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.

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.

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.

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.

Verapamil inhibits inflammation and promotes autophagy to alleviate ureteral scar by regulation of CaMK IIδ/STAT3 axis.

BACKGROUND: Ureteral stricture (US) is a pathological stenosis in the urinary tract characterized by increased collagen synthesis and inflammation. Autophagy activation has been shown to ameliorate tissue fibrosis and protect against fibrotic diseases. Verapamil has beneficial therapeutic benefits on fibrotic disorders. The pharmacological effects of verapamil on fibroblast autophagy in US and the underlying mechanism need to be investigated further. METHODS: US patients were recruited to isolate scar tissues, hematoxylin-eosin (HE) and Masson trichrome staining were performed to analyze histopathological changes. The US animal model was established and administered with verapamil (0.05 mg/kg) in the drinking water. Transforming growth factor (TGF)-ß1 was adopted to facilitate collagen synthesis in fibroblasts. The mRNA and protein expressions were examined by qRT-PCR, western blot, immunofluorescence and immunohistochemistry. ELISA was adopted to measure interleukin (IL)-1ß and IL-6 levels. Molecular interaction experiments like dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to analyze the interaction between signal transducers and activators of transcription 3 (STAT3) and RNA polymerase II associated factor 1 (PAF1). RESULTS: Herein, our results revealed that verapamil activated TGF-ß1-treated fibroblast autophagy and inhibited inflammation and fibrosis by repressing Ca2+/calmodulin-dependent protein kinase II (CaMK II) δ-mediated STAT3 activation. Our following tests revealed that STAT3 activated PAF1 transcription. PAF1 upregulation abrogated the regulatory effect of verapamil on fibroblast autophagy and fibrosis during US progression. Finally, verapamil mitigated US in vivo by activating fibroblast autophagy. CONCLUSION: Taken together, verapamil activated TGF-ß1-treated fibroblast autophagy and inhibited fibrosis by repressing the CaMK IIδ/STAT3/PAF1 axis.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Efficacy and Safety of Verapamil Versus Triamcinolone Acetonide in Treating Keloids and Hypertrophic Scars: A Systematic Review and Meta-Analysis.

BACKGROUND: Keloids and hypertrophic scars can affect the appearance and normal function of patients, and may severely affect patients' physical and mental health. Many methods have been used for the treatment of keloids and hypertrophic scars, there is no standardized method so far. The aim of this study was to compare the efficacy and safety of verapamil and triamcinolone acetonide (TAC) in treating keloids and hypertrophic scars. METHODS: All studies from their inception date up to August 2022 were searched using four databases (PubMed, Cochrane Library, MEDLINE, and EMBASE). The weighted mean differences and the risk ratio were calculated for comparing continuous variables and dichotomous variables, respectively. RESULTS: A total of nine randomized controlled trials involving 567 patients were identified. This meta-analysis indicated that TAC group showed significantly better effects compared with verapamil group in the reduction of height at 3 and 9 weeks, pliability at 3, 9, and 18 weeks, vascularity at 3, 6, 9, 12, 18, and 24 weeks, whereas verapamil group showed significantly better effects compared with TAC group in the reduction of pliability at 21 and 24 weeks. Verapamil group showed a significantly lower incidence of skin atrophy, telangiectasia, and hypopigmentation compared with TAC group. However, the incidence of burning sensation in verapamil group was higher than that in TAC group. CONCLUSION: Concerning the treatment of keloids and hypertrophic scars, TAC was more effective than verapamil for improving vascularity; TAC was superior to verapamil in improving height within 9 weeks of treatment; TAC produced superior result for improving pliability within 18 weeks of treatment, whereas verapamil produced superior result between 18 and 24 weeks of treatment. Verapamil had fewer adverse events than TAC and can be used as a safer alternative for the treatment of keloids and hypertrophic scars. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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.

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.

Machine phenotyping of cluster headache and its response to verapamil.

Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (-4, -66, -20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P = 0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness.

Real-life treatment of cluster headache in a tertiary headache center - results from the Danish Cluster Headache Survey.

