[Systemic and local stiffness of the arteries in young patients with arterial hypertension].

UNLABELLED: The aim of the work was to study characteristics of systemic and local arterial stiffness in young patients with arterial hypertension (AH) suffering this condition in the childhood or adulthood and to relate them to risk factors of cardiovascular complications. Materials and methods. 54 patients aged 18-35 (mean 25.3 +/- 3.4) years with AH. 37 of them had AH since 18 year and 27 ones starting from the childhood or adulthood Control group included 26 healthy volunteers aged 25.8 +/- 3.7 year. The carotid-femoral pulse wave propagation rate (PWPR) was measured by applanation tonometry with a SphygmoCor apparatus. Parameters of carotid stiffness of CCA were studied by the echo-tracking method using Aloka ProSound a7 device. Results. Patients with AH and without it in the childhood or adulthood showed higher PWPR values than controls (7.1 +/- 1.2 and 7.5 +/- 1.4 vs. 6.3 +/- 1.0 m/s respectively) Ep and AC values were higher in patients who did not have AH in the childhood or adulthood: right Ep 89 +/- 24.4 and 68.7 +/- 18.4 kPa, AC 0.9 +/- 0.2 and 1.1 +/- 0.1 mm2/kPa respectively; left Ep 86.1 +/- 20.3 and 71/4 +/- 16 kP AC 0.9 +/- 0.2 and 1.1 +/- 0.1 mm2/kPA (p < 0.05). In the patients with AH since the childhood or adulthood with concomitant metabolic syndrome (MS) the PWPR values and carotid artery stiffness were higher than in the absence of MS (p < 0.05). CONCLUSION: Young patients with AH showed carotid-femoral PWPR compared with control regardless of AH in the childhood or adulthood Parameters of local carotid stiffness were increased only in patients having no AH in the childhood or adulthood Patients with AH since the childhood or adulthood with concomitant MS had higher carotid stiffness and carotid-femoral PWPR than in the absence of MS

[Blockade of the alpha3alpha4 N-cholinoreceptors and GluR1 AMPA receptors eliminates clonic-tonic nicotinic and kainate seizures].

Monoammonium N-alkyl derivative of decylamine (IEM-1678), which blocks alpha3beta4 N-cholinoreceptors (but does not block GluR1 AMPA receptors), in doses of 1.0 - 3.0 mg/kg produces a 4-fold decrease in the frequency and lethality of nicotinic clonic-tonic seizures. However, even in the maximum dose of 3 mg/kg, IEM-1678 only slightly decreases kainate clonic-tonic seizures. Bis-ammonium compound IEM-1460 (containing adamantyl radical), which blocks both GluR1 AMPA receptors and alpha3beta4 N-cholinoreceptors, in a range of doses 0.1 - 3 mg/kg produces a 5- to 8-fold decrease in the frequency and virtually completely eliminates lethality of both clonic-tonic nicotinic and kainate seizures. Hence, the complete elimination of generalized kainate and nicotinic seizures requires combined blockade GluR1 AMPA and alpha3beta4 N-cholinoreceptors.

[Combined blockade of GluR1 AMPA and NMDA receptors effectively eliminates neurological disorders in rats with experimental allergic encephalomyelitis].

The experimental allergic encephalomyelitis (EAE) developed on the 11 - 12th day after inoculation of encephalitogenic mixture in 96% of female Wistar rats in the control group. In the majority of control rats, severe EAE with a long duration of action prevailed (average cumulative index, 25.6; average duration of illness, 15.8 days). A course of NMDA-antagonist memantine administration in a doze of 10 and 20 mg/kg prevented the development of EAE in 10% of rats. In rats with EAE (on the average, 12-13 days after the administration of encephalitogenic mixture) the drug slightly reduced the severity and duration of neurological disorder: the average cumulative index and duration of illness decreased by a factor of 1.4-1.5 in comparison to the control. The antagonist of NMDA and GluR1 AMPA receptors, IEM-1913, upon a course of administration in a doze of 0.1-1 mg/kg prevented the EAE development in 23-25% of rats. In the rats with EAE treated with IEM-1913 in the maximum doze (1 mg/kg), the EAE developed only after completion of the course of drug administration (on the 19-20th day), proceeded quickly (no more than 5 days), and in the easy form (average cumulative index. 8.3). High efficacy of IEM-1913 administration in rats with EAE is apparently connected with its neuroprotective and antiinflammatory action, which is related, on the one hand, to a combined block of NMDA and GluR1 AMPA of receptors in brain and, on the other hand, to a reduction of the permeability of BBB for encephalitogenic T-lymphocytes owing to the blockade of NMDA receptors in BBB.

