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.

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.

Keloid treatments: an evidence-based systematic review of recent advances.

BACKGROUND: Keloids are pathologic scars that pose a significant functional and cosmetic burden. They are challenging to treat, despite the multitude of treatment modalities currently available. OBJECTIVE: The aim of this study was to conduct an evidence-based review of all prospective data regarding keloid treatments published between 2010 and 2020. METHODS: A systematic literature search of PubMed (National Library of Medicine), Embase (Elsevier), and Cochrane Library (Wiley) was performed in November of 2020. Search strategies with the keywords "keloid" and "treatment" were performed by a medical librarian. The search was limited to prospective studies that were peer-reviewed, reported on clinical outcomes of keloid therapies, and were published in the English language between January 1, 2010, and November 24, 2020. RESULTS: A total of 3462 unique citations were identified, of which 108 studies met inclusion criteria. Current literature supports silicone gel or sheeting with corticosteroid injections as first-line therapy for keloids. Adjuvant intralesional 5-fluorouracil (5-FU), bleomycin, or verapamil can be considered, although mixed results have been reported with each. Laser therapy can be used in combination with intralesional corticosteroids or topical steroids with occlusion to improve drug penetration. Excision of keloids with immediate post-excision radiation therapy is an effective option for recalcitrant lesions. Finally, silicone sheeting and pressure therapy have evidence for reducing keloid recurrence. CONCLUSIONS: This review was limited by heterogeneity of subject characteristics and study outcome measures, small sample sizes, and inconsistent study designs. Larger and more robust controlled studies are necessary to further understand the variety of existing and emerging keloid treatments, including corticosteroids, cryotherapy, intralesional injections, lasers, photodynamic therapy, excision and radiation, pressure dressings, and others.

Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodipine versus non-dihydropyridines.

Background: High dose insulin (HDI), an inotrope and vasodilator, is a standard therapy for calcium channel blocker (CCB) poisoning. HDI causes vasodilation by stimulating endothelial nitric oxide synthase (eNOS). Most literature supporting HDI for CCB poisoning involves verapamil toxicity; however, amlodipine now causes more CCB poisonings. Unlike other CCBs, amlodipine stimulates eNOS and may cause synergistic vasodilation with HDI. The purpose of this study was to determine if amlodipine-poisoned patients treated with HDI had more evidence of vasodilation than similarly treated patients with non-dihydropyridine (non-DHP) poisoning.Methods: This was a retrospective study from a single poison center. Cases were identified via the generic code "Calcium Antagonists" in which the therapy "High Dose Insulin/Glucose" was "performed, whether or not recommended" from 2019-2021. Evidence of vasodilation was assessed via maximum number of vasopressor infusions per case, vasopressor doses, and use of rescue methylene blue to treat refractory vasoplegia.Results: Thirty-three patients were enrolled: 18 poisoned with amlodipine, 15 with non-DHPs (verapamil n = 10, diltiazem n = 5). The median number of maximum concomitant vasopressors in the amlodipine group was 3 (IQR: 2-5; range 0-6) and 2 in the non-DHP group (IQR: 1-3; range 0-5; p = 0.04); median difference in maximum concomitant vasopressors between groups was 1 (95% confidence interval: 0-2). Median maximum epinephrine dosing was higher in the amlodipine group (0.31 mcg/kg/min) compared to non-DHPs (0.09 mcg/kg/min; p = 0.03). Use of rescue methylene blue was more common in the amlodipine group (7/18 [39%]) than in the non-DHP group (0; p = 0.009).Conclusions: Amlodipine poisoned patients treated with HDI required more vasopressors, higher doses of epinephrine, and more often received rescue methylene blue than similarly treated patients with verapamil or diltiazem poisoning. These differences suggest amlodipine-poisoned patients had more evidence of vasodilation. Further study is warranted to determine if synergistic vasodilation occurs when HDI is used to treat amlodipine poisoning.

Improved fatigue properties, bone microstructure and blood glucose in type 2 diabetic rats with verapamil treatment.

