Method for treating or preventing hypotension and shock

FIELD: medicine.

SUBSTANCE: method involves introducing effective quantity of imidazole derivative of formula 1.

EFFECT: enhanced effectiveness of treatment.

14 cl, 2 dwg, 1 tbl

 

Prerequisites to the creation of inventions

The present invention relates to a method for prevention or treatment of hypotension and shock caused by low peripheral resistance. In addition, the present invention relates to a method of treatment of cardiopulmonary resuscitation. Accordingly, the present invention relates to a method for prevention or treatment of hypotension and shock caused by low peripheral resistance, the introduction of the imidazole derivative of the formula I:

where R represents hydrogen or methyl, or its pharmaceutically acceptable ester or salt.

In addition, the present invention relates to a method of treatment of cardiopulmonary resuscitation, the introduction of the imidazole derivative of formula I or its pharmaceutically acceptable ester or salt.

The present invention relates also to the use of the imidazole derivative of formula I or its pharmaceutically acceptable ester or salt for the manufacture of a medicinal product for the prevention or treatment of hypotension and shock caused by low peripheral resistance. In addition, the present invention relates also to the use of the imidazole derivative of formula I or its pharmaceutically acceptable ester or salt for the manufacture of a medicinal product for cured the I in connection with cardiopulmonary resuscitation.

Additional objectives and advantages of the present invention will be partially contained in the description and will be partly clear from the description, or can be understood in the practical implementation of the present invention. Objectives and advantages of the present invention will be understood with the help of the elements and combinations particularly described in the enclosed claims.

It should be understood that the following General description and the detailed description are only examples and explanation and do not limit the present invention in the form in which it is declared.

Getting imidazole derivatives of the formula I in General is described in WO 97/12874. Enteral, local and parenteral routes of administration and their use as agonists α2-adrenoceptors suitable for the treatment of hypertension, glaucoma, migraines, diarrhoea, ischaemia, addiction to chemical substances, alarm condition, especially preoperative anxiety, and various neurological, musculoskeletal, psychiatric and cognitive disorders, as well as a sedative and analgesic agent, a nasal decongestant agent and as an auxiliary agent in anesthesia are discussed in WO 97/12874.

Agonists α2-adrenoceptors, such as dexmedetomidine, as you know, is called the characteristic range of cardio-vessel is the simple reactions, including, for example, bradycardia and hypotension, and, therefore, they are usually considered as potential candidates for the treatment of hypertension.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows changes over time of the average blood pressure (SBP) (top) and heart rate (bottom) in rats under anesthesia, after slow intravenous injection (over 5 min) 3-(1H-imidazol-4-ylmethyl)indan-5-ol in doses of 1 and 3 μg/kg Shows averages ±WITH the average percentage change from the initial value in each group n=6.

Figure 2 shows changes over time of the average blood pressure (SBP) (top) and heart rate (bottom) in rats under anesthesia, after slow intravenous injection (over 5 minutes) of dexmedetomidine (DMD) at doses of 3 and 10 mcg/kg Shows averages ±WITH the average percentage change from the initial value in each group n=6.

DETAILED description of the INVENTION

Applicants unexpectedly found that, unlike other agonists α2-adrenoceptors, imidazole derivatives of the formula I does not lower blood pressure after intravenous, intramuscular or subcutaneous administration to a mammal. Accordingly, they cause a rise in blood pressure with reflex cardiac ischemia) the claims after injection. Thus, the imidazole derivatives of the formula I or their pharmaceutically acceptable ester or salt can be used in situations where the required return of blood from the peripheral circulation into the Central circulation, as in circulatory shock caused by low peripheral resistance and cardiac arrest. Moreover, an advantage of the compounds of the present invention in comparison with the adrenaline, which are widely used in these situations is the lack of direct stimulation of the heart, that heart rate is not increased and is not causing further ischemia of the heart. Accordingly, the present invention is to provide a method for prevention or treatment of hypotension and shock caused by low peripheral resistance, which is the introduction of the imidazole derivative of formula I or its pharmaceutically acceptable ester or salt to a mammal. In addition, the present invention is to provide a method for treatment of cardiopulmonary resuscitation, which is the introduction of the imidazole derivative of formula I or its pharmaceutically acceptable ester or salt to a mammal.

