["Ictal" Bradyarrhythmias in Patients with Drug-Resistant Epilepsy: Results of Long-Term Heart Rhythm Monitoring].

Aim      To determine the type and incidence of ictal bradyarrhythmias in patients with drug-resistant types of epilepsy by long-term electrocardiogram (ECG) monitoring.Material and methods  Subcutaneous ECG monitors programed for recording pauses >3 sec and episodes of bradycardia ≤45 bpm were implanted in 193 patients with persistent epileptic seizures without organic pathology of the myocardium. Recording was activated by the patient/family at the onset of epileptic seizure. The follow-up period was 36 months with visits to the clinic every three months.Results For 36 months of monitoring, 6494 ECG fragments were recorded. Ictal bradycardia was observed in 6.7 % of patients, including ictal asystole in 2.6 % of patients. Episodes of bradycardia and asystole during epileptic seizures were transient and developed significantly more frequently in men, patients with long duration of the disease, bilateral tonic-clonic or focal seizures with disorder of consciousness, during sleep, on the background of treatment with several antiepileptic agents, mostly from the group of potassium channel blockers.Conclusion      Bradyarrhythmias accompanying epileptic seizures are transient and reproducible from seizure to seizure. They reflect functional changes in the myocardium and do not determine the life prediction for patients with epilepsy without organic pathology of the heart.

[COMPARISON OF CHRONIC ANTICONVULSANT ACTIVITY AND SAFETY OF IEM-2062, SODIUM VALPROATE AND ME-MANTINE IN THE PENTYLENETETRAZOL KINDLING MODEL IN RATS].

IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], causing a combined block NMDA and AMPA receptors, after chronic oral administration in doses, respectively, 0.3 and 3 mg/kg, induce maximal anticonvulsant effect in the pentylenetetrazol kindling rats because decrease the number of completely kindling rats by 100 %, and also decrease in 2.5-3.3 times the average severity of clonic-tonic kindling seizures. IEM-2062 causes significant anticon- 299 vulsant effects in the widest range of doses, 1-48 mg/kg, which is 24-22 times more than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine cause significant disturbances of locomotor activity in the «open field¼ test in doses causing maximal anticonvulsant effect in the kindling rats. At the same time IEM-2062 cause disturbance of locomotor activity only in very high dose of 92 mg/kg, which exceeds in 30.7 times the dose causing the maximum anticonvulsive effect in the kindling rats. Thus, IEM-2062 reduces the severity of kindling seizures in 1.7-1.9 times stronger than sodium valproate and memantine and also by 30.7 times is safer than sodium valproate and memantine.

Comparison of Pharmacological Potency and Safety of Glutamate Blocker IEM-1913 and Memantine.

Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.

[Current possibilities of treatment of generalized convulsive seizures].

Current possibilities of treatment of generalized convulsive seizures are presented. Progress in the field of pharmacotherapy of epilepsy allowed to introduce new antiepileptic drugs (AED). Some of them are modified AED with higher efficacy or better tolerability and others represent a generation of new drugs with different mechanisms of action. Perampanel, an agonist of AMPA-receptors, is a new drug approved in more than 40 countries, including Russia. At present, the use of some AED is limited by the high risk of sudden death (sudden unexpected death in epilepsy (SUDEP)). SUDEP is a common cause of death directly associated with epilepsy, with the highest frequency in patients with active epilepsy. Subtherapeutic concentrations of SED in the serum of SUDEP patients may be the consequence of inadequate treatment and low compliance to treatment that causes the development of pseudoresistant seizures and, hence, the higher risk of SUDEP. At the same time, AED per se play an important role in the modification of functions of the autonomic nervous system and may induce disturbances of heart rate and conductivity.

[The Use of Rivaroxaban in Perioperative Period of Pulmonary Vein Antrum Isolation in Patients With Paroxysmal Atrial Fibrillation].

Results of an observational study. devoted to prevention of thromboembolic complications in patients with atrial fibrillation undergoing catheter pulmonary vein atrium isolation are discussed. Patients (n= 199) were divided into two comparable groups depending on the anticoagulant (rivaroxaban or warfarin) used. Clinical thromboembolic and/or hemorrhagic complications as well as rate of development of asymptomatic cerebral thromboembolisms in various periods after procedure were assessed. Main conclusion: rivaroxaban was not inferior to warfarin for thromboprophylaxis in patients with atrial fibrillation undergoing catheter pulmonary vein antrum isolation.

Phenylephrine potentiates the anticonvulsant effect and neutralizes the sedative effect of diazepam in rats upon combined intragastric administration.

High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine.

Combined blockade of NMDA and AMPA receptors prevents acute kainate seizures and chronic kainate lethality in rats.

