Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy.

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.

Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence.

Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAIDs, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be α2δ-dependent suppression of voltage-gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage-gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states.

Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis.

BACKGROUND: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. METHODS: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. RESULTS: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. CONCLUSIONS: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis.

Targeting γ-secretases protect against angiotensin II-induced cardiac hypertrophy.

OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of γ-secretase, and to test preclinically the therapeutic efficacy of γ-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the γ-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the γ-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of γ-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic γ-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.

Efficacy of epinastine hydrochloride ophthalmic solution in allergic conjunctivitis by conjunctival cedar pollen allergen challenge.

BACKGROUND: Epinastine hydrochloride is a selective histamine H1 receptor antagonist that also inhibits IgE receptor-mediated histamine release from mast cells. OBJECTIVE: To show the superiority of epinastine 0.05% ophthalmic solution (epinastine) to placebo ophthalmic solution (placebo) and noninferiority to olopatadine 0.1% ophthalmic solution (olopatadine) for cedar pollen antigen-induced ocular itching and conjunctival hyperemia. METHODS: The study was conducted in ophthalmologically asymptomatic adult volunteers with seasonal allergic conjunctivitis using a conjunctival allergen challenge test. Subjects were randomized into 3 groups (n = 87) to evaluate superiority to placebo (visits 4 to 6) and 2 groups (n = 86) to evaluate noninferiority to olopatadine (visit 7). At each visit, a single administration of the study medication was instilled at 15 minutes (visit 4), 4 hours (visit 5), 8 hours (visit 6), and 4 hours (visit 7) before the conjunctival allergen challenge test. Ocular itching and conjunctival hyperemia of allergic conjunctivitis were assessed after the conjunctival allergen challenge test. RESULTS: For the primary end point, epinastine showed superiority to placebo for the inhibition of ocular itching and conjunctival hyperemia induced at 4 hours after the dose (equivalent to 4-times-daily dosing). For the secondary end points, epinastine significantly inhibited itching and conjunctival hyperemia induced at 15 minutes and 8 hours after the dose (equivalent to 2-times-daily dosing) compared with placebo. In addition, epinastine demonstrated noninferiority to olopatadine for ocular itching and conjunctival hyperemia. No adverse drug reactions or serious adverse events were reported throughout the study, indicating that epinastine has a good safety profile. CONCLUSION: Epinastine is effective and safe for the treatment of allergic conjunctivitis. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01363700.

Establishment of a rescue program for anorectal malformations induced by retinoic acid in mice.

AIMS OF STUDY: Retinoid-mediated signal transduction plays a crucial role in the embryogenesis of various organs. We previously reported the successful induction of anorectal malformations in mice using retinoic acid (RA). Retinoic acid controls the expression of essential target genes for cell differentiation, morphogenesis, and apoptosis through a complicated interaction in which RA receptors form heterodimers with retinoid X receptors. In the present study, we investigated whether the retinoid antagonist, LE135, could prevent the induction of anorectal malformations (ARMs) in mice. METHODS: Retinoic acid was intraperitoneally administered as 100 mg/kg of all-trans RA on E9; and then the retinoid antagonist, LE135, was intraperitoneally administered to pregnant ICR strain mice on the eighth gestational day (E8), 1 day before administration of RA (group B) or on E9, simultaneously (group C) with RA administration. All of the embryos were obtained from the uteri on E18. Frozen sections were evaluated for concentric layers around the endodermal epithelium by hematoxylin and eosin staining. RESULTS: In group A, all of the embryos demonstrated ARM with rectoprostatic urethral fistula, or rectocloacal fistula, and all of the embryos showed the absence of a tail. In group B, 36% of the embryos could be rescued from ARM. However, all of the rescued embryos had a short tail that was shorter than their hind limb. The ARM rescue rates in group B were significantly improved compared to those in group A (P < .01). In group C, 45% of the embryos were rescued from ARM, but all of the rescued embryos had short tail. The ARM rescue rate in group C was significantly improved compared to that in group A (P < .01). However, there was no significant difference in the ARM rescue rate between group B and Group C. CONCLUSION: The present study provides evidence that in the hindgut region, RAR selective retinoid antagonist, LE135, could rescue embryos from ARM. However, the disturbance of all-trans RA acid was limited to the caudal region. Further study to establish an appropriate rescue program for ARM in a mouse model might suggest a step toward protection against human ARM in the future.

Efficacy of epinastine hydrochloride for antigen-provoked nasal symptoms in subjects with orchard grass pollinosis.