BACKGROUND: Type 2 diabetes mellitus is a global epidemic disease, which leads to a severe complication named increased bone fracture risk. This study aimed to explore if verapamil treatment could improve bone quality of type 2 diabetes mellitus. METHODS: Rat models of control, diabetes and verapamil treatment with 4/12/24/48 mg/kg/d were established, respectively. Blood glucose was monitored during 12-week treatment, and bilateral tibiae were collected. Microstructural images of bilateral metaphyseal cancellous bone and high-resolution images of cortical bone of left tibial shafts were obtained by micro-computed tomography. Fatigue properties of bone were evaluated via cyclic compressive tests of right tibial shafts. FINDINGS: Verapamil treatment had no significant effect on blood glucose, but blood glucose tended to decline with the increase of verapamil-treated time and dose. Compared with controls, osteocyte lacunar and canal porosities in diabetes and verapamil-treated groups were significantly decreased (P < 0.05), trabecular separation and degree of anisotropy were significantly increased (P < 0.05), while trabecular tissue mineral density, trabecular bone volume fraction and trabecular number in verapamil-treated (48 mg/kg/d) group were significantly higher than those in diabetes (P < 0.05). Compared with diabetes, initial compressive elastic moduli in verapamil-treated (12/24/48 mg/kg/d) groups were significantly increased (P < 0.05), while secant modulus degradations in verapamil-treated (24/48 mg/kg/d) groups were significantly decreased (P < 0.05). INTERPRETATION: Verapamil could improve bone microstructure and fatigue properties in type 2 diabetic rats; and high-dose verapamil presented a significant effect on improving bone quality. These findings provided a new possibility for preventing the high bone fracture risk of type 2 diabetes mellitus in clinics.

Antidiarrheal and antispasmodic activities of Trillium govanianum rhizomes extract: involvement of calcium channel blockade.

The antidiarrheal effect of methanolic extract of Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae) was studied at doses of 12.5, 25, and 50 mg/kg in different animal models of diarrhea including castor oil (6 mL/kg), magnesium sulfate (2 gm/kg), sodium picosulfate (2 mL/kg) and lactitol (0.25 mL/kg). The antispasmodic effect of T. govanianum was studied on isolated rabbit's jejunum, using acetylcholine as tissue stabiliser and verapamil as calcium channel blocker. T. govanianum attenuated the diarrhea by producing a significant decrease in the number and weight of stool, and an increase in stool latency time. T. govanianum completely inhibited both spontaneous as well as high potassium induced contractions of isolated rabbit's jejunum, which was analogous to verapamil. Moreover, T. govanianum produced a right shift in calcium concentration response curve, confirming its calcium channel blocking activity. These findings provide scientific ground to its medicinal use in diarrhea and gut spasms.

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.

The effects of verapamil and heparin co-administration on sperm parameters and oxidative stress in prevention of testicular torsion/detorsion damage in rats.

In this research, the impacts of combined administration of verapamil and heparin on testicular torsion damage were examined. In this experimental study, 30 sexually mature male Wistar albino rats were divided into five equal groups haphazardly (n = 6): Group 1 was the sham group. In group 2, a 2-hr testicular torsion was induced, and thereafter, detorsion was done. Rats in group 3 and group 4 experienced an identical surgical procedure like group 2, but verapamil and heparin were administered in 0.3 mg/kg and 800 IU/kg doses respectively, and in group 5, a combination of verapamil and heparin were administered. Intraperitoneal drug injection in all treatment groups was done 30 min before testicular detorsion. Testicular torsion significantly changed sperm parameters, oxidative stress biomarkers and Cosentino's histological score compared to the sham group (p < .05). All treatment groups reduced testicular damage by decreasing oxidative stress and improving sperm parameters, but heparin and co-administration of verapamil and heparin were significantly better than verapamil injection alone. However, heparin injected group was more effective than other treatment groups (p < .05). Overall, an anticoagulant like heparin is more effective than a calcium channel blocker such as verapamil, and it is more likely to reduce testicular torsion injuries.

Verapamil attenuates scopolamine induced cognitive deficits by averting oxidative stress and mitochondrial injury - A potential therapeutic agent for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disorder where amyloid beta (Aß) plaques, Ca2+ dysregulation, excessive oxidative stress, mitochondrial dysfunction and synaptic loss operate synergistically to bring about cholinergic deficits and dementia. New therapeutic interventions are gaining prominence as the morbidity and mortality of AD increases exponentially every year. Treating AD with antihypertensive drugs is thought to be a promising intervention; however, its mechanism of action of ameliorating AD needs further investigation. In this context, the present study explores the protective effect of verapamil, an antihypertensive agent of Ca2+ channel blocker (CCB) class against scopolamine-induced in vitro neurotoxicity and in vivo cognitive impairment. Supplementation of verapamil was found to attenuate oxidative stress by preventing mitochondrial injury, and augment the expression of genes involved in the cholinergic function (mACR1), synaptic plasticity (GAP43, SYP) and Ca2+-dependent memory-related genes (CREB1, CREBBP, BDNF). Further, verapamil treatment in mice attenuated the cognitive and behavioural deficits induced by scopolamine as measured by the elevated plus maze and passive avoidance test (P < 0.05). Thus, the present study demonstrates the neuroprotective effect of verapamil against the pathogenesis of AD such as oxidative stress, mitochondrial dysfunction and cognitive decline. These observations emphasize the importance of ?Ca2+ dysregulation' and ?mitochondrial dysfunction' theories in AD and recommends the supplementation of compounds that regulate Ca2+ homeostasis and mitochondrial function in susceptible AD individuals.