BACKGROUND: Pharmacological treatment of cluster headache constitutes the core of clinical management, but evidence is sparse. We aimed to generate insight in the existing treatment and identify associations between clinical features and treatment response. METHODS: Patients aged 18-65 diagnosed with cluster headache according to the ICHD-2 completed a questionnaire followed by a structured interview. Multiple logistic regression was used to identify associations. RESULTS: The population consisted of 400 patients with an episodic: chronic ratio of 1.7:1. Episodic patients were more likely to respond to triptans (odds ratio = 1.77, confidence interval: 1.08-2.91, p = 0.023) and oxygen (odds ratio = 1.64, confidence interval: 1.05-2.57, p = 0.031) than chronic. Oxygen response was less likely if pain intensity was very severe (odds ratio = 0.53, confidence interval: 0.33-2.57, p = 0.006) and the risk of a poor response increased with disease duration (odds ratio = 0.79, confidence interval: 0.65-0.96, p = 0.016). Among current users of sumatriptan injection and oxygen, the proportion achieving 100% relief was higher with sumatriptan injection (p > 0.001) than with oxygen. No associations were identified regarding verapamil. Only 57% of current users of preventive medication responded at a 50% level. CONCLUSION: Episodic cluster headache is more responsive to acute therapy than chronic. Further, sumatriptan injection was more effective than oxygen and the responder-rate was limited with verapamil. More effective acute and preventive therapies are needed for cluster headache patients.

Cluster headache in children and adolescents: a systematic review of case reports.

AIM: To describe the clinical characteristics and therapeutic options available to paediatric patients with cluster headache. METHOD: Based on a literature search of the medical databases PubMed, LILACS, and Web of Science and using selected descriptors, we carried out a systematic review of case reports on cluster headache in paediatric patients published from 1990 to 2020. RESULTS: Fifty-one patients (29 males, 22 females) with a mean (SD) age of 9 years 7 months (3y 10mo; range 2-16y) were diagnosed with cluster headache. The mean (SD) diagnosis was made 27.8 months (26.2mo) after the onset of cluster headache. Pain occurred at night or on waking up (76.5%) and consisted of 1 to 3 attacks per day (62.7%) lasting 30 to 120 minutes (68.6%). Headaches were unilateral (90.2%), had a pulsatile character (64.7%), and severe intensity (100%). There were autonomic manifestations (90.2%) predominantly ipsilateral to pain, in this order: lacrimation; conjunctival injection; nasal congestion; ptosis; eyelid oedema; and rhinorrhoea. Sumatriptan and oxygen inhalation were the most effective treatments for acute manifestation. Prophylaxis, corticosteroids, verapamil, and gabapentin were the most effective drugs. INTERPRETATION: Due to the small number of published studies, this review could not provide reliable data; however, it appears that cluster headache in children and adolescents is similar to adults, both in clinical characteristics and treatment. What this paper adds Cluster headache in children and adolescents is poorly studied. Cluster headache is uncommon before 10 years of age and diagnosis is difficult in the first few years of life. Treatment of cluster headache in children and adolescents is similar to that used in adults. The notion of the effectiveness of prophylactic treatment is based only on authors' experience.

Comparison of the catheter ablation outcome in patients between targeting the entrance and exit of the reentry circuit in verapamil-sensitive atrial tachycardia originating from the atrioventricular-node vicinity.

Verapamil-sensitive atrial tachycardia originating from the atrioventricular node vicinity (AVN-AT) can be eliminated with radiofrequency energy (RF) deliveries targeting either the entrance or exit of its reentry circuit. However, the outcome of these different approaches has not been clarified well. Thus, we compared the catheter ablation outcome targeting the entrance of reentry circuit, identified by the entrainment method (Ent-Group; 21 patients) with that targeting the earliest atrial activation site (EAAS) during AT (Exit-Group; 16 patients). There was no significant difference in the tachycardia cycle length (441.4 ± 87.4 vs. 392.8 ± 64.8 ms, p = 0.0704) or distance from the His bundle (HB) site to the EAAS (6.5 ± 2.0 vs. 7.6 ± 1.8 mm, p = 0.0822) between the Ent- and Exit-Groups. However, distance from the successful ablation site to the HB site in the Ent-Group was significantly longer than that in the Exit-Group (13.4 ± 3.1 vs. 7.6 ± 1.8 mm, p < 0.0001), resulting in more frequent transient atrioventricular block episodes in the Exit-Group than Ent-Group (31.3 vs. 0%, p < 0.01). Initial ATs (AT1s) were terminated in all patients in both Groups. However, ATs accompanied by shifting in the EAAS (AT2) were induced more frequently in the Exit-Group than Ent-Group (50.0 vs. 14.3%, p < 0.02) after eliminating AT1. RF deliveries to the EAAS eliminated all AT2s. The number of RF deliveries was greater in the Exit-Group than Ent-Group (6.9 ± 3.3 vs. 3.9 ± 1.6, p < 0.001). In conclusion, RF ablation targeting the entrance sites can avoid AVN injury and is superior in reducing the number of RF deliveries and occurrence of different ATs than targeting the exit sites in the AVN-AT.

