BACKGROUND: Type 2 diabetes is a common chronic disease that continues to increase in prevalence globally and is a major healthcare burden. Diabetes and hypertension frequently occur concurrently, and the use of antihypertensive agents is common in diabetic patients. One antihypertensive agent, verapamil, has tentatively shown potentially positive effects on glycemic control in assorted pre-clinical models.
OBJECTIVE: To evaluate the effect of verapamil on glycemic control in hypertensive type 2 diabetic patients.
METHODS: Type 2 diabetic hypertensive patients were recruited from King Fahad Medical City, Riyadh, KSA, to receive oral verapamil therapy. Blood pressure and glycometabolic parameters, including fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), C-peptide, and homeostatic model assessment insulin resistance (HOMA-IR), were monitored at baseline and after 6 months of verapamil therapy.
RESULTS: Thirty-five patients (16 male, 19 female) with a mean age of 57.2 years were recruited. The use of verapamil was associated with non-significant decreases in HbA1c, FPG, C-peptide, and HOMA-IR. However, a sub-group of 17 participants showed a decrease in HbA1c that was ≥0.5%. Univariate logistic regression showed that baseline BMI, HOMA-IR, and C-peptide were significantly (P < 0.05) associated with HbA1c reductions of ≥0.5%.
CONCLUSIONS: Verapamil is metabolically neutral and allows the stabilization of glycometabolic parameters in type 2 diabetic individuals. Additional research exploring the mechanism behind the variable response to verapamil therapy is warranted.

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: The purpose of this study was 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 January 1, 2011, to December 31, 2019. We used a cohort design to estimate hazard ratios for ischemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality, comparing DOACs + amiodarone/diltiazem/verapamil users and DOACs + beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window vs referent window within an individual also was 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 vs DOACs + beta-blocker users in the cohort design. However, in the case-crossover design, we observed an odds ratio (OR) of 2.09 (99% confidence interval [CI] 1.37-3.18) for all-cause mortality associated with 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 showed no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem, or verapamil. Elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.

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.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil\'s mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

OBJECTIVE: Ripretinib was developed to target a whole range of KIT proto-oncogene mutations and platelet-derived growth factor receptor A (PDGFR-A) kinases found in certain cancers and myeloproliferative neoplasms, particularly gastrointestinal stromal tumours (GISTs). This study investigated the effect of verapamil, a potential inhibitor of P-glycoprotein-1 (P-gp1) and cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics of ripretinib in rats when administered orally together. This study also assessed the metabolic stability and in vitro cellular absorption of ripretinib in the presence of verapamil.
METHODS: A novel sensitive time-saving liquid chromatography tandem mass spectometry (LC-MS/MS) technique for determining ripretinib in rat plasma was developed and validated. A Zorbax SB C18 column was used for the separation and analysis of ripretinib with a mobile phase consisting of 50:50 (%v/v) acetonitrile and 10 mM ammonium formate buffer at a flow rate of 0.4 mL/min. Imatinib was used as an internal standard (IS) in the method. The pharmacokinetic characteristics of ripretinib were evaluated in Wistar rats by successfully administering an oral dosage of 5 mg/kg body weight of ripretinib in the presence of verapamil (10 mg/kg body weight). Subsequently, rat liver microsomes were used to assess the effect of verapamil on ripretinib metabolic stability, and absorption was tested using a Caco-2 cell transwell model.
RESULTS: Ripretinib and IS were identified using multiple reaction monitoring (MRM) modes by mass spectrometry and showed ion transitions of 510.09→94.06 m/z and 494.26→ 394.16 m/z, respectively. The high-performance liquid chromatography (HPLC) method successfully eluted ripretinib and IS at retention times of 0.91 and 0.68 min, respectively, and the method was validated for all parameters and met the criteria for acceptance. Co-administration of verapamil increased the maximum concentration (Cmax) of ripretinib from 437 ± 84 ng/mL to 492 ± 50 ng/mL (12%), and the area under the concentration-time curve from 0 to the last sampling time t (AUC0-t) increased by approximately 40.6%. Verapamil significantly reduced the basolateral-to-apical transfer of ripretinib through Caco-2 cells. Findings also showed that verapamil increased the metabolic stability of ripretinib.
CONCLUSIONS: The study results indicate that the co-administration of ripretinib with CYP3A4 and/or P-gp1 inhibitors is associated with significant drug-drug interactions that affect the pharmacokinetics of ripretinib. Further research in human subjects is suggested to confirm dosage adjustment and therapeutic drug monitoring of ripretinib when administered along with P-gp1/CYP3A4 inhibitors ensuring patient safety and optimizing the therapeutic benefits of ripretinib.

