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Life (Basel, Switzerland) Aug 2023Alzheimer's disease (AD) is an age-related neuropsychiatric disorder and a common cause of progressive dementia. Diltiazem (DTZ), the non-dihydropyridine benzothiazepine...
Alzheimer's disease (AD) is an age-related neuropsychiatric disorder and a common cause of progressive dementia. Diltiazem (DTZ), the non-dihydropyridine benzothiazepine class of calcium channel blocker (CCB), used clinically in angina and other cardiovascular disorders, has proven neurological benefits. In the present study, the neuroprotective anti-dementia effects of DTZ against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced sporadic AD (SAD)-type rat model was investigated. ICV-STZ-induced cognitive impairments were measured via passive avoidance and Morris water maze tasks. Anti-oxidative enzyme status, pro-inflammatory markers, and amyloid-beta (Aβ) protein expression in rat brain tissues were measured using ELISA kits, Western blotting, and immunostaining techniques. The data revealed that ICV-STZ injection in rats significantly induced cognitive deficits and altered the levels of oxidative and pro-inflammatory markers ( < 0.05~ < 0.001). Treatment with DTZ (10 mg/kg, 20 mg/kg, and 40 mg/kg, p.o.) daily for twenty-one days, 1 h before a single ICV-STZ (3 mg/kg) injection, significantly improved cognitive impairments and ameliorated the ICV-STZ-induced altered nitrite, pro-inflammatory cytokines (TNF-α, and IL-1β) and anti-oxidative enzyme levels (superoxide dismutase, lipid peroxidation, and glutathione). Further, DTZ restored the increased Aβ protein expression in ICV-STZ-induced brain tissue. Considering the results obtained, DTZ might have a potential therapeutic role in treating and managing AD and related dementia pathologies due to its anti-dementia activity in SAD-type conditions in rats induced by ICV-STZ.
PubMed: 37629545
DOI: 10.3390/life13081688 -
Genes & Diseases Jan 2024Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release... (Review)
Review
Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
PubMed: 37588227
DOI: 10.1016/j.gendis.2023.01.026 -
BMJ Neurology Open 2023Acute blood pressure (BP) reduction is standard of care after acute intracerebral haemorrhage (ICH). More acute BP reduction is associated with acute kidney injury...
BACKGROUND
Acute blood pressure (BP) reduction is standard of care after acute intracerebral haemorrhage (ICH). More acute BP reduction is associated with acute kidney injury (AKI). It is not known if the choice of antihypertensive medications affects the risk of AKI.
METHODS
We analysed data from the ATACH-II clinical trial. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. We analysed antihypertensive medication from two sources. The first was a case report form that specified the use of labetalol, diltiazem, urapidil or other. We tested the hypothesis that the secondary medication was associated with AKI with χ test. Second, we tested the hypotheses the dosage of diltiazem was associated with AKI using Mann-Whitney U test.
RESULTS
AKI occurred in 109 of 1000 patients (10.9%). A higher proportion of patients with AKI received diltiazem after nicardipine (12 (29%) vs 21 (12%), p=0.03). The 95%ile (90%-99% ile) of administered diltiazem was 18 (0-130) mg in patients with AKI vs 0 (0-30) mg in patients without AKI (p=0.002). There was no apparent confounding by indication for diltiazem use.
CONCLUSIONS
The use of diltiazem, and more diltiazem, was associated with AKI in patients with acute ICH.
PubMed: 37529670
DOI: 10.1136/bmjno-2023-000458 -
Cureus Jul 2023Angioedema is a documented but uncommon adverse effect of dihydropyridine calcium channel blockers such as amlodipine. We present the case of a 38-year-old man who...
Angioedema is a documented but uncommon adverse effect of dihydropyridine calcium channel blockers such as amlodipine. We present the case of a 38-year-old man who presented to the emergency department (ED) with severe swelling of his upper lip that had begun earlier in the day. His medical history was notable for hypertension treated with amlodipine; his only other medication was a multivitamin. The patient denied any known drug allergies, new foods, insect bites, recent travel, or sick contacts. Physical examination showed hypertension and massive edema isolated to the upper lip; it was otherwise unremarkable. Laboratory results showed no abnormalities aside from a slight normocytic anemia. The patient was diagnosed with angioedema, with amlodipine suspected as the cause. Amlodipine was discontinued and treatment was initiated with IV glucocorticoids and diphenhydramine. The swelling improved steadily over the next 36 hours and the patient was discharged on hospital day 3.