Preconditioning with hyperbaric oxygen and calcium and potassium channel modulators in the rat heart.

The aim of this study was to establish the effect of combined therapy with hyperbaric oxygen (HBO2) therapy and verapamil, amlodipine or nicorandil on functional recovery and oxidative stress markers after ischemia in the isolated rat heart. The study included 48 rats (Wistar albino, male gender, eight weeks old, body weight 200±50g). All animals were exposed to HBO2 treatment over 14 days. Isolated heart rats were perfused by the Langendorff retrograde method at a constant coronary pressure of 70 cm H2O. After stabilization period the hearts were divided into the following groups: HBO2 group (animals exposed to only HBO2 preconditioning); HBO2 + verapamil; HBO2 + amlodipine; andHBO2 + nicorandil (animals pretreated with HBO2 and appropriate pharmacological agent). Afterward, the hearts in all groups were subjected to 20-minute global ischemia and 30-minute reperfusion. Parameters of heart function were registered, including maximum and minimum rate of pressure development, systolic and diastolic left ventricular pressure, heart rate and coronary flow. Levels of pro-oxidants such as index of lipid peroxidation, measured as thiobarbituric acid-reactive substances, nitrites, levels of superoxide anion radicals and hydrogen peroxide were determined in coronary venous effluent. Changes in cardiac tissue were evaluated by hematoxylin and eosin staining. Obtained results clearly indicate that blockage of calcium channel or the activation of adenosine triphosphate-sensitive potassium (KATP) in combination with HBO2 prevented ischemia/reperfusion-induced cardiac deleterious effects, thus contributing to improvement of functional recovery of the heart. However, future studies are certainly necessary for better understanding the mechanisms through which combination of these two maneuvers of preconditioning triggers cardioprotection.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.

AIM: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 µg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

Alternating hemiplegia of childhood: First South African case report and verapamil as a possible treatment option.

In this case report we describe a child with alternating hemiplegia of childhood, a rare neurodevelopmental disorder, and the effectiveness of an unconventional drug, verapamil, in treating this condition.

Successful control of hidradenitis suppurativa with verapamil: a case report.

An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF-α inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39-year-old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF-α and IL-1ß in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF-α/IL-1 pathway involved in the HS physiopathology. Compared to biologic agents as anti-TNF-α (adalimumab) and anti-IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF-α/IL-1, verapamil may represent an alternative therapeutic option in mild and moderate HS.

Potassium chloride mixture may maintain hypokalaemia and hypertension.

Hypokalaemia can be treated with potassium chloride mixture. Some mixtures contain liquorice extract (glycyrrhizin) as a supplement to improve taste. Glycyrrhizin can cause pseudohyperaldosteronism and thereby result in hypertension and hypokalaemia. We here present a case where treatment with potassium chloride mixture causes hypertension and hypokalaemia in a 50-year-old woman. After unravelling differential diagnosis, the potassium chloride mixture was stopped. After the discontinuation, the patient's blood pressure was well managed and the potassium levels normalised.

Chemical angioplasty for medically refractory reversible cerebral vasoconstriction syndrome.

PURPOSE: Medically refractory reversible cerebral vasoconstriction syndrome (RCVS), a rare variant of RCVS, poses a significant therapeutic challenge. Herein we describe a case of medically refractory RCVS that required treatment with intra-arterial (IA) verapamil and subsequent nimodipine, resulting in both angiographic and clinical improvement after failing to respond to hemodynamic augmentation. We also supplement a description of our case with a review of other case studies and case series in which IA calcium channel blockers were used to treat RCVS. We propose that the case we outline below demonstrates that neurointerventional management with IA verapamil is appropriate and effective as an early intervention of medically refractory RCVS. METHODS AND MATERIALS: Using PubMed and Google Scholar, we performed a search of the English language literature with several combinations of the keywords "intra-arterial", "calcium channel blockers", "reversible cerebral vasoconstriction syndrome", "RCVS", "nimodipine", "verapamil", "milrinone", and "nicardipine" to identify studies in which RCVS was treated with IA calcium channel blockers. RESULTS: We identified eight case studies and case series that met our inclusion criteria. Eighteen patients are encompassed in these eight studies. CONCLUSIONS: IA administration of calcium channel blockers has been shown to return cerebral vessels to their normal caliber in patients with medically refractory RCVS. However, there are no randomized controlled trials of the treatment of RCVS, and further studies are needed to elucidate the optimal treatment protocol for medically refractory RCVS.

