Pharmacogenomic study-A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention.

OBJECTIVE: To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. BACKGROUND: Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. METHODS: This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed. RESULTS: Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status. CONCLUSIONS: We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Calcium Channel Inhibitory Effect of Marjoram (Origanum majorana L.): Its Medicinal Use in Diarrhea and Gut Hyperactivity.

BACKGROUND: The leaves of Origanum majorana (O. majorana) are traditionally renowned for treating diarrhea and gut spasms. This study was therefore planned to evaluate its methanolic extract. METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to identify the phytochemicals, and Swiss albino mice were used for an in vivo antidiarrheal assay. Isolated rat ileum was used as an ex vivo assay model to study the possible antispasmodic effect and its mechanism(s). RESULTS: The GC-MS analysis of O. majorana detected the presence of 21 compounds, of which alpha-terpineol was a major constituent. In the antidiarrheal experiment, O. majorana showed a substantial inhibitory effect on diarrheal episodes in mice at an oral dosage of 200 mg/kg, resulting in 40% protection. Furthermore, an oral dosage of 400 mg/kg provided even greater protection, with 80% effectiveness. Similarly, loperamide showed 100% protection at oral doses of 10 mg/kg. O. majorana caused complete inhibition of carbachol (CCh, 1 µM) and high K+ (80 mM)-evoked spasms in isolated ileal tissues by expressing significantly higher potency (p < 0.05) against high K+ compared to CCh, similar to verapamil, a Ca++ antagonist. The verapamil-like predominant Ca++ ion inhibitory action of O. majorana was further confirmed in the ileal tissues that were made Ca++-free by incubating the tissues in a physiological salt solution having ethylenediaminetetraacetic acid (EDTA) as a chelating agent. The preincubation of O. majorana at increasing concentrations (0.3 and 1 mg/mL) shifted towards the right of the CaCl2-mediated concentration-response curves (CRCs) with suppression of the maximum contraction. Similarly, verapamil also caused non-specific suppression of Ca++ CRCs towards the right, as expected. CONCLUSIONS: Thus, this study conducted an analysis to determine the chemical constituents of the leaf extract of O. majorana and provided a detailed mechanistic basis for the medicinal use of O. majorana in hyperactive gut motility disorders.

Comparative Efficacy of Drug Interventions for Keloids: A Network Meta-analysis.

BACKGROUND: Keloids are common benign skin lesions originating from a disorganized fibroproliferative collagen response; these lesions often lead to both physical and psychological problems. The optimal treatment for keloids is yet to be standardized. Intralesional injection, which is simple and nontraumatic, is one of the most commonly used treatment modalities for these lesions. In this study, we compared 5 different drugs (intralesional injections) for the treatment of keloids in terms of efficacy. METHODS: We systemically searched relevant studies on PubMed, EMBASE, and Cochrane Library. Randomized clinical trials on the safety and efficacy of triamcinolone acetonide (TAC), 5-fluorouracil (5-FU), botulinum toxin A (BTA), verapamil, and bleomycin were included in this study. RESULTS: This network meta-analysis included a total of 1114 patients from 20 randomized controlled trials. Botulinum toxin A alone and TAC plus 5-FU exhibited significantly better efficacy than did 5-FU, TAC, and verapamil. No significant difference in efficacy between BTA alone and TAC combined with 5-FU was observed. No significant differences were noted in the adverse event rate between BTA, TAC plus 5-FU, 5-FU, and TAC. Furthermore, we performed surface under the cumulative ranking curve analyses to predict the rank of each intervention (by efficacy and adverse event rate). The predicted ranking by efficacy was as follows: TAC plus 5-FU, BTA, bleomycin, TAC, 5-FU, and verapamil; the predicted ranking by adverse events was as follows: TAC, 5-FU, TAC plus 5-FU, and BTA. Funnel plot analysis revealed no publication bias. CONCLUSIONS: Botulinum toxin A and TAC plus 5-FU appear to have outstanding therapeutic efficacy for keloids. The rate of adverse events was similar among BTA, TAC, 5-FU, and TAC plus 5-FU. Nonetheless, additional reviews of rigorous, large-scale randomized controlled trials are warranted for further validation of our findings.

Efficacy of High-Density Three-Dimensional Mapping for Verapamil-Sensitive Left Posterior Fascicular Ventricular Tachycardia in Pediatric Patients.

