Method of preoperative preparation of patients with thyrotoxicosis

FIELD: medicine.

SUBSTANCE: to reduce tachycardia in such patients used is ivabradin (coraxan) in dose 5-7.5 mg for 7-14 days with further supporting course in dose 5 mg to the moment of when preoperative reparation is finished.

EFFECT: application of ivabradin in preoperative period in case of manifest thyrotoxicosis instead of traditional beta-adrenoblockers makes it possible to weaken sympathetic impact on sinus node and increase chronotropic myocardium reserve, avoiding at the same time undesirable cardioplegic effects, characteristic of beta-adrenoblockers.

2 tbl, 1 ex

 

The invention relates to medicine, namely to endocrinology and cardiology.

According to the literature (Ametov, A.S. cardiovascular system thyrotoxicosis / Ashamedof, Moudania, Iwholename. // Consilum Medicum. - 2003. Vol 5. No. 11. - S-29; G.J. Kahaly, Dietlein m Cost estimation of thyroid disorders in Germany // Thyroid. - 2002. - Vol.12. - P.909-914) and own the results of ECG study, all the patients had tachycardia (heart rate more than 90 min) is the dominant component of the development of secondary cardiomyopathy, combined with such processes as glycolytic effect of thyroid hormones and reducing the level of oxygen saturation of cardiomyocytes, ultimately leading to the deterioration of contractile function of the myocardium (Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart // Endocrinology. - 2000. - Vol.141. - P.2139-2144).

It is known that the generally accepted recommendations of preoperative preparation of patients with thyrotoxicosis important is the appointment of urugauy heart rhythm medications such until recently were primarily beta-blockers (Alexandrov GF Syndrome thyrotoxicosis / Grahakara // Diseases of the endocrine system / edited Dev. - M.: Medicine, 2000. - S-277).

A prototype of the proposed method is the use in the preoperative period combination thyreostatic and beta-blocker the patients with thyrotoxicosis (Mazurina, NV Diffuse toxic goiter / Navrazhina // Practical endocrinology / edited Gasolinera. - M.: Practical medicine, 2009. - P.137-140). However, along with the suppression effect on the heart sympathetic innervation, positive antianginal, hypotensive and antiarrhythmic effect of beta-blockers have a negative impact on heart (slow AV conduction, decreased contractility), respiratory patterns (increase the tone of smooth muscles of the bronchi), and cause hypotension and reduce erectile dysfunction (Blizzard VI Reference of clinical pharmacology cardio-sadistic medicines [Text] / Vietemese. - M.: Malpractice, 1996. - 468 S.; drugs in Russia [Text]: a Handbook. - M.: Attraversare, 2003. - S).

Therefore, as an alternative to beta-blockers was first used in medical practice new original drug, ivabradine, mechanism of action which involves the selective and specific inhibition of the If channels sinus node that controls the spontaneous diastolic depolarization in the sinus node and regulates heart rate. Ivabradine does not change intracardiac conduction, contractile function, the processes of ventricular repolarization, providing only a minor influence on UB is Yan HELL and the peripheral resistance of the vascular system. The main indication for ivabradine - the need to reduce heart rate angina to decrease the requirement of a myocardium in oxygen at the same time without proxemically and cardioplegic effects (Makolkin VI application Experience (ivabradine) Coracana in clinical practice [Text] /Weakacid, VII, Have, Ontrance // Cardiology. - 2008). These opportunities for relief of sinus tachycardia in patients with thyrotoxicosis in the available literature no. Therefore, in cases of contraindications or limitations on the use of beta-blockers, it was decided to use ivabradine when conducting pre-training.

The objective of the invention is the use of the drug of ivabradine to reduce tachycardia in patients manifest thyrotoxicosis with limitations in the use of beta-blockers.

The proposed method of preoperative preparation of patients manifest hyperthyroidism is characterized by the fact that to reduce tachycardia use ivabradine (coracan) at a dose of 5-7 .5 mg for 7-14 days, followed by a supporting course in the dose of 5 mg until completion of preoperative preparation.

Research conducted at the endocrinology Department of state Bureau of Tver.

Research methods included non-invasive assessment of PA is amerov HELL mechanical function of the heart, patency precapillaries channel using volumetric compression oscillometry Central hemodynamics (OCIG), and 5-minute ECG recording software analysis of heart rate variability to assess mathematical, time and frequency parameters.

