Topical transient receptor potential ankyrin 1 antagonist treatment attenuates nociception and inflammation in an ultraviolet B radiation-induced burn model in mice.

BACKGROUND: Ultraviolet B (UVB) radiation exposure promotes sunburn and thereby acute and chronic inflammatory processes, contributing to pain development and maintenance. New therapeutic alternatives are necessary because typical treatments can cause adverse effects. An attractive alternative would be to target the transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable, non-selective cation channel, which is involved in a variety of inflammatory pain models. OBJECTIVE: Evaluate the peripheral participation of TRPA1 using a topical treatment (HC030031 gel formulation; a selective TRPA1 antagonist) in nociception and inflammation caused by a UVB radiation-induced burn model in male mice (25-30 g). METHODS: The mice were anaesthetised, and just the right hind paw was exposed to UVB radiation (0.75 J/cm2). Topical treatments were applied immediately after irradiation and once a day for 8 days. RESULTS: HC030031 gel presented suitable pH and spreadability factor, ensuring its quality and the therapeutic effect. HC030031 0.05 % reversed UVB-induced mechanical and cold allodynia, with maximum inhibition (Imax) of 69 ± 13 % and 100 % (on day 4), respectively. HC030031 0.05 % also reduced the paw edema and MPO activity, with Imax of 77 ± 6 % (on day 5) and 69 ± 28 %, respectively. Likewise, UVB radiation increased the H2O2 levels (a TRPA1 agonist) and the Ca2+ influx in mice spinal cord synaptosomes. UVB radiation-induced Ca2+ influx was reduced by HC030031. CONCLUSION: These findings confirm the activation of the TRPA1 channel by UVB radiation, suggesting that topical TRPA1 antagonists can be a new strategy for the adjuvant treatment of sunburn-associated pain and inflammation.

Mirabegron: ß3-adrenergic receptor agonist for the treatment of overactive bladder.

OBJECTIVE: To review the place in therapy of mirabegron, a new oral ß3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB). DATA SOURCES: A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-April 2013) was conducted using the key words mirabegron, receptor, adrenergic, beta-3; adrenergic beta-3 receptor; beta-3 receptor, and overactive bladder; urinary bladder; overactive. All published articles regarding mirabegron were included. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of mirabegron in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: Mirabegron is the newest option for treatment of OAB with symptoms of urge incontinence. As a ß3-receptor agonist, it reduces bladder muscle contractions. In two 12-week, randomized, double-blind, placebo-controlled Phase 3 studies, mirabegron significantly reduced the number of incontinence episodes per 24 hours from baseline (-1.47, -1.63, and -1.13; p < 0.05; and -1.57, -1.46, and -1.17; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). Micturitions per 24 hours were also reduced from baseline (-1.66, -1.75, and -1.05; p < 0.05; and -1.93, -1.77, and -1.34; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). A 12-month trial found mirabegron to have a safety and efficacy profile similar to that of tolterodine. CONCLUSIONS: Treatment of OAB initially includes lifestyle and nonpharmacologic intervention; for patients with persistent symptoms despite these treatments, drug therapy represents a next-step approach for symptom control. Mirabegron alleviates symptoms of OAB while having a mechanism of action that provides an alternative for patients who are intolerant of or who have contraindications to anticholinergic agents. The place in therapy of mirabegron relative to anticholinergics in the treatment of urge incontinence has not yet been established.

Role of TRPV1 and TRPA1 in visceral hypersensitivity to colorectal distension during experimental colitis in rats.