[Thyroid dysfunction in long-term amiodarone administration. Correlation of the antiarrhythmic activity of amiodarone with its effect on thyroid function].

Relationship between amiodarone-associated thyroid dysfunction and antiarrhythmic activity of amiodarone was studied in 27 patients (13 with hypothyroidism, 8 with hyperthyroidism, 6 with euthyroid hyperthyroxinemia). Amiodarone-associated hypothyroidism and euthyroid hyperthyroxinemia were not associated with loss of antiarrhythmic efficacy of amiodarone. Hypothyroidism did not require amiodarone withdrawal and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. Achievement of euthyroid state was not followed by recurrence of heart rhythm disturbances. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been given because of life threatening arrhythmias or proven resistance to other antiarrhythmic therapy. In 12.5% of patients it was possible to substitute other drugs for amiodarone. Correction of thyroid status and achievement of euthyroidosis in these patients was associated with restoration of amiodarone antiarrhythmic activity.

[Lipid blood spectrum in patients with amiodarone associated hypothyroidism. Effect of replacement therapy with L-thyroxine].

Blood lipid levels were measured in 23 patients with amiodarone associated hypothyroidism (most of them had ischemic heart disease). Abnormalities of lipid spectrum were found in 12 of these patients. All 12 patients were subjected to replacement therapy with l-thyroxine. Compensation of thyroid status was associated with average 12.6 and 12.3% lowering of total and low density lipoprotein cholesterol, respectively. However target levels of low density lipoprotein cholesterol were achieved only in 1 patient. There were no significant changes of high density lipoprotein cholesterol and triglycerides.

[Incidence and predictors of thyroid dysfunction caused by long-term intake of amiodaron].

AIM: To analyze occurrence of thyroid dysfunction due to regular long-term intake of amiodaron (for one year), to search for predictors of amiodaron-induced hypothyroidism and thyrotoxicosis. MATERIAL AND METHODS: Sixty two patients with different types of arrhythmia have undergone examination including tests for TTH (once in three months), free T3 and T4 (once in 6 months), ultrasound thyroid investigation, general clinical and physical check-up, resting ECG in 12 leads, echocardiography, chest x-ray, biochemical blood tests, blood count, urinalysis. RESULTS: Amiodaron intake for 1 year was associated with amiodaron-induced thyroid dysfunction in 25% patients: 19.2% developed hypothyroidism, 5.8%--thyrotoxicosis. Organic pathology of cardiovascular system, cardiac failure, left ventricular aneurysms, low global myocardial contractility, organic thyroid pathology, elevated levels of antithyroid antibodies predicted hypothyroidism. Thyrotoxicosis was associated with a young age and male sex. CONCLUSION: Amiodaron may cause thyroid dysfunction in patients with arrhythmia.

[Ion channel topography of the neuronal nicotinic acetylcholine receptor : pharmacochemical approaches]. / Topografiia ionnogo kanala neironal'nogo nikotinovogo kholinoretseptora: farmakokhimicheskie podxody.

Forty-three bisammonium ganglionic blockers were synthesized to study the structure of the ion channel of nicotinic acetylcholine receptor. The conformational parameters of these blockers were studied, and their effects toward the ganglionic transmission in situ on the sympathetic feline upper cervical ganglions and in vitro on the parasympathetic guinea-pig small intestine ganglions were determined. A model of the binding site for the bisammonium ganglionic blockers in the neuronal ion channel was proposed.

[Amiodarone-associated thyroid dysfunction: prevalence and possibilities of correction]. / Amiodaron-assotsiirovannaia disfunktsiia shchitovidnoi zhelezy: chastota razvitiia, vozmozhnosti korrektsii.

During 1 year of amiodarone intake development of amiodarone-associated thyroid dysfunction was observed in 25% of patients (hypothyroidism and thyrotoxicosis in 19.2 and 5.8%, respectively). Development of hypothyroidism was not accompanied with loss of antiarrhythmic efficacy of amiodarone and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. In all patients with clinical and in less than one half (47.6%) of patients with subclinical forms of hypothyroidism replacement therapy with L-thyroxin was carried out. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. In all patients with thyrotoxicosis which developed during amiodarone intake thyrostatic therapy with mercasolil was carried out and in case of its inefficacy prednisolone was added. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been prescribed because of life saving indications. Achievement of euthyroid state was followed by restoration of antiarrhythmic efficacy of amiodarone. Amiodarone was discontinued just in 1 patient with ventricular extrasystole as correction of thyroid status and restoration of euthyroidosis enabled effective use of other antiarrhythmic drugs.