Short coupled torsade de pointes: Critical timing of the ventricular premature beats.

In this case report, we describe a 73 year old female with structuraly normal heart that developed shortcoupled torsades de pointes (TdP) resulting in an electrical storm unresponsible to several antiarrhythmic drugs, but fully controlled with verapamil. The critical timing of the ventricular premature beats that initiated TdP corresponded to those that occurred at the peak of the previous T wave. This behavior differentiates this entity from other forms of malignant ventricular arrhythmias in patients with structurally normal heart. It is imperative that the clinical set-up and unique electrocardiographic fingerprint of this unusual malignant entity be assiduously recognized since verapamil can be life-saving in this condition.

Verapamil-sensitive idiopathic left ventricular tachycardia and concomitant atrioventricular nodal reentrant tachycardia.

We describe the case of a young patient with runs of repetitive monomorphic left ventricular tachycardia. He was diagnosed with verapamil-sensitive, idiopathic left ventricular tachycardia (ILVT) and underwent an electrophysiological study, in which dual atrioventricular (AV) nodal physiology was evident, with an AV nodal reentrant tachycardia (AVNRT) being easily and reproducibly induced. Both the AVNRT and the ILVT were successfully ablated using high-density electroanatomical mapping and an open-irrigation catheter. In conclusion, verapamil-sensitive ILVT might coexist with AVNRT. In case of invasive therapy, a thorough electrophysiological evaluation is mandatory to exclude or treat other co-existing reentrant supraventricular arrhythmias.

Co-administration of Salvia miltiorrhiza and verapamil inhibits detrimental effects of torsion/detorsion on testicular tissue in rats.

Testicular torsion/detorsion is one of the important emergencies that requires fast surgical intervention. This study aimed to investigate the effects of Salvia miltiorrhiza hydroalcoholic extract combined with verapamil on testicular ischaemia/reperfusion damage in Wistar albino rats. All animals were distributed in 3 groups (n = 8), including the sham-operated group, torsion/detorsion (TD) group and torsion/detorsion + pretreatment with 200 mg/kg Salvia miltiorrhiza extract combined with 0.3 mg/kg verapamil (SMV) group. Oxidative stress biomarkers (MDA, GPx, CAT and TAC) both in plasma and testicular tissue, sperm parameters (motility, vitality, concentration and morphology) and histopathological parameters (MSTD, GECT, Johnson's score, Cosentino's score and testicular cell thickness) were assessed in all groups. Ischaemia/reperfusion significantly increased MDA and decreased GPx, CAT and TAC levels (p < .05). Pretreatment with SMV significantly increased GPx, CAT and TAC levels (p < .05). SMV group increased progressive sperm motility and vitality and reduced non-progressive motility of spermatozoon (p < .05). Testicular torsion significantly decreased all histopathological parameters compared to the sham group (p < .05). SMV pretreatment remarkably increased MSTD, GECT and Cosentino's score in comparison with the TD group (p < .05). A combination of Salvia miltiorrhiza with verapamil could reduce damages triggered by testicular torsion detorsion and improve sperm functionality parameters and oxidative stress defence systems.

The Efficacy of Anti-Arrhythmic Drugs in Children With Idiopathic Frequent Symptomatic or Asymptomatic Premature Ventricular Complexes With or Without Asymptomatic Ventricular Tachycardia: a Retrospective Multi-Center Study.