The aim of the present study is to investigate the effects of TRPV1 and TRPA1 receptor antagonists and their synergism on the visceromotor responses during experimental colitis in rats. Colitis was induced in rats by a TNBS/ethanol enema at day 0 and was assessed at day 3 using endoscopy, histology and a myeloperoxidase assay. The visceromotor response to colorectal distension (10-80 mmHg) was evaluated in conscious rats before (control condition) and 3 days after 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration (colitis condition). At day 3, visceromotor responses were assessed before and after treatment with a TRPV1 (BCTC) or TRPA1 (TCS-5861528) receptor antagonist either alone or in combination and either after intraperitoneal or intrathecal administration. Endoscopy, microscopy and myeloperoxidase activity indicated severe colonic tissue damage 3 days after TNBS administration. Colorectal distension-evoked visceromotor responses demonstrated a 2.9-fold increase during acute colitis (day 3) compared to control conditions. Intraperitoneal and intrathecal administration of BCTC or TCS-5861528 partially reversed the colitis-induced increase in visceromotor responses compared to control conditions (P<0.05). Intraperitoneal blockade of TRPA1 plus TRPV1 further decreased the enhanced visceromotor responses at high distension pressures (40-80 mmHg) compared to blockade of either TRPV1 or TRPA1 alone. This synergistic effect was not seen after combined intrathecal blockade of TRPA1 plus TRPV1. The present study demonstrates that in the rat, TRPV1 and TRPA1 play a pivotal role in visceral hypersensitivity at the peripheral and spinal cord level during acute TNBS colitis. Target interaction, however, is presumably mediated via a peripheral site of action.

Ranolazine: new drug. Stable angina: not worth the risk.

(1) Betablockers such as atenolol are the first-line symptomatic treatment for stable angina. Calcium channel blockers such as verapamil and amlodipine are second-line alternatives; (2) Ranolazine is now authorized for symptomatic adjuvant treatment of angina in patients who are poorly controlled by a betablocker and/or a calcium channel blocker. Its mechanism of action is poorly understood; (3) In two randomised double-blind trials in respectively 565 and 823 patients treated for 7 and 12 weeks, ranolazine (500 mg to 1000 mg twice a day), added to ongoing amlodipine therapy only provided a limited benefit, preventing less than one angina attack per week; (4) Comparative trials failed to show whether ranolazine has a clear-cut impact on mortality; (5) Ranolazine prolongs the QT interval in a dose-dependent manner and thus exposes patients to the risk of torsades de pointes. It is also associated with gastrointestinal disorders (constipation, nausea, vomiting) and dizziness; (6) Ranolazine is metabolised by the cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6 and is also a P-glycoprotein substrate. There is therefore a high risk of pharmacokinetic interactions. There is also a risk of pharmacodynamic interactions with drugs that prolong the QT interval; (7) In practice, the efficacy of ranolazine in the prevention of angina attacks does not outweigh the risk of severe adverse effects.

Ranolazine attenuates behavioral signs of neuropathic pain.

Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain.

Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart.

INTRODUCTION: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals. METHODS AND RESULTS: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (approximately 9 microM plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29-50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24-34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71-109) ms to 98 (86-121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811-1220) seconds to 621 (549-761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7-20.5) Hz to 7.6 (2.9-8.8) Hz (P = 0.02, n = 6). CONCLUSIONS: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation.

[Conduction blocks in the complex treatment of humeroscapular periarthritis]. / Provodnikovye blokady v kompleksnom lechenii plechelopatochnogo periartrita.

The authors propose a method of treatment of humeroscapular periarthritis by high conduction blocks of the brachial plexus by supraclavicular approach. The influence of high conduction blocks of the brachial plexus on the peripheral circulation in the upper extremities has been studied. The results of the treatment of 192 patients with humeroscapular periarthritis (mostly) with neglected forms of the disease) are presented.

Topical bupivacaine and etidocaine analgesia following fallopian tube banding.

The purpose of this study was to compare the effectiveness and safety of etidocaine and bupivacaine for postoperative analgesia after laparoscope sterilization. The study was performed in 22 healthy patients who received either one per cent etidocaine, 2 mg.kg-1, or bupivacaine 1.5 mg.kg-1 in a double-blind, randomized fashion. The local anaesthetic was dropped onto the fallopian tubes from uterus to fimbriae before tubal occlusion. To establish safety, blood concentrations of the parent drug and its metabolites were measured before application and at 1, 3, 6, 10, 15, 30, 60 and 120 min. The mean peak concentrations were 501.8 +/- 71.3 (SEM) for etidocaine with a range of 225 to 905 ng.ml-1. For bupivacaine, the mean peak concentration was 468 +/- 73.8 SEM with a range from 191 to 1005 ng.ml-1. The mean values are one eighth of the toxic convulsive dose for humans. Etidocaine was metabolized at a faster rate than bupivacaine with a rapid appearance of 2-amino-2'-butyroxylidide (ABX). The bupivacaine metabolite 2,6-pipecoloxylidide (PPX) was detected in low concentrations in the 60-minute samples. We conclude that the topical application of either etidocaine or bupivacaine is a safe procedure in the doses and concentrations used during general anaesthesia for laparoscopic tubal banding.