BACKGROUND: Among the gramineae species, orchard grass is a typical causative pollen that provokes seasonal rhinitis. The purpose of this study was to examine the protective efficacy of epinastine hydrochloride for signs and symptoms caused by repeated nasal provocation with discs containing orchard grass pollen. METHODS: A single-dose, placebo-controlled, double-blind, crossover clinical study was conducted in subjects with orchard grass pollinosis. The pollen challenge was conducted with the use of provocation discs containing orchard grass pollen. RESULTS: Epinastine hydrochloride suppressed nasal symptoms caused by nasal provocation tests using orchard grass pollen discs. Among the nasal symptoms, the number of sneezing was significantly inhibited 30 minutes and 60 minutes after the administration of epinastine hydrochloride, as compared with placebo. There were no adverse reactions to the study drugs. CONCLUSIONS: Our results suggest that nasal provocation tests with discs containing orchard grass pollen is a useful method for evaluating the onset of action of antiallergic drugs. As compared with placebo, epinastine hydrochloride decreased early-phase sneezing and the total nasal symptom score after repeated nasal provocations with orchard grass pollen discs.

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction.

OBJECTIVES: Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD. METHODS: Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls. RESULTS: Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses. CONCLUSIONS: These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.

Ocular anti-allergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo.

BACKGROUND: Conjunctival mast cells (MCs) are important effector cells in seasonal allergic conjunctivitis, via histamine and cytokine secretion. Several new anti-allergic eye drops stabilize MCs and block histamine receptors, but their anti-inflammatory effects are unclear. OBJECTIVE: Anti-allergic drugs were compared for their anti-inflammatory effects in an in vitro model of human MC activation and in an experimental murine model of allergic conjunctivitis. METHODS: Human cord blood stem cell-derived (CBMC) and conjunctival biopsy-derived MCs were stimulated via FcepsilonRI, degranulation and histamine release were assayed at 1 h and cytokine secretion at 24 h using multiplex arrays. Mice sensitized to short ragweed pollen were given anti-allergics topically before allergen challenge, and conjunctival immuno-staining was performed at 24 h. RESULTS: After a 1 h stimulation, 80% of the CBMC had degranulated and secreted histamine (27.9+/-4.7 ng/10(6) cells; P<0.05). Pre-treatment by all drugs significantly reduced histamine and TNF-alpha, whereas IL-5, IL-8, IL-10 and TNF-beta profiles were differentially decreased. For conjunctival biopsy-derived cultures (n=11), FcepsilonR1 stimulation increased histamine, TNF-alpha, TNF-beta, IL-5 and IL-8 levels and the production of IL-5, IL-6 (P<0.05), histamine and IL-8 (P<0.01) was inhibited by epinastine. In vivo, epinastine and olopatadine pre-treatment significantly reduced the clinical scores and eosinophil numbers (n=6; P<0.05) while epinastine also reduced neutrophils (P<0.02). CONCLUSION: Differential effects on MC cytokine inhibition were observed, with epinastine inhibiting MC secretion of IL-5, IL-8, IL-10 and conjunctival neutrophil infiltration. The anti-allergic drugs have anti-histamine and mast-cell stabilizing properties but might differ in clinical improvement depending on the individual and the cytokines involved.

Antitussive effects of the H1-receptor antagonist epinastine in patients with atopic cough (eosinophilic bronchitis).

Chronic cough is the only symptom of eosinophilic bronchitis (EB). There is considerable overlap between EB and atopic cough. To investigate the antitussive effects of a histamine H1-recetor antagonist, epinastine hydrochloride (epinastine, CAS 80012-43-7, Alesion; 20 mg/day, once daily), cough scores, pulmonary function, capsaicin cough threshold, and bronchial hyperresonsiveness (BHR) to methacholine (MCh) were evaluated before and after a 4-week treatment with epinastine in patients with EB. In the epinastine group, the cough scores were decreased significantly (18.3 +/- 6.1 in week 1, 17.4 +/- 6.7 in week 2, 15.1 +/- 6.2 in week 3, 14.0 +/- 4.8 in week 4) in comparison with the value of 35.3 +/- 8.7 in week -2). The cough threshold for capsaicin improved from 1.70 +/- 3.04 micromol/l to 12.7 +/- 17.6 micromol/l in the epinastine group (p < 0.05; baseline vs. week 4) The bronchial hyperresponsiveness to MCh (Dmin) did not change significantly either in the epinastine or the placebo groups. The morning and evening peak expiratory flow rate (PEFR, L/min) did not change from the baseline period in either the epinastine or the placebo groups. These results suggested that epinastine may be useful for treating patients with EB and that histamine H1-receptor is related to the pathophysiology of coughing in EB.

[A comparative study of the antiarrhythmic action of bonnecor and the mesidide derivatives of alpha-azacycloalkane carboxylic acids]. / Sravnitel'noe izuchenie antiaritmicheskogo deistviia bonnekora i nekotorykh proizvodnykh mezididov al'fa-azatsikloalkankarbonovyykh kislot.

The antiarrhythmic properties of the dibenzazepine derivative bonnecor and derivatives of mesidides of alpha-azacycloalkanocarboxylic acids were studied in various experimental arrhythmia models. The comparative study revealed different antiarrhythmic effects in different arrhythmia models. Bonnecor was found to have a higher antiarrhythmic activity in most arrhythmic models. Tertiary salts were demonstrated to be more potent than quaternary ones.