The preferred compound of the present invention is 3-(1H-imidazol-4-ylmethyl)indan-5-ol.

It should be noted that a method of treating hypotension is a shock, due to the low peripheral resistance, covers all possible conditions that require treatment of hypotension and shock, such as hypotension caused by vasodilatation, anaphylactic shock, septic shock and shock after surgery on the heart.

The exact number of medicines, which should be introduced to a mammal for the prevention and treatment of hypotension and shock caused by low peripheral resistance, as well as for treatment in connection with cardiopulmonary resuscitation, depends on many factors known in the art, such as the input connection, the General condition of the patient, the condition, which are treated, the desired duration of use, the type of mammal, the route of administration, etc. of the Required dose can be administered intravenously by bolus or continuous infusion, intramuscularly or subcutaneously. For example, the dose of 3-(1H-imidazol-4-ylmethyl)indan-5-ol, which is administered to a human intravenously may range from about 10 to 500 μg per patient, preferably about 30-200 μg per patient.

Specialist recognizes dosage forms suitable for the method according to the present invention. Preparations for injection or infusion may contain one or more diluents or carriers.

The present invention is further illustrated by the following example, which is presented only to demonstrate the implementation of the present invention.

EXAMPLE 1

The influence of 3-(1H-imidazol-4-ylmethyl)indan-5-ol on blood pressure and heart rate after slow intravenous injection was studied in rats under anesthesia. Dexmedetomidine (Orion Corporation Orion Pharma, Finland), a specific agonist α2-adrenoceptors studied as reference compounds (compounds for comparison).

The male rats Sprague-Dawley (B&K, Sweden) weighing 290-400 g gave anaesthesia pentobarbital sodium (Mebunat® 60 mg/ml) at a dose of 75 mg/kg intraperitoneally. For the implementation of the slow injection of drugs was catheterizable left femoral vein (PE-50). Was catheterizable the left femoral artery for (PE-60) and continuously recorded mean arterial pressure (SBP) and heart rate (HR) using a transducer Micro Mr-15, connected to a polygraph (Grass Model 7D. Blood pressure was recorded with a frequency of 150 measurements per second were recorded on the computer Pinus PC using AcqKnowledge version 3.5.3 and device for receiving data MRA for analog-to-digital conversion (BIOPAC Systems, Inc.). To obtain a permanent image on the monitor, heart rate used pulse wave of the blood pressure. Body temperature (rectal maintained at a constant level 37± 0,5°With a heating lamp above the rib cage of the animal. For tests used only the rats with GARDEN 73 mm Hg or higher. After a stabilization period of 10-20 min was injected dose 3-(1H-imidazol-4-ylmethyl)indan-5-ol (1 and 3 mg/kg, in the form of hydrochloride) or dexmedetomidine (3 and 10 mg/kg, in the form of the hydrochloride) as a slow intravenous injection (over 5 minutes) or by using infusion pump (Perfusor® ED 2, B.Braun). The total amount of injections in each experimental group was brought to 1 ml

3-(1H-imidazol-4-ylmethyl)indan-5-ol induced an immediate and dose-dependent increase of the GARDEN (to a maximum of +31%) and continuing decrease in heart rate (maximum -19%) after a slow (within 5 minutes) in the/in a dose of 1 and 3 μg/kg (see figure 1 and table 1). On the contrary, the reference connection dexmedetomidine (3 and 10 mg/kg) induced an immediate and dose-dependent decrease as a GARDEN, and heart rate (maximum -37% and -21%, respectively) (see figure 2 and table 1) after a slow intravenous injection of the tested doses.