Long-acting local anesthetics in oral surgery: an experimental evaluation of bupivacaine and etidocaine for oral infiltration anesthesia.

The effect of bupivacaine 7.5 mg/ml with epinephrine 5µg/ml, etidocaine 15 mg/ml with epinephrine 5 µg/ml, and lidocaine 20 mg/ml with epinephrine 12.5 µg/ml was studied when used for oral infiltration anesthesia. Twenty healthy volunteers took part in the experimental and double-blind study. One ml of the respective anesthetic solution was deposited supraperiosteally in the apical area of the maxillary right lateral incisor. Onset time, frequency of analgesia, gingival spread, and duration of tooth analgesia were studied and duration of soft-tissue numbness registered. The present investigation showed that lidocaine had a shorter onset time compared with bupivacaine. No difference with regard to frequency was found. Bupivacaine and etidocaine had a longer period of soft-tissue numbness, but a significantly shorter duration of tooth analgesia than lidocaine.

Evaluation of etidocaine hydrochloride for local anesthesia and postoperative pain control in oral surgery.

Etidocaine hydrochloride, an amide-type local anesthetic with prolonged duration of action, was evaluated and compared with a standard local anesthetic, lidocaine, to determine its efficacy as a local anesthetic and its effect on postoperative pain following removal of impacted third molars. The findings indicate that 1.5% etidocaine hydrochloride with 1:200,000 epinephrine, in comparison with 2% lidocaine hydrochloride with 1:100,000 epinephrine, suppresses the magnitude of postoperative pain, and results in anesthesia comparable with that obtained by lidocaine, but results in greater blood loss during surgery.

Comparison of bupivacaine, etidocaine, and saline for trigger-point therapy.

Injections of local anesthetics, saline, "dry needling," or other stimuli at specific, tender loci (trigger or acupuncture points) are reportedly efficacious in treatment of chronic pain syndromes. In a randomized, double-blind crossover study, subjective responses of 15 patients with myofascial syndrome to trigger-point injections of either bupivacaine 0.5%, etidocaine 1%, or physiologic saline without preservative were compared. Responses in six pain-related categories were determined before treatment and 15 minutes, 24 hours, and 7 days after treatment. Trigger-point injections with bupivacaine and etidocaine were generally preferred over saline in several pain-tested categories. Implications and possible mechanisms are discussed.

Advantages of long-acting local anesthesia using etidocaine hydrochloride.

A double-blind clinical evaluation comparing 1% etidocaine with 1/200,000 epinephrine and 2% lidocaine with 1/100,000 epinephrine for third molar surgery was done on 42 patients. Aspects of long-acting and short-acting local anesthesia were compared, including time of onset, potency, regression, duration, and appraisal by the patient. The preference of patients and the experience of postoperative pain are emphasized.

A re-assessment of the efficacy of febantel (Rintal) and fenbendazole (Panacur) against Strongyloides papillosus in sheep and goats.

An efficacy evaluation using febantel and fenbendazole was carried out against Strongyloides papillosus in sheep and goats in the Grootfontein area of South West Africa/Namibia. Three groups with five sheep and three goats in each group were artificially infested with this species. When the worms had reached the adult stage one group was treated with febantel, the other group with fenbendazole and the third group left as controls. Both anthelmintics were dosed at 5 mg/kg. All animals were sacrificed one week after treatment and total worm-counts carried out. Both anthelmintics were found to be highly effective.