[Bis-ammonium adamantane derivatives--novel modulators of polyamine binding sites]. / Bis-ammonievye adamantan-soderzhashchie soedineniia--novye moduliatory poliaminovogo uchastka sviazyvaniia.

Experiments on intact rats and mice showed that the polyamine agonist spermine and the bis-ammonium adamantyl-containing compounds IEM-1460 and IEM-1754 potentiate the NMDA induced analgesia and convulsions and eliminate the analgesic effects of nicotine and kainate. Arcain, a competitive polyamine antagonist, eliminated (at the same dose) the activating and blocking effects of spermine, IEM-1460 and IEM-1754. In small doses, IEM-1754 (similarly to arcain) removed the analgesic effect of NMDA. It is suggested that IEM-1460 (similarly to spermine) is a polyamine agonist, while IEM-1754 is an antagonist/agonist of the polyamine site of NMDA, AMPA/kainate, and nicotinic receptors. The potentiating activity of IEM-1460 is two orders higher as compared to that of spermine.

[Comparative study of the NMDA-blocking activity and safety of mono- and bis-cationic compounds in animals]. / Sravnitel'nyi analiz NMDA-blokiruiushchei aktivnosti i bezopasnosti mono-kationnykh i bis-kationnykh soediennii v opytakh na zhivotnykh.

Experiments on intact mice and rats showed that the monoammonium adamantyl-containing compounds memantine, amantadine, and IEM-1958 (an N-propyl amantadine analog) are capable of blocking the NMDA receptors and producing the anticonvulsant and antihypoxant effects in the case of a systemic administration in doses close to toxic. The acute toxicity of these compounds upon intraperitoneal injections to mice is manifested in doses only 2-8 times the minimum effective dose level. The bis-cationic compounds (arcaine, IEM-1464, and IEM 1490) containing two identical cation groups, exhibit a more pronounced activity and higher safety as compared to those of their monocationic counterparts. This is explained by the ability of the bis-cationic compounds to block a polyamine site of the NMDA receptor. Arcaine (the polyamine site blocker) and IEM-1464 produce the NMDA-receptor-blocking effect and exhibit the anticonvulsant and antihypoxant activity in doses 5-10 times smaller as compared to the effective dose of memantine. At the same time, arcaine is 5 times less toxic than memantine. The bis-adamantyl derivative IEM-13490 is 100-150 times more active and has a 139 times greater therapeutic ratio than memantine.

[The search for selective blockers of NMDA and AMPA/kainate receptors in a series of bis-ammonium compounds with adamantyl radicals]. / Poisk izbiratel'nykh blokatorov NMDA i AMPA/kainatnykh retseptorov v riadu bis-ammonievykh soedinenii s adamantil'nymi radikalami.

Two groups of substances capable of selectively blocking the NMDA and AMPA/kainate receptors in experiments on intact animals were found in a series of bis-ammonium compounds with adamantyl radicals. The selective NMDA receptor blockers (IEM-1754, IEM-1755, IEM-1752), as well as the reference agents MK-801 and memantine, produced anticonvulsant, anti-ischemic, and antihypoxant effects and prevented the loss of experimental animals from toxic doses of NMDA. The selective AMPA/kainate receptor blockers (IEM-1553, IEM-1751, IEM-1592, and DNQX)) also produced the anticonvulsant, anti-ischemic, and antihypoxant effects, but did not prevent from the loss of animals caused by the toxic doses of NMDA. The maximum activity was observed for IEM-1754, the activity of which exceeded that of MK-801 (by a factor of 5-10) and memantine (by a factor of 300-800) in all the test objects.

[A comparative study of the central H-cholinergic-blocking and NMDA-blocking actions of MK-801, memantin, amantadine, pyrilen and IEM-1754 in experiments on intact rats]. / Sravnitel'noe issledovanie tsentral'nogo H-kholinoblokiruiushcheo o NMDA-blokiruiushchego deistviia MK-801, memantina, amantadina, pirilena i IEM-1754 v opytakh na intaktnykh krys.

Pyrilene acts as a central H-cholinoblocker upon intramuscular injection at a dose of 0.02-0.08 mg/kg, and as an NMDA-blocker, when the dose is increased to 0.2-0.8 mg/kg. Similarly, amantadine exhibits the properties of H-cholinoblocker and NMDA-blocker in the dose intervals 10-15 mg/kg and 120-180 mg/kg, respectively. The activity of MK-801 markedly exceeds that of memantine, although close doses of both NMDA-blockers inhibit the NMDA and corazole effects, as well as the central effects (analgesia and seizure) of nicotine, thus showing no significant selectivity with respect to NMDA. IEM-1754 tested on intact animals exhibited a selective action upon the NMDA receptors, preventing the NMDA-induced analgesia and lethality and the corazole-induced convulsions at doses 10-100 times lower as compared to those preventing nicotine-induced seizure and analgesia.