In verapamil-sensitive left posterior fascicular ventricular tachycardia (LPF-VT), radiofrequency catheter ablation (RFA) is performed targeting mid-to-late diastolic potential (P1) and presystolic potential (P2) during tachycardia. This study included four patients who had undergone electrophysiological study (EPS) and pediatric patients with verapamil-sensitive LPF-VT who had undergone RFA using high-density three-dimensional (3D) mapping. The included patients were 11-14 years old. During EPS, right bundle branch block and superior configuration VT were induced in all patients. VT mapping was performed via the transseptal approach. P1 and P2 during VT were recorded in three of the four patients. All patients initially underwent RFA via the transseptal approach. In three patients, P1 during VT was targeted, and VT was terminated. The lesion size indices in which VT was terminated were 4.6, 4.6, and 4.7. For one patient whose P1 could not be recorded, linear ablation was performed perpendicularly in the area where P2 was recorded during VT. Among the three patients in whom VT was terminated, linear ablation was performed in two to eliminate the ventricular echo beats. In all patients, VT became uninducible in the acute phase and had not recurred 8-24 months after RFA. High-density 3D mapping with an HD Grid Mapping Catheter allows recording of P1 and P2 during VT and may improve the success rate of RFA in pediatric patients with verapamil-sensitive LPF-VT.

Biomechanical response of ultrathin slices of hypertrophic cardiomyopathy tissue to myosin modulator mavacamten.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder of the heart, but effective treatment options remain limited. Mavacamten, a direct myosin modulator, has been presented as novel pharmacological therapy for HCM. The aim of this study was to analyze the biomechanical response of HCM tissue to Mavacamten using living myocardial slices (LMS). LMS (n = 58) from patients with HCM (n = 10) were cultured under electromechanical stimulation, and Verapamil and Mavacamten were administered on consecutive days to evaluate their effects on cardiac biomechanics. Mavacamten and Verapamil reduced contractile force and dF/dt and increased time-to-relaxation in a similar manner. Yet, the time-to-peak of the cardiac contraction was prolonged after administration of Mavacamten (221.0 ms (208.8 - 236.3) vs. 237.7 (221.0 - 254.7), p = 0.004). In addition, Mavacamten prolonged the functional refractory period (FRP) (330 ms (304 - 351) vs. 355 ms (313 - 370), p = 0.023) and better preserved twitch force with increasing stimulation frequencies, compared to Verapamil. As such, Mavacamten reduced (hyper-)contractility and prolonged contraction duration of HCM LMS, suggesting a reduction in cardiac wall stress. Also, Mavacamten might protect against the development of ventricular tachyarrhythmias due to prolongation of the FRP, and improve toleration of tachycardia due to better preservation of twitch force at tachycardiac stimulation frequencies.

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-ß-Blocking R-Enantiomer Carvedilol.

BACKGROUND: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. ß-Adrenergic receptor antagonists (ß-blockers) are the first-line therapy for HCM. However, ß-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. METHODS: We screened 21 ß-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (MYH7R403Q/+). RESULTS: We identified that carvedilol, a ß-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a ß1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of ß-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes. CONCLUSIONS: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes.

BACKGROUND: Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro. METHODS: Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs. RESULTS: The voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control. CONCLUSIONS: By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.

Comparing intralesional triamcinolone and verapamil-triamcinolone injections in keloids: A single-blinded randomised clinical trial.

INTRODUCTION: In this clinical trial, we investigated the efficacy of two treatment methods for keloids resulting from surgical incisions: intralesional triamcinolone injections alone versus in combination with verapamil. MATERIAL AND METHODS: Patients were divided into two groups: one received triamcinolone alone (Group T) and the other received a triamcinolone-verapamil blend (Group VT). Regular treatments were conducted until the keloids were nearly flat or for a maximum of eight sessions. RESULTS: Both groups showed significant improvements, but Group VT saw quicker resolution of skin redness and needed fewer sessions. Though the Vancouver Scar Scale (VSS) scores were generally similar across both groups, Group VT exhibited greater improvements, leading to lower final scores. The VT group also attained normal scar flexibility faster than the T group. CONCLUSION: These findings suggest that the combination of verapamil and triamcinolone provides a more effective treatment for keloids, thereby highlighting the potential of verapamil in scar reduction.

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Clinical characteristics and treatment patterns of patients with episodic cluster headache: results from the United States, United Kingdom and Germany.