Mathematical processing of the obtained results was carried out using a computer software package "Microsoft Excel 7.0 and SPSS.VER.12.0, which included the following methods of mathematical statistics: descriptive statistics - nonparametric student's criterion (t). The critical value of significance level (P) for the testing of statistical hypotheses were taken as 0.05.

It turned out that before taking ivabradine (table 1) in patients with manifest hyperthyroidism, compared with those in healthy individuals (Shpak L.V. features of a computer oscillometry hemodynamics during examination of healthy persons [Text] / Lowspec, Esseltine // Theory and practice of regional medicine. - Tver: the Factor 2008. - P.124-127), on the background of tachycardia and normal level GARDEN tended to increase shock the HELL and the increased tension of the inner wall of the artery (BAA) in the absence of increased

Table 1
The dynamics of couples who TRS circulation thyrotoxicosis according to OKOTH before and after treatment with ivabradine (M±M)
IndexHealthy (Lowspec. Eshaust, 2008)The study period
before the treatmentafter the treatment
n=50n=50
Blood pressure:
GARDEN, mm Hg113,6±1,6USD 114.9±1,4to 102.2±0,84**
Dad, -//-69,6±1,466,8±0,967,6±1,05
BAD, -//-to 87.1±1,5of 89.2±2,8*85,6±1,2
HELL Wed, -//-80,8±1,779,5±1,776,0±1,4
PAD, -//-44,0±1,949,1±2,3*42,6±1,6 **
Speed PAD, mm Hg/s388,6±17,8400,4±20,1*355,8 is 16,5
HELL UD, mm Hg35,3±2,240,7±2,4*34,8±1,3 **
Cardiac activity:
HR 1 min76,3±1,5of 97.3±3,1*77,6±0,81**
MO, l/min5,4±0,15,5±0,25,1±0,1**
C, l/min* m23.3V±0,093,6±0,12*3,0±0,04**
PP, ml71,0±1,8to 74.7±1,268,7±0,81**
AP, ml/m244,4±1,450,7±1,8*42,7±0,58**
WWS ml/s223,8±5,6237,5±7,9*198,2±4,5**
SLI, W2,4±0,082,9±0,11*2,0±0,03**
Re 1 l With the, W*s/l10,7±0,211,9±0,2*9,6±0,07**
Vascular parameters:
BFV, cm/s37,1±0,740,8±0,9 *35,2±0,7**
SST -//-900,3±24,7910,8±10,2 *755,8±8,4**
PSS, ml/mm Hg1,87±0,041,53±0,012,04±0,02**
SVR, Dyne*cm-5*1180,2±23,21075,4±18,7*1324,3±22,0**
Oops, srvc. ed24,5±0,625,8±0,728,0±0,8**
The reliability of the difference (p<0,05-0,001) specified before (*) and after (**) treatment.

peripheral vascular resistance to blood flow (decreased DBP). In addition, there is some increase in pulse arterial pressure due to increased catecholamine effects on the myocardium induced by the action isback the thyroid hormones (PS Slavina The defeat of heart and vascular diseases of the endocrine glands [Text] / Lislevane. // Diseases of the heart and blood vessels. / Under. edit Ehitatava. - M., 1992. - V.3. - S-290; Petunia N.A. TO the question about the state of the cardiovascular system in violation of the functions of the thyroid gland [Text] / Naidunia. // Farmateka. - 2007. No. 3. - P.51-55)that comprehensively brought to a state of hyperthyroidism infarction with increasing kinetic parameters of the circulatory system (C, PP, AP) and force of heart contractions (WWS SLI and ER) with little changing of the minute volume of blood.

Described cardiac hyperthyroidism thyrotoxicosis caused excessive permeability precapillaries channel (the tendency to increase the linear velocity of blood flow and pulse wave velocity by reducing the compliance of the vascular wall and the peripheral resistance)that could be due to passive stretching of elastic vessels pressure inside the mass of circulating blood during systole.

After treatment with ivabradine (table 1) modify cardiovascular hemodynamics compared with the original data, was characterized by a decrease in heart rate by 20.2% (p<0.001) and an improvement in HELL. So, with little changing dad, the BAD and the BPA significantly (p<0.001) decreased the GARDEN (10.3%), speed pulse HELL (11.1%), reflex reflecting the weakening of diastolic N. the load of the heart due to the decrease in heart rate, what is most clear (p<0.001) reflected a decrease in the level of pulse PRESSURE (13.2%) and Adad (14.5%). This corresponded to a significant decrease (p<0.001) in all kinetic parameters, particularly SI (16.6%), AP (15.7%), indicating that increasing the effectiveness and efficiency of the heart (lower TCO by 16.5%, MSLI 31.0% and re 19.3%; p<0,001) due to the increase in chronotropic reserve.

