated stability tests supported these findings, underscoring the promise of Ca-CAP in controlled drug release applications.

Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.
To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.
This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.
Diltiazem and metoprolol.
The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.
The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).
In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Carbamazepine remains a first-line antiepileptic medication for the treatment of partial seizures. Despite its widespread use, carbamazepine has significant neurotoxicity and hypersensitivity reactions. We report a case of a patient post-kidney transplant who was on regular carbamazepine for childhood epilepsy and developed nystagmus, diplopia and a broad-base gait after receiving diltiazem. Understanding of the interaction between diltiazem and carbamazepine is necessary to prevent the neurotoxic effects.

UNASSIGNED: Despite atrial fibrillation guideline recommendations, many patients with heart failure with reduced ejection fraction (EF) continue to receive IV diltiazem for acute rate control.
UNASSIGNED: Our institution recently implemented a clinical decision support system (CDSS)-based tool that recommends against the use of diltiazem in patients with an EF ≤ 40%. The objective of this study was to evaluate outcomes of adherence to the aforementioned CDSS-based tool.
UNASSIGNED: This multi-hospital, retrospective study assessed patients who triggered the CDSS alert and compared those who did and did not discontinue diltiazem. The primary outcome was the occurrence of clinical deterioration. The primary endpoint was compared utilizing a Fisher\'s Exact Test, and a multivariate logistic regression model was developed to confirm the results of the primary analysis.
UNASSIGNED: A total of 246 patients were included in this study with 146 patients in the nonadherent group (received diltiazem) and 100 patients in the adherent group (did not receive diltiazem). There was a higher proportion of patients experiencing clinical deterioration in the alert nonadherence group (33% vs 21%, P = 0.044), including increased utilization of inotropes and vasopressors, and higher rate of transfer to ICU.
UNASSIGNED: In patients with heart failure with reduced EF, diltiazem use after nonadherence to a CDSS alert resulted in an increased risk of clinical deterioration. This study highlights the need for improved provider adherence to diltiazem clinical decision support systems.