OBJECTIVE: To describe clinical characteristics and regional treatment patterns of episodic cluster headache (CH). METHODS: A point-in-time survey of physicians and their patients with CH was conducted in the United States, United Kingdom and Germany in 2017. RESULTS: Overall, 1012 patients with episodic CH were analyzed. Demographic and clinical findings were generally consistent across regions. Most patients were men (66.6%) and the mean age was 40.9 years. The greatest proportion of patients (38.3%) had ≤1 attack per day. The mean number of attacks per day (APD) was 2.4 and mean number of cluster periods per year was 2.6; the mean cluster period duration was 30.8 days. Most patients (69.3%) did not report a specific or predicable time when cluster periods occurred. Acute treatment was prescribed for 47.6% of patients, 10.3% of patients received preventive treatment, and 37.9% of patients received combined acute and preventive treatment; 4.2% of patients were not receiving treatment. Frequently prescribed acute treatments were sumatriptan, oxygen, and zolmitriptan; oxygen use varied considerably across countries and was prescribed least often in the United States. Frequently prescribed preventive treatments were verapamil, topiramate, and lithium. Lack of efficacy and tolerability were the most common reasons for discontinuing preventive treatment. CONCLUSIONS: We observed high use of acute treatments, but only half of patients used preventive treatments despite experiencing several cluster periods per year with multiple cluster APD. Further studies about the need for and benefits of preventive treatment for episodic CH are warranted.

People with cluster headache (CH) experience headache attacks of excruciating stabbing pain, usually on one side of the head around the eye. These headache attacks typically last between 15 min and 3 h, and come in clusters (or bouts) occurring up to several times a day for a few weeks or months at a time. This greatly impacts a patient's quality of life.We surveyed doctors and their patients across the United States, the United Kingdom and Germany, looking at symptoms that occurred during CH attacks, how long the headache attacks lasted, how often the patient had them, and what medicines were being given.Our results showed that patients with CH suffered from clusters (bouts) of headache attacks several times a year. Nearly, a third of patients had a wrong diagnosis before being diagnosed with CH. Patients experienced stress, agitation, restlessness, difficulty relaxing and depression during a headache attack, especially those who had more CH attacks each day.Although many patients were taking medication, only half of patients were prescribed medicines to prevent their headache attack from starting. Side effects and the medicines not working were the most common reasons patients stopped taking medicine to prevent their headache attacks. The differences seen in medicines prescribed between countries suggest differences in guidance, or in doctors' awareness of current medication guidelines. Further studies about the need for and benefits of medicines to prevent CH attacks are needed.

Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis.

BACKGROUND AND OBJECTIVE: At present, the therapies of dilated cardiomyopathy concentrated on the symptoms of heart failure and related complications. The study is to evaluate the clinical efficacy of a combination of various conventional and adjuvant drugs in treating dilated cardiomyopathy via network meta-analysis. METHODS: The study was reported according to the PRISMA 2020 statement. From inception through 27 June 2022, the PubMed, Embase, Cochrane library, and Web of Science databases were searched for randomized controlled trials on medicines for treating dilated cardiomyopathy. The quality of the included studies was evaluated according to the Cochrane risk of bias assessment. R4.1.3 and Revman5.3 software were used for analysis. RESULTS: There were 52 randomized controlled trials in this study, with a total of 25 medications and a sample size of 3048 cases. The network meta-analysis found that carvedilol, verapamil, and trimetazidine were the top three medicines for improving left ventricular ejection fraction (LVEF). Ivabradine, bucindolol, and verapamil were the top 3 drugs for improving left ventricular end-diastolic dimension (LVEDD). Ivabradine, L-thyroxine, and atorvastatin were the top 3 drugs for improving left ventricular end-systolic dimension (LVESD). Trimetazidine, pentoxifylline, and bucindolol were the top 3 drugs for improving the New York Heart Association classification (NYHA) cardiac function score. Ivabradine, carvedilol, and bucindolol were the top 3 drugs for reducing heart rate (HR). CONCLUSION: A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings.

Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro.

Low back pain is usually caused by intervertebral disc degeneration (IVDD), during which the involvement of oxidation system imbalance and inflammasome activation cannot be neglected. In this study, we aimed to validate the expression level of TXNIP in IVDD and investigate the function and potential mechanism of action of verapamil. TXNIP is upregulated in the degenerate nucleus pulposus in both humans and rats, as well as in tert-butyl hydroperoxide (TBHP)-stimulated nucleus pulposus cells. Administration of verapamil, a classic clinical drug, mitigated the TBHP-induced overproduction of reactive oxygen species and activation of the NLRP3 inflammasome, thus protecting cells from pyroptosis, apoptosis, and extracellular matrix degradation. The Nrf2/TXNIP/NLRP3 axis plays a major role in verapamail-mediated protection. In vivo, a puncture-induced IVDD rat model was constructed, and we found that verapamil delayed the development of IVDD at both the imaging and histological levels. In summary, our results indicate the potential therapeutic effects and mechanisms of action of verapamil in the treatment of IVDD.