[The effect of bonnecor on blood coagulability and thrombocyte aggregation in transient myocardial ischemia]. / Vliianie bonnekora na svertyvaemost' krovi i agregatsiiu trombotsitov v usloviiakh tranzitornoi ishemii miokarda.

The experiments on conscious rabbits have indicated that bonnecor given in doses of 0.05 mg/kg and 0.5 mg/kg accelerates clot formation and platelet aggregation, without changing the density of a thrombus. In experimental transient myocardial ischemia, the agent decreases the hypercoagulative change associated with the damaging effect of occlusion and reperfusion.

[The relationship between the chemical structure and anti-arrhythmia action of a number of omega-aminoacyl-3-carbalcoxyaminodibenzazepines]. / Izuchenie zavisimosti mezhdu khimicheskim stroeniem i antiaritmicheskim deistviem v riadu omega-aminoatsil-3-karbalkoksiaminodibenzazepinov.

The antiarrhythmic activity of 20 derivatives of dibenzazepine (the effects on the maximal effective rabbit heart auricle contraction rate, aconitine-induced arrhythmia in rats under or without anesthesia) was studied. It was shown that the most active compounds are those with carbethoxyamine group in position 3 in combination with dimethylamino- or diethylamino-acetyl groups in position 5 of dibenzazepine ring. 5-dimethyl-aminoacetyl-10,11-dihydro-5H-dibenz b, f azepine (GS-015, bonnecor) was selected for the further detailed investigation.

[The antifibrillatory properties of bonnecor]. / Protivofibrilliatornye svoistva bonnekora.

The preventive and therapeutic effects of bonnecor were shown in the experiments on awake and anesthetized rats under conditions of acute myocardial ischemia. It was concluded that the relieving influence of bonnecor on the course of acute myocardial ischemia was related to its antifibrillatory and antiarrhythmic properties.

[The effect of bonnecor on cardiac hemodynamics, blood supply and function in experimental myocardial ischemia]. / Vliianie bonnekora na gemodinamiku, krovoobrashchenie i funktsiiu serdtsa pri éksperimental'noi ishemii miokarda.

The effect of a new antiarrhythmic drug bonnecor on the hemodynamics, blood supply and function of the ischemic heart as compared with the famous antiarrhythmic drugs lidocaine and ethacizine was studied in the experiments on anesthetized animals (rats, dogs) under artificial respiration. It was shown that bonnecor administered in a dose of 0.5 mg/kg was able of relieving disturbances of the cardiac hemodynamics and function produced by occlusion of the coronary artery. The drug exerted no significant effect on the blood supply to the focus of acute and chronic myocardial ischemia.

[Bonnecor--a new anti-arrhythmia preparation]. / Bonnekor--novyi antiaritmicheskii preparat.

The antiarrhythmic properties of a new drug bonnecor being a derivative of dibenzazepine were studied on different models of arrhythmias. Bonnecor proved to be effective in the treatment of both atrial and ventricular arrhythmias of various genesis except rhythm disorders induced by ouabain intoxication. The drug was shown to exert a pronounced antifibrillatory effect and to increase the electrical stability of the intact and ischemic myocardium.

[The anti-arrhythmia properties of bonnecor metabolites]. / Antiaritmicheskie svoistva metabolitov bonnekora.

The experiments on the model of aconitine-induced arrhythmia in anesthetized rats and awake dogs with cardiac rhythm disorders caused by the coronary artery occlusion showed that all four metabolites of bonnecor possessed the antiarrhythmic activity. Metabolite 4 proved to be the most active on both models of cardiac rhythm disorders.

[A comparative study of the pharmacokinetics and pharmacodynamics of bonnecor]. / Sravnitel'noe izuchenie farmakokinetiki i farmakodinamiki bonnekora.

The pharmacokinetics and pharmacodynamics of bonnecor were studied simultaneously in animals with experimental arrhythmia. It was shown that irrespective of the animal species and individual features of the drug elimination kinetics the level of bonnecor concentration correlated with the antiarrhythmic effect. The data on the excretion of bonnecor and its metabolites in the urine in the dog and man were obtained. The decrease of bioavailability at oral administration of bonnecor was demonstrated to be related to its intensive conversion in metabolite M-I.

[Effect of the new anti-arrhythmia preparation Bonnecor on the hemodynamics and activity of the ischemic heart]. / Vliianie novogo antiaritmicheskogo preparata bonnekor na gemodinamiku i deiatel'nost' ishemizirovannogo serdtsa.

The effect of newly-developed anti-arrhythmia drug Bonnecor compared to that of ethacizin and lidocaine has been studied on anesthetized rats under acute myocardial ischemia. The drugs injected intravenously prior to coronary artery occlusion have been shown to prevent to a great degree the appearance of hemodynamic and functional disturbances of the heart. When compared to control, less reduction in systemic arterial pressure, systolic discharge cardiac output, contractility and heart power were observed. In addition, Bonnecor has been found to have certain advantages over reference drugs.