[The role of the chemosensory systems in the inhibitory regulation of cholinergic transmission in the small intestine]. / Rol khemosensornykh sistem v tormoznoi reguliatsii kholinergicheskoi peredachi v tonkoi kishke.

The double bath method has been used to study reflex inhibition of cholinergic transmission in the guinea-pig ileum segment. It is shown that adenosine, noradrenaline, 5-methylfurmethide as well as acute hypoxia, which affect the oral part of the intestine are able to evoke two kinds of effects in its anal part firstly, the depression of cholinergic transmission, and secondly, the stimulation of non-adrenergic, non-cholinergic contractions. A preliminary treatment with capsaicin and with hexamethonium on the oral part of the gut prevents these effects, and the chymotrypsin abolishes these effects. A mechanism of this reflex descending inhibition of cholinergic transmission is realised apparently through the stimulation of the chemoreceptors in afferent capsaicin-sensitive nerves with participation of cholinergic interneurons and activation of the inhibitory, most probably vasoactive intestinal peptidergic (VIP) neurons in the enteric plexuses.

[The specific features of thyrotoxicosis and euthyroid hyperthyroxinemia developed due to the use of cordarone]. / Osobennosti tireotoksikoza i eutireoidnoi gipertiroksinemii, razvivaiushchikhsia na fone priema kordarona.

Thyrotoxicosis (TT) is one of the thyroid (T) dysfunctions occurring with the use of cordarone. The clinical features of TT were studied in cordarone-treated patients living in Moscow and its regions (mild and moderate iodine deficiency regions). The patients were examined by using currently available procedures for measuring thyroid-stimulating hormone, free thyroxine, free triiodothyronine, antibodies to TH, TPO, interleukin-6 (IL-6), and C-reactive protein (CRP), and by employing T ultrasound study, Holter ECG monitoring. TT was ascertained to develop in the presence of both the pathologically altered (16/23, 69%) and intact T (7/23, 31%). Examining the course of cardiac arrhythmias (CA) in developed TT has established that this condition gives rise to their recurrence. As compared with the control group, the patients with TT were not found to have higher levels of IL-6 and CRP (p > 0.05; Mann-Whitney test). Therapy with thyrostatic agents alone or in combination with glucocorticosteroids normalizes the levels of thyroid hormonesfollowing, on the average, 2-3 months. Euthyroid hyperthyxinemia (EHT) is frequently recorded with the use of cordarone. Examination of 20 patients with EHT has revealed organic pathology in 13 (65%) patients and its absence in 7 (35%). Recurrences of prior CA have not been found in EHT (p < 0.05; McNemar test). The confidence interval for the difference of relative frequencies of signs did not include 0). Thus, TT is a condition that leads to the fact that cordarone loses its antiarrhythmic effects and TT requires compulsory treatment. If required, therapy should be performed during the continued administration of the drug. EHT is not thyrotoxicosis, which is to be followed up.

[Phenylephrine potentiates antidepressive and eliminates sedative action of amitriptyline in rats].

Single i. m. injection of amitriptyline in rats in high doses of 10-30 mg/kg causes a weak an- tidepressive effect because only in 1.3-1.7 times decrease immobilization in Porsolt test. In the specified doses amitriptyline exhibits appreciable sedative effect because in 3-6 times decrease horizontal activity, and also in 2-2.5 times decrease vertical activity of rats in the open field test. Combined single i.m. injection of amitriptyline in a small dose of 3 mg/kg and high dose of 30 mg/kg with phenylephine in threshold, noneffective alone dose of 0.02 mg/kg, causes the ma- ximal antidepressive effect because decreases immobilization in Porsolt test, accordingly, in 3 and 4.6 times, but does not produce side sedative effect in the open field test. The basis of the mec- hanism of potentiation of antidepressive action and elimination of sedative action of amitriptyline is the stimulation of gastric mucosa afferents by phenylephine.

[Stimulation of gastric mucosa afferents by phenylephrine potentiates anticonvulsive and eliminates sedative action of sodium valproate in the pentylenetetrazol kindling model in rats].