Such positive dynamics in the treatment ivabradine occurred against the background of improvement of vascular tone. As can be seen from table 1, reduction in the incidence of cardiac rhythm and, as a consequence - volume cardiac output was associated with a significant slowing of linear blood flow velocity (13.7%) and pulse wave velocity (by 17.0%) in combination with a reflex increase in peripheral vascular resistance (SVR - by 23.1%, COC - 8.5%>), reflecting the shift from Hyper - total akineticheskie (in 100% of patients) option circulation.

Thus, the evaluation of the various parts of the circulatory system in the conditions of their lump-sum relationship suggests that an important feature of early development tirewheel cardiomyopathy is a combination of myocardial (increased contractility - increase WWS SLI and OM) and vascular (increase in ISC, ISL and reduction of PSS, the CSO and oops) factors with the establishment of a guy who erminations option hemodynamics, when the appointment of ivabradine change. The latter, primarily attributable to a decrease automaticity of sinus node, the improvement of redox processes and the contractile function of the myocardium, as well as the optimization of resistive properties of peripheral vessels with the establishment of akineticheskie shift that is most clearly expressed by lower TCO (16.5%), SLI (31.0%), SST (by 17.0%) and increased SVR (23.1%). Consequently, the use of coracana patients manifest hyperthyroidism improves chronotropy reserve of the myocardium, which indicates the possibility of its use as a preoperative preparation in cases of restrictions on the use of beta-blockers in these patients. Particular importance in this process acquires the study of trigger mechanisms, in particular the total heart rate variability, temporal and frequency characteristics in comparison with the above-described (table 1) complex indices of Central hemodynamics.

As can be seen from table 2, prior to the appointment of ivabradine noted the predominance of sympathetic influences, indicating that the setting is accented sympathetic synergy (decrease BP, SDNN, RMSSD, pNN50%, HRVtr, TF, HF increase in Sabout, IN LF/HF>1,0). This comparative decrease in VLF combined with optimal BP levels, Thu the, despite the presence of tachycardia, pointed to the continuing hypothalamic integration of metabolic processes. The results again confirm the sympathetic dependence of the hyperthyroidism of the circulatory system in terms of the manifestation of thyrotoxicosis.

After treatment with ivabradine (table 2) parallel to the decrease in heart rate is a decrease in the intensity of the sympathetic shift (decrease in Sabout, IN, IIA, VLOOKUP, TF, VLF, LF and LF/HF with a slight increase in SDNN, RMSSD, pNN50%, HRVtr; p<0.001) in the result of inhibiting ion If-currents sinus node. The most sensitive vegetative indices to the weakening of automaticity of sinus node under the influence of ivabradine was RMSSD and HRVtr (increase by 49.3% and 53.3% or 2-fold, respectively), pNN50% (an increase of 93,0% or 14.3 times) and LF/HF (reduction 48.1%, or 2 times), reflecting the change Hyper - on more adaptive akineticheskie option circulation.

Table 2
Dynamics of HRV with thyrotoxicosis before and after treatment with ivabradine (M±M)
Indicators CIGThe study period
before the treatment after the treatment
n=50n=50
Mathematical:
Maboutwith0,5±0,010,7±0,02*
Sabout, %636±1,752,3±1,5*
BP0,15±0,010,18±0,02*
IN units332,6±33,7to 252.7±25,2*
PAPR88,0±13,873,0±16,3
VLOOKUP, units9,0±0,46,8±0,3*
IIA, units239,1±0,1to 130.6±8,7*
Time:
SDNN, MS20,6±1,734,8±2,0*
RMSSD, MS16,3±1,231,7±2,0*
pNN50, %0,3±0,02HRVtr3,5±0,17,5±0,4*
Frequency:
TF, MS2766,7±39,2520,7±29,4*
VLF, MS2406,1±21,1258,1±16,3*
LF, MS2248,4±19,8to 150.2±12,1*
HF, MC2of 92.5±10,1107,3±13,2*
LF/HF2,7±0,71,4±0,3*
The significance of differences (p<0,05-0,001) indicated between groups before (*) and after surgery (**; ***) in the respective groups.