TABLE 1
We also studied the effect of 3-(1H-imidazol-4-ylmethyl)indan-5-ol and dexmedetomidine on mean arterial pressure (SBP) and heart rate (HR) after a slow (within 5 minutes) intravenous rat is anesthetized. Values are presented as average ±medium, n=6 in each group.
Dose

(ug/kg)
Time

(min)
MPV-2426 AlDose

(ug/kg)
Time (min)Dexmedetomidine
GARDEN (mm Hg)Heart rate (tank/min)GARDEN

(mm Hg)
Heart rate (tank/min)
1097±4373±83089±5348±12
3114±3324±9386±5310±6
5112±3321 ±9579±7310±5
1083±4327±71061±4308±4
2084±4319±92065±2309±5
3080±3317±930 67±2309±5
3094±5366±1110092±2383±11
3123±9309±7294±4308±5
5117±12311±4575±6309±3
1088±4321 ±41059±3303±3
2083±5321 ±62068±2296±7
3077±3305±63073±2297±6

Immediate and dose-dependent initial-hypertensive effect was observed after administration of 3-(1H-imidazol-4-ylmethyl)indan-5-ol in all studied doses. In addition, 3-(1H-imidazol-4-ylmethyl)indan-5-ol in all studied doses caused an immediate and prolonged bradycardia. On the contrary, slojnoe connection dexmedetomidine (3 and 10 μg/is d) after slow intravenous lowered as a GARDEN, and heart rate. After a slow intravenous injection of 3-(1H-imidazol-4-ylmethyl)indan-5-ol was called as hypertension and bradycardia, unlike dexmedetomidine, which, in turn, had a typical agonist alpha-2-adrenoceptor effect on the cardiovascular system.

Specialists will be clear that, although illustrated and described specific embodiments of the present invention, it is possible to make various modifications and changes without derogating from the idea and scope of the present invention.

Other embodiments of the present invention will be clear to experts in the consideration of the present description and the practical implementation of the invention described herein. The present description and examples are intended only to illustrate the present invention, the true scope and idea of the present invention is indicated in the following claims.

All the sources discussed herein entirely incorporated in it by reference.

1. The way to prevent or treat hypotension and shock caused by the low resistance of the peripheral circulation, including the introduction to a mammal in need, an effective amount of a derivative of imidazole of the formula I:

DG is R represents hydrogen or methyl,

or its pharmaceutically acceptable ester or salt.

2. The method of cardiopulmonary resuscitation, including the introduction to a mammal in need, an effective amount of a derivative of imidazole of the formula I:

where R represents hydrogen or methyl,

or its pharmaceutically acceptable ester or salt.

3. The method according to any one of claims 1 to 2, which is administered 3-(1H-imidazol-4-ylmethyl)indan-5-ol.

4. The method according to claim 3, in which injected hydrochloride 3-(1H-imidazol-4-ylmethyl)indan-5-ol.

5. The method according to any one of claims 1 to 4, in which the introduction is carried out intravenously.

6. The method according to any one of claims 1 to 5, in which the mammal is man.

7. The method according to any of pp.5-6, which introduced the effective amount is about 10-500 μg per patient.

8. The method according to claim 7, in which the input effective amount is approximately 30-200 μg per patient.

9. The use of imidazole derivative of the formula I:

where R represents hydrogen or methyl,

or its pharmaceutically acceptable ester or salt for the manufacture of a medicinal product for the prevention or treatment of hypotension and shock caused by the low resistance of the peripheral circulation.

10. The use of derived them is desola formula I:

where R represents hydrogen or methyl,

or its pharmaceutically acceptable ester or salt for the manufacture of drugs for cardiopulmonary resuscitation.

11. The use according to any one of p-10, in which the drug is 3-(1H-imidazol-4-ylmethyl)indan-5-ol.

12. The application of claim 11, wherein the drug is a hydrochloride of 3-(1H-imidazol-4-ylmethyl)indan-5-ol.

13. The use according to any one of p-11, in which the drug is administered to a human intravenously in the amount of approximately 10-500 µg per patient.

14. Use item 13, in which the drug is administered in the amount of approximately 30-200 μg per patient.



 

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