Arritmias ventriculares sustentadas: a tempestade chegou / Sustained ventricular arrhythmias: the storm has arrived

Um dos grandes desafios no atendimento dos pacientes nas unidades de emergência é o tratamento das arritmias ventriculares, principalmente, quando sustentadas e recorrentes, pois são de difícil tratamento e estão associadas à alta mortalidade. O principal mecanismo envolvido na sustentação das taquicardias ventriculares é o mecanismo de reentrada, devido às cicatrizes miocárdicas secundárias a diversas cardiopatias estruturais. A tempestade elétrica pode ser séria quando ocorre em portadores de desfibriladores automáticos, provocando múltiplos choques correspondentes fora do ambiente hospitalar. Nesses casos é necessária a internação hospitalar, onde medidas específicas e escalonadas de tratamento são realizadas, indo desde o manejo clínico até intervenções específicas, como programação de dispositivos eletrônicos, intervenções eletrofisiológicas ou cirúrgicas

One of the biggest challenges in the care of patients in emergency units is the treatment of ventricular arrhythmias, particularly when sustained and relapsing, as they are difficult to treat and are associated with high mortality. The main mechanism involved in the maintenance of ventricular tachycardias is the mechanism of reentry, due to myocardial scars secondary to various structural heart diseases. The electrical storm may be serious when it occurs in patients with automatic defibrillators, causing multiple corresponding shocks outside the hospital setting. In these cases, admission to hospital is necessary, where specific and stepwise treatment measures are performed, ranging from clinical management to specific interventions, such as programming of electronic devices, and electrophysiological or surgical interventions

Protective effect of tadalafil and verapamil on testicular function and oxidative stress after torsion/detorsion in adult male rat.

OBJECTIVE: This study used a rat model to investigate the protective effect of tadalafil and verapamil on testicular function and oxidative stress after torsion/detorsion. METHODS AND MATERIALS: Animals were randomly divided into five groups: G1, Sham group; G2, testicular torsion followed by detorsion (TD); G3, testicular torsion/detorsion received 0/4 mg/kg of tadalafil (TDT); G4, testicular torsion/detorsion received 0/1 mg/kg of verapamil (TDV); and G5, testicular torsion/detorsion received 0/1 mg/kg of verapamil and 0/4 mg/kg of tadalafil (TDTV). All treated groups were received the treatment 30 min before detorsion. Also, after reperfusion period (24 hr), the parameters of spermatozoa were assayed, and blood was measured for oxidative stress markers such as superoxide dismutase (SOD), glutathione peroxidase (GPx), activity of malondialdehyde (MDA) and blood levels of testosterone. The histological parameters investigated by Johnson's scores (JS), and also the seminiferous tubule diameter (STD) and the height of the germinal epithelium (HE) were measured using the linear eyepiece grids on the light microscope. RESULTS: Between Sham and other groups were observed a significant change in histological parameters. Also, the levels of SOD, GPx and testosterone hormone were significantly decreased in TD while these increased in therapeutic groups. In the duration of ischaemia, the MDA level increased. Treatment with tadalafil and verapamil decreased the MDA level in treatment groups and also observed a significant change in sperm parameters between Sham and other groups. CONCLUSIONS: Tadalafil and verapamil can be protected the testis tissue damage and replaced the testicular function by suppressing oxidative stress after testicular torsion.

Treatments for diabetes mellitus type II: New perspectives regarding the possible role of calcium and cAMP interaction.

Diabetes mellitus (DM) is among the top ten causes of death worldwide. It is considered to be one of the major global epidemics of the 21st century, with a significant impact on public health budgets. DM is a metabolic disorder with multiple etiologies. Its pathophysiology is marked by dysfunction of pancreatic ß-cells which compromises the synthesis and secretion of insulin along with resistance to insulin action in peripheral tissues (muscle and adipose). Subjects presenting insulin resistance in DM type 2 often also exhibit increased insulin secretion and hyperinsulinemia. Insulin secretion is controlled by several factors such as nutrients, hormones, and neural factors. Exocytosis of insulin granules has, as its main stimulus, increased intracellular calcium ([Ca+2]i) and it is further amplified by cyclic AMP (cAMP). In the event of this hyperfunction, it is very common for ß-cells to go into exhaustion leading to failure or death. Several animal studies have demonstrated pleiotropic effects of L-type Ca2+ channel blockers (CCBs). In animal models of obesity and diabetes, treatment with CCBs promoted restoration of insulin secretion, glycemic control, and reduction of pancreatic ß-cell apoptosis. In addition, hypertensive individuals treated with CCBs presented a lower incidence of DM when compared with other antihypertensive agents. In this review, we propose that pharmacological manipulation of the Ca2+/cAMP interaction system could lead to important targets for pharmacological improvement of insulin secretion in DM type 2.

Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids.

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. Part 2 focuses on scar revision for hypertrophic and keloids scars. Scar revision options for hypertrophic and keloid scars include corticosteroids, bleomycin, fluorouracil, verapamil, avotermin, hydrogel scaffold, nonablative fractional lasers, ablative and fractional ablative lasers, pulsed dye laser (PDL), flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage.

Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke.

Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.