Therefore, the selective suppression of ivabradine ion activity If-currents, resulting in improvement of cardiac function and vascular tone, obligatorily combined with a decrease in the sympathetic parameters. Therefore, ivabradine can be used in the preoperative period when the manifest hyperthyroidism as an adequate substitute of the beta blockers.

Thisway, the ratio myocardial hemodynamic and autonomic changes thyrotoxicosis reflects sympathetic dependence of the hyperthyroidism patients with secondary cardiomyopathy. Under these conditions, a reflection of the positive effect of ivabradine is the weakening of the sympathetic effects on the sinus node and the increase in chronotropic reserve of the myocardium, which improves preoperative preparation, without inducing cardioplegic effects typical of beta-blockers.

Method of preoperative preparation of patients with thyrotoxicosis is illustrated by the following example:

Example.

Patient C., 29 years old, was in the endocrinology Department Bureau diagnosed with Diffuse toxic Struma of II degree, the manifest form of thyrotoxicosis". When receiving complains of fatigue, irritability, loss of body weight by 3 kg within 6 months, increased sweating, tremor of the fingers, palpitations, feeling of "sand" and pressure in the eyes, tearing, compression in the neck at rest and during swallowing. From the anamnesis it is known that the patient has chronic obstructive bronchitis, limiting the use of beta-blockers.

When viewed celebrate the enlargement of the thyroid gland to II degree painless to palpation, potowatomi consistency; exophthalmos, put the performance communications ocular symptoms Kraus, Graefe and Kocher; tremor of the outstretched fingers.

Auscultation of heart sounds clear, rhythmic, HR - 94 minutes; BP - 120/80 mm Hg

At lower levels of TSH (0,18; the rate of 0,2-3,2 mIU/l) observed increase in T4 St. (43,0 pmol/l; normal 10-27 pmol/l).

According to OKOTH the patient on the background of tachycardia, an increase in AP (57 ml/m2), Salt (53 ml/s), SLI (3,2 W) and ER (12 W*s/l), decreased SVR (DIN 988*cm-5*c)that the total reflected hyperkinetic variant hemodynamics, due to sharply positive chronotropic and inotropic effect tirewheel stimulation. Vegetative regulation, compared with the physiological norm, was characterized by an increase IN (552 ed), LF/HF (5,0) while reducing BP (0,11), RMSSD (17 MS)pNN50% (1 item), HRVtr (3 units), VLF (571 MS), indicating intense simvastatine with excessive centralization of control heart rhythm.

The patient had been assigned thyreostatic medicinal drug mercazole and additionally ivabradine. With ivabradine applied according to the following scheme:

7.5 mg twice a day for 10 days, followed 2 weeks later by a supporting rate of ivabradine at a dose of 5 mg for 2 weeks until the cancellation at the time of achieving a euthyroid state.

As a result of the treatment against edema tachycardia was a decrease AP (44 ml/m2), WWS (44 ml/s), SLI (2,8 W) and ER (10.5 W*s/l), decreased the s SVR (1277 Dyne*cm -5*C), which reflected changes in a hyperkinetic variant circulation on akineticheskie. The dynamics of vegetative regulation was to increase BP (0.2 s), RMSSD (28 MS)pNN50% (10 IU), HRVtr (11 units) with a corresponding decrease IN (189 units) and LF/HF until eatonii (LF/HF=1,0).

Method of preoperative preparation of patients manifest hyperthyroidism, characterized in that to reduce tachycardia use ivabradine (coracan) at a dose of 5-7 .5 mg for 7-14 days, followed by a supporting course in the dose of 5 mg until completion of preoperative preparation.



 

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8 cl, 6 ex

FIELD: food industry.

SUBSTANCE: invention relates to a biologically active composition and may be used as a remedy with geroprotective activity. The composition contains a concentrate of vegetal saponins - 0.5-5.0 weight parts, Ala-Glu-Asp-Gly / Ala-His peptides composition - 0.001-0.01 weight parts, a complex of acetyl-L-carnitine and alpha lipoic acid - 10.0-25.0 weight parts. The composition with preventive and corrective action is orally administered in an amount of 140-300 mg per day during 28-30 days.