PubMed: 37484793
DOI: 10.7759/cureus.42202 -
Indian Heart Journal 2023Despite successful mitral valve replacement (MVR), many patients remain in AF. Flecainide can be useful in these patients but has not been used because of underlying...
BACKGROUND
Despite successful mitral valve replacement (MVR), many patients remain in AF. Flecainide can be useful in these patients but has not been used because of underlying structural heart disease.
METHODS
We assessed oral flecainide for conversion and maintenance of SR in 25 patients of chronic rheumatic AF following MVR (age 34.4 yrs, mean AF duration: 3.6 yrs). Non-converters underwent DC cardioversion at 24 h and 4 weeks. Patients received flecainide and bb/diltiazem at discharge.
RESULTS
Single oral dose of Flecainide achieved SR in 6/25 (24%) while 19/25 achieved SR after DCC; at24 h 21/25 (84%) were in SR. With mean flecainide dose (93.10 ± 9.40 mg), successful maintenance of SR at 6 months was seen in 16/23 (69.5%). No significant changes in PR interval, QRS duration or QTc were noted; flecainide was well tolerated. Patients in SR had significantly better functional status, QOL scores and higher LA strain at 6 months (25.25 vs 17.43%, p < .0001). Baseline LA diameter ≤ 61 mm predicted SR at 6 months (sensitivity/specificity 93.7% and 85.71%) while the values for AF duration ≤ 4 years and LA strain > 21% for predicting SR were 87.5/71.43% and 100/85.71% respectively.
CONCLUSION
Oral flecainide was safe and effective in post MVR rheumatic AF patients; maintenance of SR was achieved in 76% of initial converters and 64% of overall population, with better LA strain values. More studies are needed to validate these results.
Topics: Humans; Adult; Atrial Fibrillation; Flecainide; Mitral Valve; Quality of Life; Electric Countershock; Treatment Outcome
PubMed: 37473806
DOI: 10.1016/j.ihj.2023.07.001 -
Journal of Medical Case Reports Jul 2023Atrial flutter with 1:1 conduction to the ventricles is a dangerous cardiac arrhythmia. Contemporary guidelines recommend atrioventricular nodal blocking agents should...
BACKGROUND
Atrial flutter with 1:1 conduction to the ventricles is a dangerous cardiac arrhythmia. Contemporary guidelines recommend atrioventricular nodal blocking agents should be co-administered with class 1C anti-arrhythmics, as prophylaxis against 1:1 flutter. No guidance is provided on the type or strength of atrioventricular nodal blockade required, and in practice, these agents are frequently prescribed at low dose, or even omitted, due to their side effect profile.
CASE PRESENTATION
A 62 year old Caucasian man with a history of paroxysmal atrial fibrillation treated with flecainide, presented with atrial flutter with 1:1 conduction to the ventricles and was cardioverted. Diltiazem was added to prevent this complication and he again presented with atrial flutter with 1:1 conduction to the ventricles, despite prophylaxis with coadministration of diltiazem.
CONCLUSIONS
This case report demonstrates failure of diltiazem to prevent 1:1 flutter in a patient chronically treated with flecainide for paroxysmal atrial fibrillation.
Topics: Male; Humans; Middle Aged; Diltiazem; Atrial Flutter; Flecainide; Atrial Fibrillation; Electrocardiography; Anti-Arrhythmia Agents; Atrioventricular Block
PubMed: 37464369
DOI: 10.1186/s13256-023-03947-5 -
Case Reports in Emergency Medicine 2023The most frequent atrioventricular tachycardia in the emergency room is atrioventricular nodal reentrant tachycardia (AVNRT). The first treatment option for ending...
BACKGROUND
The most frequent atrioventricular tachycardia in the emergency room is atrioventricular nodal reentrant tachycardia (AVNRT). The first treatment option for ending stable narrow QRS complex SVTs is vagal maneuvers and adenosine. When adenosine or vagal maneuvers fail to change a patient's rhythm to normal sinus rhythm, long-acting AV nodal-blocking medications, including nondihydropyridine calcium channel blockers (verapamil and diltiazem), flecainide, or beta-blockers, are employed. Electricity (synchronized cardioversion) is the preferred form of treatment for unstable patients. . A 40-year-old male patient presented to the Emergency Department of Dubti General Hospital, the Afar regional state in Ethiopia, with a complaint of shortness of breath, palpitation, extreme fatigue, and chest pain of a day's duration. His blood pressure was 80/50 mmHg, he had cold extremities and a weak radial pulse, and his apical heart rate was fast, making it difficult to count. His electrocardiogram (ECG) showed paroxysmal supraventricular tachycardia (PSVT) with a heart rate of 200. He was a candidate for electrical cardioversion due to unstable PSVT, but he and his family members refused to give consent. Even though he is not indicated for pharmacologic therapy, none of the commonly used drugs were available at the hospital. We managed him with digoxin, and the outcome was positive.
