verapamil (Verelan Chrono / Veralan / Veratensin)

Reversible verapamil-induced atrial pacing and sensing failure in an atrial leadless pacemaker.

Mannoji Hiroshi H, Ikenaga Takeru T, Nozoe Masatsugu M, Kubota Toru T

Multimodal Monitoring in Eclamptic Intracerebral Hemorrhage Complicated by Reversible Cerebral Vasoconstriction Syndrome (RCVS): A Case Report.

Cucciolini Giada G, Pillitteri Marta M, Vegnuti Lara L, De Masi Francesco F et al.

Eclampsia is a rare but severe obstetric condition associated with maternal morbidity and mortality. Neurological complications are rare and often compounded by systemic involvement such as HELLP syndrome and coagulopathy. In this complex setting, multimodal neuromonitoring may support individualized management. A 32-year-old woman at 37 weeks' gestation presented with new-onset tonic-clonic seizures, severe hypertension, and laboratory findings consistent with HELLP syndrome and disseminated intravascular coagulation. Following emergency cesarean section, brain CT revealed a right frontal intracranial hemorrhage (ICH) with mass effect. Given the high surgical risk related to coagulopathy, conservative management was pursued after placement of an invasive intracranial pressure (ICP) monitoring. In the neuro-ICU, a multimodal monitoring strategy combining ICP waveform analysis, continuous electroencephalography, cerebral near-infrared spectroscopy, and transcranial color-coded duplex ultrasound (TCCD) guided therapy. Medical treatment successfully controlled intracranial hypertension and restored cerebral compliance. Daily TCCD examinations revealed progressively increased middle cerebral artery flow velocities, leading to early suspicion and radiological confirmation of reversible cerebral vasoconstriction syndrome (RCVS). Treatment with verapamil and levosimendan resulted in rapid normalization of Doppler velocities without systemic hypotension. The patient showed progressive neurological recovery and was discharged to rehabilitation. After 6 months, functional outcome was favorable (modified Rankin Scale = 2). This case underscores the value of bedside TCCD integrated with multimodal neuromonitoring in the management of a complicated eclampsia with ICH and RCVS. Assessment of cerebral hemodynamics and perfusion may support safe conservative management in high-risk neuro-intensive care patients.

A hERG blocker facilitates K+ channel current by promoting pore opening while blocking.

Docken Steffen S SS, Marquis Matthew J MJ, Ngo Khoa K, Wada Yuumu Y et al.

Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

Biopharmaceutical Characterization of Grapiprant Within the BCS Framework Under Canine-Relevant Conditions: Solubility and Caco-2 Permeability Assessment.

Wen Zeyu Z, Sun Xilu X, Chen Sumeng S, Meng Jinyan J et al.

Background: The Biopharmaceutics Classification System (BCS) classifies drug substances according to their aqueous solubility and intestinal permeability; however, its application to veterinary drugs should account for species-specific gastrointestinal physiology. Grapiprant is a selective prostaglandin E2 receptor subtype 4 (EP4) antagonist approved as an oral tablet to control pain and inflammation associated with osteoarthritis in dogs, but its properties within the BCS framework remain unclear. Methods: This study evaluated the equilibrium solubility of grapiprant across pH conditions relevant to the canine gastrointestinal tract and calculated the dose number (D0) based on different gastric fluid volumes. A Caco-2 cell monolayer model was used to assess grapiprant intestinal permeability and the effects of time, concentration, pH, and efflux transporter inhibitors on its transepithelial transport. Results: Grapiprant showed relatively small changes in solubility across the tested pH range. D0 varied with pH and gastric fluid volume and approached or fell below 1 at larger fluid volumes. In the Caco-2 model, grapiprant showed generally limited apparent absorptive permeability, with permeability varying with pH. Efflux ratios were greater than 1, and verapamil reduced the efflux ratio, suggesting possible P-glycoprotein (P-gp) involvement. Conclusions: These findings suggest that both solubility and apparent intestinal permeability may limit the oral absorption of grapiprant under certain canine-relevant conditions. Accordingly, this study provides a biopharmaceutical characterization of grapiprant within the BCS framework rather than a definitive canine BCS classification, highlighting the importance of considering canine gastrointestinal conditions when interpreting its solubility and permeability. The results may support future optimization of dosing conditions and oral formulations.