EFFECT: biologically active substances composition stimulates production of dehydroepiandrosterone, reconditions epiphysis functions and increases melatonin level, protects against oxidation with mitochondrion free radicals.

8 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine.

SUBSTANCE: present invention refers to medicine and describes prolonged release therapeutic tablets for oral administration containing a first layer including a first active substance with the first layer arranged between the two adjoining controlled release layers with at least one of said adjoining layers containing at least one second active substance containing acetaminophen with the two adjoining layers enclosed in substantially integrally whole first layer around an external border wherein said tablet provides the applied serum concentration of acetaminophen Tmax from approximately 2 hours to approximately 8 hours after administered in a subject. What is also described is the therapeutic tablet wherein the first layer is provided between the two adjoining controlled release layers combined in one continuous layer. There are described methods for controlling drug release.

EFFECT: invention provides preparing the prolonged release composition of simple formulation and structure which can effectively integrate a number of active substances in a stable state and which can provide effective combination drug-induced treatment over a long periods of time.

44 cl, 10 dwg, 9 tbl, 7 ex

Chemical compounds // 2462472

FIELD: chemistry.

SUBSTANCE: invention relates to certain glucocorticoids derived by unsaturated fatty acids having anticancer therapeutic action and pharmaceutical compositions containing said compounds.

EFFECT: improved properties of the compound.

26 cl, 7 ex, 3 tbl

Compounds // 2461559

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives possessing the properties of an inhibitor of the enzyme CDK specified in CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9. In formula (I): R1 and R2 each independently represents H, C1-6alkyl or C1-6halogenalkyl; R3 and R4 each independently represents H, C1-6-alkyl or C1-6-halogenalkyl; R5 represents C1-6-alkyl or C3-12-cycloalkyl, or C3-12-cycloalkyl-C1-6-alkyl each of which may be optionally substituted by one or more OH groups; R6 represents wherein Y represents N, X and Z represents CR9; R7, R8 and R9 optionally represent H, alkyl or C1-6-halogenalkyl; wherein at least one of R7 , R8 and R9 is other than H. The invention also refers to a pharmaceutical composition containing said compounds, using the compounds for treating alopecia, stroke, a proliferative disease, such as cancer, leukaemia, glomerulonephritis, rheumatoid arthritis, psoriasis, viral diseases, such as a disease caused by human cytomegalovirus, type 1 herpex simplex virus, type 1 human immunodeficiency virus, a neurodegenerative disease, a CNS disease, such as Alzheimer's disease.

EFFECT: preparing new purine derivatives possessing the properties of the inhibitor of the enzyme CDK.

30 cl, 8 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely obstetrics and gynaecology, and may be used for treating early miscarriage in females with primary hyperprolactinemia. That is ensured by prescribing a sparing regimen combined with the administration of dufaston. It is added with prescribing the preparation dostinex 0.125 mg - 0.250 mg at bedtime to a pregnant woman 1-2 times a week to the 10-12th week of pregnancy.

EFFECT: method provides higher clinical effectiveness, reduced side effects and complications.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to peptidyl analogues of ghrelin having greater stability which are active with respect to the GHS receptor, having the formula given below: (R2)-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-Rl, where values of A1-A28, R1 and R2 are given in the description, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing an effective amount of said compound, as well as therapeutic and non-therapeutic applications thereof.

EFFECT: high stability.

22 cl, 3 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for prevention or treatment of inflammatory intestinal diseases (IID), which contains 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triasolo[4,5-c][1]-benzazepine, or its prodrug, preferably 2-(1-isopropoxycarbonyloxy-2-methypropyl)-7,8-dimethoxy-4(5H), 10-dioxi-2H-1,2,3-triasolo[4,5-c] [1]benzazepine, or its pharmaceutically acceptable salt; respective method of prevention or IID treatment and application of said compounds for manufacturing preventive or therapeutic substance against IID. Demonstrated is efficiency of claimed pharmaceutical composition, more powerful than sulfasalazine and prednisolon with respect to said purpose, in combination with high safety. Shown are few side effects of compounds, absence of inhibition of IL-2, IL-4, IL-5, IFN-gamma, absence of weight gain restraint resulting from treatment.

EFFECT: pharmaceutical composition in accordance with claimed invention can demonstrate powerful preventive and therapeutic action, even in case of severe form of disease with resistance to conventional therapeutic agents.

28 cl, 3 dwg, 9 tbl

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