Sodium valproate after chronic intragastric administration in the high dose of 100-200 mg/kg eliminates generalized clonic-tonic pentylenetetrazol seizures in 100 % of rats, but only in 33-57 % of rats it prevents local clonic kindling seizures. Strong sedation is induced by the specified doses of sodium valproate. The combined oral chronic administration of phenylephrine in threshold, noneffective alone dose of 0.2 mg/kg and sodium valproate in high doses of 100 mg/kg and 200 mg/kg potentiates anticonvulsive action of sodium valproate, because prevents both clonic-tonic kindling. seizures in 100 % of rats and clonic kindling seizures in 86-100 % of rats, and also it increases in 1.7-1.9 times anticonvulsive activity of valproate. The specified combinations of sodium valproate with phenylephrine do not produce the sedative side effect. The basis of the mechanism of potentiation of anticonvulsive action and elimination of sedative action of sodium valproate in high doses is the stimulation of gastric mucosa afferents by phenylephrine.

[IEM-1460 and spermine potentiate analgesic effect of fentanyl and dipyrone in rats].

Intramuscular (i. m.) administration in the minimum effective dose (MED) of central analgesics of fentanyl and dipyrone, polyamine agonist spermine and also IEM-1460 (IEM-1460 is AMPA receptors antagonist and agonist of the NMDA polyamine receptor site) causes the maximal analgesic effect in the tail flick test in rats. The combined i.m. administration of dipyrone with IEM-1460 and spermine in threshold, noneffective alone doses according 1/5 part from their MED leads to decrease of MED dipyrone in the combination with IEM-1460 in 120 times, and MED dipyrone in combination with spermine--in 10 times. The combined i.m. administration of fentanyl with IEM-1460 and spermine in above mentioned threshold doses leads to decrease of MED fentanyl in the combination with IEM-1460 in 150 times, and MED fentanyl in the combination with spermine--in 15 times.

[Combined blockade of AMPA- and NMDA-receptors has maximum effect to eliminate development of pentylenetetrazole-induced kindling in rats].

Peroral chronic administration the standard antiepileptic drug sodium valproate in a dose of 200 mg/kg eliminates development of generalized clonic-tonic pentylenetetrazol kindling seizures in 100% of rats, but only in 57% of rats this treatment prevents clonic kindling seizures. In the specified dose sodium valproate decreases in 1.7 times average severity of pentylenetetrazol kindling seizures compare with control. IEM-2121, causing combined blockade of NMDA- and AMPA-glutamate receptors, as well as IEM-1676, which also blocks AMPA-, NMDA- and N-cholinoreceptors, both after peroral chronic administration in a doses 10 mg/kg and 20 mg/kg accordingly, possess higher, than sodium valproate, anticonvulsant activity because reduce average severity of pentylenetetrazol kindling seizures in 2.4-2.7 times in comparison with control and prevents clonic kindling seizures in 87% of rats. Combined blockade of AMPA- and NMDA-receptors and perhars N-cholinoreceptors has maximum effect to eliminate epileptogenesis both clonic, and clonic-tonic pentylenetetrazol kindling seizures.

[Peripheral acting mediators pain and analgesia potentiate the central analgesic action of fentanyl and dipyrone].

UNLABELLED: Intramuscular (i.m.) administration of the central analgesics fentanyl and dipyrone, and also mediators of pain such as L-glutamate, CCK, ATP, phenylephine and analgesic mediator adenosine, slightly penetrating in CNS, in the minimum effective dose (MED) cause the maximal analgesic effect in the tail flick test in rats. MED of dipyrone and fentanyl are decreased 50-220-fold after combined i.m. administration of each analgesic with L-glutamate, CCK, adenosine, ATP and phenylephrine in threshold, independently noneffective doses. The intragastric administration of lidocaine and also subdiaphragmatic vagotomy completely eliminate analgesic effects of the above mentioned combinations. CONCLUSION: the peripherically acting mediators of pain and analgesia after systemic administration potentiate central analgesic action of fentanyl and dipyrone as a result of the stimulation of vagal afferents of gastric mucosa.

[Adrenaline potentiates antiepileptic but not sedative action of diazepam in rats].

Intramuscular (i.m.) administration ofdiazepam in a dose of 10 mg/kg and adrenaline in a dose of 0.2 mg/kg prevents generalized clonic-tonic pentylenetetrazol (PTZ) seizures in 75-80 % of rats, but only in 35-40 % of rats it prevents local clonic PTZ seizures. In the above mentioned dose, diazepam causes a strong sedation, but adrenaline does not cause a sedative effects. The combined administration of diazepam and adrenaline in threshold independently ineffective doses prevents both clonic-tonic and clonic PTZ seizures in 80 % of rats without a sedation development. The basis for mechanism of potentiation of anticonvulsant action of diazepam is the stimulation of gastric mucosa afferents by adrenaline.