CONCLUSION
Even though we could not find a clear recommendation regarding the use of digoxin for patients with unstable PSVT (AVNRT), by taking into consideration its negative chronotropic effect and its action to suppress the AV nodal conduction velocity, it may reduce the heart rate, and it can be used as an alternative in such difficult scenarios and a resource-limited setting. But this should be further investigated.
PubMed: 37457790
DOI: 10.1155/2023/7301460 -
Journal of Pharmaceutical Sciences Nov 2023Equilibrium dialysis (ED) is widely used in pharmacokinetics to determine the fraction of unbound (f) compounds in plasma; however, the kinetics of drugs in the ED...
Equilibrium dialysis (ED) is widely used in pharmacokinetics to determine the fraction of unbound (f) compounds in plasma; however, the kinetics of drugs in the ED system with respect to their permeation across semi-permeable membranes has not been systemically studied. Here, the kinetics of the ED system, including the binding of drugs to plasma proteins, non-specific binding, and permeation across the membrane, was described to enable verification of the equilibrium, prediction of the time to reach equilibrium, and estimations of f with data obtained during pre-equilibrium. Using data obtained during pre-equilibrium, the time to reach 90% equilibrium (t) and f were estimated with reasonable accuracy. Notably, f could be estimated reasonably well using one-time-point data for the calculation. Furthermore, the current modeling approach allowed concurrent estimations of f and the decomposition rate of compounds that were metabolically unstable in the plasma. Reasonable metabolic rate constants were determined for cefadroxil and diltiazem, demonstrating the practicality of this method for determining kinetics related to f characterization. Because the determination of f of compounds with 'unfavorable' physicochemical properties is known to be experimentally challenging, the current method may be useful in determining the f of compounds in vitro.
PubMed: 37392902
DOI: 10.1016/j.xphs.2023.06.015 -
Heart (British Cardiac Society) Aug 2023Atrial fibrillation (AF) is associated with adverse events including conduction disturbances, ventricular arrhythmias and sudden death. The aim of this study was to... (Observational Study)
Observational Study
OBJECTIVE
Atrial fibrillation (AF) is associated with adverse events including conduction disturbances, ventricular arrhythmias and sudden death. The aim of this study was to examine brady- and tachyarrhythmias using continuous rhythm monitoring in patients with paroxysmal self-terminating AF (PAF).
METHODS
In this multicentre observational substudy to the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V), we included 392 patients with PAF and at least 2 years of continuous rhythm monitoring. All patients received an implantable loop recorder, and all detected episodes of tachycardia ≥182 beats per minute (BPM), bradycardia ≤30 BPM or pauses ≥5 s were adjudicated by three physicians.
RESULTS
Over 1272 patient-years of continuous rhythm monitoring, we adjudicated 1940 episodes in 175 patients (45%): 106 (27%) patients experienced rapid AF or atrial flutter (AFL), pauses ≥5 s or bradycardias ≤30 BPM occurred in 47 (12%) patients and in 22 (6%) patients, we observed both episode types. No sustained ventricular tachycardias occurred. In the multivariable analysis, age >70 years (HR 2.3, 95% CI 1.4 to 3.9), longer PR interval (HR 1.9, 1.1-3.1), CHADS-VASc score ≥2 (HR 2.2, 1.1-4.5) and treatment with verapamil or diltiazem (HR 0.4, 0.2-1.0) were significantly associated with bradyarrhythmia episodes. Age >70 years was associated with lower rates of tachyarrhythmias.
CONCLUSIONS
In a cohort exclusive to patients with PAF, almost half experienced severe bradyarrhythmias or AF/AFL with rapid ventricular rates. Our data highlight a higher than anticipated bradyarrhythmia risk in PAF.
TRIAL REGISTRATION NUMBER
NCT02726698.
Topics: Aged; Humans; Atrial Fibrillation; Atrial Flutter; Bradycardia; Heart Ventricles; Tachycardia, Ventricular
PubMed: 36948572
DOI: 10.1136/heartjnl-2022-322253