Verapamil Prevents Decline of IGF-I in Subjects With Type 1 Diabetes and Promotes ß-Cell IGF-I Signaling.

Verapamil promotes functional ß-cell mass and improves glucose homeostasis in diabetic mice and humans with type 1 diabetes (T1D). Now, our global proteomics analysis of serum from subjects with T1D at baseline and after 1 year of receiving verapamil or placebo revealed IGF-I as a protein with significantly changed abundance over time. IGF-I, which promotes ß-cell survival and insulin secretion, decreased during disease progression, and this decline was blunted by verapamil. In addition, we found that verapamil reduces ß-cell expression of IGF-binding protein 3 (IGFBP3), whereas IGFBP3 was increased in human islets exposed to T1D-associated cytokines and in diabetic NOD mouse islets. IGFBP3 binds IGF-I and blocks its downstream signaling, which has been associated with increased ß-cell apoptosis and impaired glucose homeostasis. Consistent with the downregulation of IGFBP3, we have now discovered that verapamil increases ß-cell IGF-I signaling and phosphorylation/activation of the IGF-I receptor (IGF1R). Moreover, we found that thioredoxin-interacting protein (TXNIP), a proapoptotic factor downregulated by verapamil, promotes IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R. Thus, our results reveal IGF-I signaling as yet another previously unappreciated pathway affected by verapamil and TXNIP that may contribute to the beneficial verapamil effects in the context of T1D. ARTICLE HIGHLIGHTS: Verapamil prevents the decline of IGF-I in subjects with type 1 diabetes (T1D). Verapamil decreases the expression of ß-cell IGF-binding protein 3 (IGFBP3), whereas IGFBP3 is increased in human and mouse islets under T1D conditions. Verapamil promotes ß-cell IGF-I signaling by increasing phosphorylation of IGF-I receptor and its downstream effector AKT. Thioredoxin-interacting protein (TXNIP) increases IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R in ß-cells. Regulation of IGFBP3 and IGF-I signaling by verapamil and TXNIP may contribute to the beneficial verapamil effects in the context of T1D.

Verapamil in the treatment of reversible cerebral vasoconstriction syndrome: A systematic review.

INTRODUCTION: Extrapolating from efficacy in subarachnoid haemorrhage (SAH), nimodipine has been used as a treatment for reversible cerebral vasoconstriction syndrome (RCVS). However, 4-hourly dosing is a practical limitation and verapamil has been proposed as an alternative. The potential efficacy, adverse effects, preferred dosing and formulation of verapamil for RCVS have not been systematically reviewed previously. METHOD: A systematic review was conducted of the databases PubMed, EMBASE, and the Cochrane Library from inception to July 2022 for peer-reviewed articles describing the use of verapamil for RCVS. This systematic review adheres to the PRISMA guidelines and was registered on PROSPERO. RESULTS: There were 58 articles included in the review, which included 56 patients with RCVS treated with oral verapamil and 15 patients treated with intra-arterial verapamil. The most common oral verapamil dosing regimen was controlled release 120 mg once daily. There were 54/56 patients described to have improvement in headache following oral verapamil and one patient who died from worsening RCVS. Only 2/56 patients noted possible adverse effects with oral verapamil, with none requiring discontinuation. There was one case of hypotension from combined oral and intra-arterial verapamil. Vascular complications including ischaemic and haemorrhagic stroke were recorded in 33/56 patients. RCVS recurrence was described in 9 patients, with 2 cases upon weaning oral verapamil. CONCLUSIONS: While no randomised studies exist to support the use of verapamil in RCVS, observational data support a possible clinical benefit. Verapamil appears well tolerated in this setting and represents a reasonable treatment option. Randomised controlled trials including comparison with nimodipine are warranted.

Association of Nondihydropyridine Calcium Channel Blockers Versus ß-Adrenergic Receptor Blockers With Risk of Heart Failure Hospitalization.

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 ß blockers. Because recent studies suggested that ß-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 ß blockers. We examined fee-for-service Medicare beneficiaries who were aged ≥66 years, had HFpEF or AF, and newly initiated a ß 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 ß 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 ß 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.

Bayesian Network Meta-analysis of Randomized Controlled Trials on the Efficacy of Antiarrhythmics in the Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation.

PURPOSE: Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. MATERIALS AND METHODS: A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. RESULTS: Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil-quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone-ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. CONCLUSIONS: In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).