Single intramuscular injection of selective of NMDA receptor blocker memantine in the maximum dose of 20 mg/kg prevented the development of acute generalized tonic-clonic kainate seizures in 60% rats, but did not alleviate clonic kainate seizures and prevented chronic kainate lethality in only 30% rats. Intramuscular injection of NBQX, a selective blocker of AMPA receptors (10 mg/kg), produced more pronounced anticonvulsant and neuroprotective effects: it prevented generalized kainate seizures and chronic kainate lethality in 100 and 80% rats, respectively. However, even the high dose of NBQX prevented the clonic kainate seizures only in 30% rats. The intramuscular injection of novel agent IEM-2121 (0.03-1.00 mg/kg) known to block both AMPA and NMDA receptors, prevented the clonic kainate seizures only in 50-70%, although it precluded the chronic kainate lethality in 100%.

Combined blockade of AMPA and NMDA receptors in the brain of rats prevents pentylenetetrazole-induced clonic and tonic-clonic seizures without ataxia.

Intramuscular injection of selective NMDA receptor antagonists memantine and arcaine 4-fold decreased the incidence of pentylenetetrazole-induced generalized tonic-clonic seizures in rats, while the incidence of clonic seizures decreased by 1.2-1.3 times. Memantine and arcaine are characterized by low therapeutic index, i.e. induced ataxia in rats in doses exceeding the effective anticonvulsant dose by only 3.5-10 times. Intramuscular injection of IEM-1913 (combined blockade of NMDA and AMPA receptors in the brain) decreased the incidence of pentylenetetrazole-induced clonic and tonic-clonic seizures in rats by 4-8 times. The therapeutic index of IEM-1913 surpassed that of memantine and arcaine by 200-600 times.

Peripheral and central routes of administration of quaternary ammonium compound IEM-1460 are equally potent in reducing the severity of nicotine-induced seizures in mice.

Peripheral administration of nicotinic receptor antagonists with a quaternary ammonium group (hexamethonium and chlorisondamine) did not prevent the development of seizures induced by systemic treatment with nicotine in the toxic dose. The Me3N+ group with stable positive charge inhibits transport of these compounds into the brain through the blood-brain barrier. Intracerebral and peripheral (intraperitoneal) administration of compound IEM-1460 with the Me3N+ group was equally potent in reducing the severity of nicotine-induced seizures in mice. This phenomenon is related to the fact that IEM-1460 acts as a nicotinic receptor antagonist and polyamine agonist, which increases blood-brain barrier permeability for polar compounds. These features contribute to IEM-1460 transport into the brain. High anticonvulsant activity of IEM-1460 on the model of nicotine-induced seizures is associated with combined blockade of nicotinic receptors (alpha3beta4 receptors) and glutamate receptors (GluR1 AMPA receptors).

Epinephrine potentiates the analgesic and antidepressant effects of amitriptyline as a result of stimulation of the gastric mucosal afferents.

Intramuscular amitriptyline in the minimum effective dose causes maximum analgesic and antidepressant effect and significant sedation in rats. Combined injection of amitriptyline with epinephrine in the threshold doses (ineffective if used alone), 1/10 and 1/30 minimum effective doses, respectively, leads to the development of the maximum analgesic and antidepressant effect, but causes no sedative side effect. This potentiation is mediated by stimulation of afferents in the gastric mucosa with epinephrine.

Combined blockade of alpha3beta4 nicotinic acetylcholine receptors and GluR1 AMPA receptors in rats prevents kainate-induced tonic-clonic seizures.

Intramuscular injection of IEM-1754, a blocker of cerebral GluR1 AMPA receptors, in doses of 0.5-3.0 mg/kg decreased the incidence of kainate-induced tonic-clonic seizures and mortality rate by 2.7-4 times. IEM-1678, an alpha3beta4 nicotinic acetylcholine receptor antagonist administered intramuscularly in a maximum dose of 3 mg/kg decreased the incidence of kainate-induced tonic-clonic seizures and mortality rate by 2.3-2.7. IEM-1460 blocking both GluR1 AMPA receptors and alpha3beta4 nicotinic acetylcholine receptors, injected intramuscularly in doses of 0.5-3.0 mg/kg produced the maximum anticonvulsant activity and 8-fold decreased the incidence of kainate-induced tonic-clonic seizures and mortality rate.

Epinephrine potentiates antipsychotic, but not cataleptogenic effect of haloperidol in rats.

Intramuscular injection of haloperidol or epinephrine in a minimum effective dose produces the maximum antipsychotic effect in rat model of schizophrenia, i.e. completely removes stereotypy, hyperlocomotion, and ataxia induced by MK-801. Haloperidol in the specified dose induces catalepsy, while epinephrine exhibits no cataleptogenic effect. Combined intramuscular injection of haloperidol and epinephrine in the threshold doses, ineffective in monotherapy, causes the maximum antipsychotic effect, but not catalepsy. Preliminary anesthesia of the gastric mucosa with 1% lidocaine and blockade of intramural ganglia in the gastric mucosa with hexamethonium completely abolished the potentiated antipsychotic effects produced by combined treatment with haloperidol and epinephrine. Hence, potentiation of the antipsychotic effect of haloperidol with epinephrine is related to stimulation of afferents in the gastric mucosa.