The aim of the study is to compare the efficacy of flecainide, beta-blockers, sotalol, and verapamil in children with frequent PVCs, with or without asymptomatic VT. Frequent premature ventricular complexes (PVCs) and asymptomatic ventricular tachycardia (VT) in children with structurally normal hearts require anti-arrhythmic drug (AAD) therapy depending on the severity of symptoms or ventricular dysfunction; however, data on efficacy in children are scarce. Both symptomatic and asymptomatic children (≥ 1 year and < 18 years of age) with a PVC burden of 5% or more, with or without asymptomatic runs of VT, who had consecutive Holter recordings, were included in this retrospective multi-center study. The groups of patients receiving AAD therapy were compared to an untreated control group. A medication episode was defined as a timeframe in which the highest dosage at a fixed level of a single drug was used in a patient. A total of 35 children and 46 medication episodes were included, with an overall change in PVC burden on Holter of -4.4 percentage points, compared to -4.2 in the control group of 14 patients. The mean reduction in PVC burden was only significant in patients receiving flecainide (- 13.8 percentage points; N = 10; p = 0.032), compared to the control group and other groups receiving beta-blockers (- 1.7 percentage points; N = 18), sotalol (+ 1.0 percentage points; N = 7), or verapamil (- 3.9 percentage points; N = 11). The efficacy of anti-arrhythmic drug therapy on frequent PVCs or asymptomatic VTs in children is very limited. Only flecainide appears to be effective in lowering the PVC burden.

Hyperbaric oxygen therapy and fluorescence angiography in arterial insufficiency secondary to injection of crushed hydromorphone.

INTRODUCTION: Foreign body emboli can lead to acute arterial insufficiency. We present a case report of upper extremity arterial insufficiency in an intravenous (IV) drug user secondary to intra-arterial injection of crushed tablet particles successfully treated with hyperbaric oxygen (HBO2) therapy. CASE: A 37-year-old right-hand-dominant male developed pain and swelling of the left hand after attempting to inject crushed hydromorphone tablets into his venous circulation. Angiography revealed incomplete distal filling of the proper digital arteries, princeps pollicis, and radialis indicis branches of the left hand. The patient was treated with HBO2 for acute arterial insufficiency, secondary to these findings. Fluorescence angiography was performed prior to, during and after completion of HBO2, which showed improved perfusion of the hand upon completion of serial imaging. The patient underwent subsequent partial amputation of the left second digit and removal of the thenar and third finger pads. DISCUSSION: Much of the literature on treatment of arterial insufficiency with HBO2 are in relation to chronic problem wounds. However, there is limited data on adjunctive treatment with HBO2 for foreign body embolism. Fluorescence angiography and clinical exam were used to track tissue perfusion and progression throughout course of therapy with HBO2. CONCLUSION: Acute arterial insufficiency induced by foreign body embolism was successfully treated with HBO2 and provided increased tissue salvage of the patient's hand. The use of fluorescence angiography as a secondary measure of perfusion can provide additional insight regarding qualitative tissue oxygenation and may be a viable tool to track patient progress during HBO2 treatment.

Verapamil-containing silicone gel reduces scar hypertrophy.

A hypertrophic scar is a common dermal fibroproliferative lesion usually treated with topical silicone. Verapamil, a type of calcium channel blocker, is considered a candidate drug for the treatment of hypertrophic scars. Here, we report that the addition of verapamil to topical silicone gel enhances treatment outcomes of hypertrophic scars. Upon creation of hypertrophic scars with the rabbit ear model, varying concentrations of verapamil-added silicone gel (0.1, 1, and 10 mg/g) were applied daily for 28 days. After the animals were euthanised, microscopic measurement was performed for (a) scar elevation index (SEI), (b) fibroblast count, and (c) capillary count. On gross analysis, features of hypertrophic scars were significantly alleviated in the verapamil-added groups. On histologic examination, verapamil-added groups showed (a) reduced SEI (1.93 (1.79-2.67) for control vs 1.34 (1.21-1.51) for silicone only and 1.13 (1.01-1.65) for verapamil-added silicone), (b) fibroblast count 700.5 (599.5-838.5) for control, 613.25 (461-762.5) for silicone only, and 347.33 (182.5-527) for verapamil-added silicone), and (c) capillary formation (52 (35.5-96.5) for control, 46 (28-64.5) for silicone only, and 39.83(24-70) for verapamil-added silicone) (Kruskal-Wallis test, P < .05). On western blot, expression levels of collagen I protein was lower in the 1 mg/g and 10 mg/g verapamil-added silicone compared with control. Therefore, we suggest a therapeutic concentration of verapamil-added silicone gel of at least over 1 mg/g. Further study regarding maximally effective concentration and deeper insight into the mechanism of action should follow.