BACKGROUND: 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.
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.
CONCLUSIONS: 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.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil\'s mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

BACKGROUND: Different combinations of medications are utilized during wrist access for radial artery (RA) or ulnar artery (UA) catheterization in neuroendovascular procedures to preclude vasospasm. These \"cocktails\" commonly include the calcium channel blocker Verapamil, without established benefit. We analyze outcomes in patients with and without Verapamil in their \"cocktail\" by using a case-control cohort of our single-center experience.
METHODS: A prospective log of consecutive patients who underwent diagnostic cerebral angiograms using RA/UA access was retrospectively reviewed, and patients were grouped into Verapamil and non-Verapamil cohorts. The primary outcomes assessed were the presence of forearm skin rashes (hives) and RA/UA spasms. Our initial management included Verapamil (5 mg) in the cocktail, but Verapamil was removed after we noticed the development of hives in multiple patients immediately following its injection.
RESULTS: A total of 221 patients underwent 241 RA/UA diagnostic cerebral angiograms and were included in our analysis. One hundred and forty-nine patients (61.8%) underwent catheterization with Verapamil and 92 (38.2%) were catheterized without it. Four of the 149 patients in the Verapamil group (2.7%) developed hives during the procedure and were treated with Benadryl (25 mg). Of the 92 patients who did not receive Verapamil, there were zero (0%) cases of hives and one (1.1%) case of vasospasm.
CONCLUSIONS: Verapamil in the \"cocktail\" for wrist access diagnostic cerebral angiograms was associated with periprocedural hives, but not associated with a significant reduction in spasm compared to the non-Verapamil group. Our findings suggest that the administration of prophylactic Verapamil for these procedures may not be necessary.

UNASSIGNED: The trans-radial approach significantly reduces access bleeding and underlying vascular complications and is associated with lower health care costs than the transfemoral approach. One of the most common complications, however, is radial artery occlusion (RAO).
UNASSIGNED: This study investigates the effects of verapamil on radial artery thrombosis in patients referred to Taleghani Hospital in Tehran between 2020 and 2021. Patients were randomized into 2 groups: the first group received verapamil, nitroglycerin, and heparin and the second group nitroglycerin and heparin. To randomly assign 100 cases to the 2 experimental and control groups, we first formed a framework for sampling 100 people (from 1 to 100); then, based on the table of random numbers, we assigned the first 50 numbers to the experimental group and the remainder to the control group. The 2 groups were compared for radial artery thrombosis.
UNASSIGNED: This study evaluated 100 candidates for coronary angiography in 2 groups of 50 with and without verapamil. The mean age was 58.6±11.2 years in the group with verapamil and 58.1±12.7 years in the group without verapamil (P=0.84). The difference between the 2 groups in terms of heart failure was statistically significant (P<0.028). The prevalence of clinical thrombosis was 2.0% in the group with verapamil and 22.0% in the group without verapamil (P<0.004). The prevalence of ultrasound-confirmed thrombosis was 4.0% in the group with verapamil and 36.0% in the group without verapamil (P<0.001).
UNASSIGNED: Intra-arterial injection of verapamil added to heparin and nitroglycerine during trans-radial angiography could significantly reduce RAO.

Only limited data are available regarding the treatment status and response to cluster headache in an Asian population. Therefore, this study aimed to provide a real-world treatment pattern of cluster headache and the response rate of each treatment in an Asian population.
Patients with cluster headache were recruited between September 2016 and January 2019 from 16 hospitals in Korea. At the baseline visit, we surveyed the patients about their previous experience of cluster headache treatment, and acute and/or preventive treatments were prescribed at the physician\'s discretion. Treatment response was prospectively evaluated using a structured case-report form at 2 ± 2 weeks after baseline visit and reassessed after three months.
Among 295 recruited patients, 262 experiencing active bouts were included. Only one-third of patients reported a previous experience of evidence-based treatment. At the baseline visit, oral triptans (73.4%), verapamil (68.3%), and systemic steroids (55.6%) were the three most common treatments prescribed by the investigators. Most treatments were given as combination. For acute treatment, oral triptans and oxygen were effective in 90.1% and 86.8% of the patients, respectively; for preventive treatment, evidence-based treatments, i.e. monotherapy or different combinations of verapamil, lithium, systemic steroids, and suboccipital steroid injection, helped 75.0% to 91.8% of patients.
Our data provide the first prospective analysis of treatment responses in an Asian population with cluster headache. The patients responded well to treatment despite the limited availability of treatment options, and this might be attributed at least in part by combination of medications. Most patients were previously undertreated, suggesting a need to raise awareness of cluster headache among primary physicians.