Effect of modulators of the polyamine site on the development of seizures induced by systemic and intracerebral administration of N-methyl-D-aspartate in albino mice.

Systemic intraperitoneal administration of polyamine agonist IEM-1460 containing the Me3N(+) group with a stable positive charge preventing permeation of this substance through the blood-brain barrier and polyamine antagonist arcaine had no effect on the development of seizures caused by intracerebral injection of N-methyl-D-aspartate in mice. Intraperitoneal injection of IEM-40 potentiated, while arcaine decreased the severity of seizures induced by intraperitoneal treatment with N-methyl-D-aspartate. This effect was related to modulation of the permeability of the blood-brain barrier for N-methyl-D-aspartate probably due to modulating effects of IEM-40 and arcaine on the polyamine site of N-methyl-D-aspartate receptors in the blood-brain barrier.

Epinephrine potentiates the analgesic and antidepressant effects of polyvinylpyrrolidone and cholecystokinin due to stimulation of afferents in the gastric mucosa.

Treatment with epinephrine, polyvinylpyrrolidone, and cholecystokinin in the minimum effective doses produced maximum analgesic and antidepressant effects and caused bradycardia in rats. Administration of epinephrine in combination with polyvinylpyrrolidone or cholecystokinin in threshold doses (1/10-1/25 of the minimum effective dose) produced maximum analgesic and antidepressant effects, but did not cause bradycardia. The potentiating effect of epinephrine is related to stimulation of afferents in the gastric mucosa.

Comparative study of preventive and therapeutic effects of IEM-1966 and memantine in rats with experimental allergic encephalomyelitis.

We compared preventive and therapeutic effects of memantine, a selective blocker of NMDA-receptors, and IEM-1966, a blocker of both NMDA- and GluR1 AMPA-receptors, on the model of acute experimental allergic encephalomyelitis. Memantine in high doses prevented the development of experimental allergic encephalomyelitis only in 10% rats, slightly (by 1.4-1.5 times) moderated the neurological disturbances, and shortened the duration of the disease. In far lower doses, IEM-1966 prevented the development of experimental allergic encephalomyelitis in 50% rats, while in the affected rats it decreased the severity of neurological disturbances and duration of the disease by 3-4 times. When applied during the clinical phase of the disease, IEM-1966 decreased the severity of neurological disturbances and duration of the disease by 2.0-2.5 times predominantly in rats with mild and moderate course of experimental allergic encephalomyelitis.

[The specific features of hypothyroidism developing with the use of cordorone].

Hypothyroidism (HT) is one of the thyroid dysfunctions occurring with the use ofcordorone. The authors examined the clinical features of this condition in 26 patients living in Moscow and its region (mild and moderate iodine deficiency areas). The blood levels of thyrotropic hormone (TTH), free thyroxine (Т4) free triiodothyronine (T3), thyroid peroxidase antibodies, and lipid spectrum were estimated. Thyroid ultrasound study and Holler ECG monitoring were performed. HT was found to develop in the presence of the abnormally changed (66%) and intact (34%) thyroid. Examining the course of cardiac arrhythmias (CA) as HT progresses has ascertained that this condition does not lead to their recurrences. As compared with the controls, the patients were found to have higher frequencies of dyslipidemias (p < 0.05). Blood lipid changes appeared as the higher levels of total and LDL cholesterol (p < 0.05); a positive correlation was also established between these parameters and the levels of TTH. The use of L-thyroxine replacement therapy, as indicated on an individual basis, during ongoing cordorone intake did not result in relapses of prior CA and it contributed to blood lipid spectrum parameters. Thus, HT is a condition that does not cause a loss of the antiarrhythmic effects ofcordarone manifests itself as the impaired blood lipid spectrum. L-thyroxine replacement therapy may be, if required, performed during the ongoing use of an antiarrhythmic agent.

Dimensions of the ion channel in neuronal nicotinic acetylcholine receptor as estimated from analysis of conformation-activity relationships of open-channel blocking drugs.

Relationship between the size of the molecule in the series of organic ions Et3+N--(CH2)5--+NR1R2R3 (Ri--alkyl or cycloalkyl substituents) and their abilities to block nicotinic acetylcholine receptors (AChRs) due to their open-channel blockade in the neurons of autonomic ganglia and in frog end-plate was analyzed. All low-energy equilibrium conformations of the drugs were calculated by the molecular mechanics method. A unique rectangular channel profile 6.1 x 8.3 A, for which the best correlation between blocking activity of the drugs and total population of their conformations being able to penetrate into the channel, was deduced from all those tested.