Method of treating thermoregulation disorder

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, namely to therapy and can be used for treatment of patient with thermoregulation disorder, in particular suffering from high temperature attacks and hot flushes, night sweats and their combinations, as well as conditions, selected from female and male hormonal changes, connected with menopause, hormonal changes, caused by chemical way, disease states, causing hormonal irregularities and any combinations of said conditions. For this purpose paroxetine dosed in terms of paroxetine component, 7.5 mg/day is introduced to said patient.

EFFECT: method ensures efficient treatment of such conditions due to optimal dose.

9 cl, 2 tbl

 

The technical field to which the invention relates.

The present invention relates to a method of treatment of a patient suffering from disorders of thermoregulation, especially from hot flashes or flushes associated with hormonal changes due to the onset of natural menopause (either male or female), or due to menopause induced by chemical or surgical manner. The method is also applicable for the treatment of hot flashes, flushes or night sweats associated with painful conditions that disrupt the normal hormonal regulationsfor body. The invention also relates to the use of paroxetine or its salts.

The level of technology

Hot flashes or hot flashes mainly typically observed in women who are in menopause, and are also observed in women who had undergone menopause induced by chemical or surgical manner. These disorders are also observed (but rarely) in men who experience so-called "male menopause" or who have undergone hormonal ablative therapy. Hot flashes and flushing associated with the hormonal control of thermoregulation. In addition, the painful conditions that disrupt the normal hormonal control thermoregulation, also lead to protopope the major sensations of heat and tides of blood.

In the past, the primary treatment for women in peri - and postmenopausal status who have such disorders of thermoregulation, was to conduct a hormone replacement therapy, mainly due to a known significant fluctuations in levels of estrogen. However, many women, especially breast cancer, or having a high risk of developing this disease, resist or reject hormone replacement therapy. Recently, to some extent, were investigated serotonergic compounds (for example, inhibitors of receptor serotonin reuptake) and connection type norepinephrine (in particular, inhibitors of reuptake of norepinephrine, for the treatment of paroxysmal sensations of heat and tides of blood both men and women. Berendsen in working Hypothesis, The role of Serotonin in hot flushes; Maturitas 36 (2000) 155-164 discusses the role of neurotransmitters, of estrogen and of such drugs, exertion and venlafaxine.

[Publication of the patent application U.S. No.] 2006/0100263 relates to combinations bicifadine and other drugs for the treatment of hot flashes. Paroxetine is one of the "other" drugs, referred to as matching funds for combinatorial therapy. In [publication of the patent application U.S. No.] 2006/0020015 States about the use of reuptake inhibitors norepine the Rina in combination with inhibitors of serotonin reuptake. In the application '015 also mentions that selective inhibitors of serotonin reuptake clinically evaluated for the treatment of sensations of heat, and in particular States that in [international publication] WO 1999/044601 in this context referred to fluoxetine. [Publication] applications for U.S. patent No. 2006/0020014 and 2004/0130987 have similar disclosure. In [publication] application for U.S. patent No. 2004/1052710 mentioned about the use of inhibitors of serotonin reuptake in combination with inhibitors of reuptake of norepinephrine for the treatment of symptoms of vasomotor disturbances functions (class of symptoms, which include hot flashes and flushes) paroxetine, which in particular is mentioned as one of the potential inhibitors of serotonin reuptake. In [publication] application for U.S. patent No. 2002/0042432 (now U.S. patent No. 6369051) the claimed combination of estrogenic substances with selective inhibitor of serotonin reuptake (SSRI) and paroxetine in particular is mentioned as one of the potential SSRI inhibitors for use in the claimed invention.

In addition, in [article] Trott et al "An Open Tial of Sertraline for Menopausal Hot Flushes: Potential Involvement of Serotonin in Vasomotor Instability" Del. Med. Jrl, September 1997, 69(9):481-2 and [article] Roth et al., "Sertraline Relieves Hot Flashes Secondary to Medical Castration as Treatment of Advanced Prostate Cancer" Psycho-Oncology, 1998, 7:129-132 it was found that sertraline (another SSRI) in some of the second degree effective in stand-alone treatment feeling the heat. In U.S. patent No. 6498184 discusses the role of substances having a selective affinity to 5-NT2 (subtype of serotonin receptor), for the treatment of paroxysmal sensations of heat. [Publication] application for U.S. patent No. 2004/0092519 refers to the use of reboxetine (a selective inhibitor of reuptake of norepinephrine, i.e. NARI) for the treatment of for the treatment of paroxysmal sensations of heat. Finally, [article] Stearns et al, "A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxif®) in controlling hot flashes in breast cancer survivors" Annals of Oncology, 2000, 11:17-22 reports a study on the female body monotherapy hydrochloride paroxetine in doses of 10 mg and 20 mg per day for regulation of the tides.

While all of the above disclosures is mentioned about the use of an SSRI in combination with other medicines for the treatment of hot flushes, or paroxetine, in particular in combination with other drugs or even paroxetine as monotherapeutic means for treatment of hot flushes, all of these references mentions only about dosages of paroxetine in the amount of 10 mg per day or higher, and usually in the range of 20-50 mg per day. The only exception is U.S. patent No. 6369051, which referred to a wide range of dosing for SSRI components from a combination of an SSRI and estrogenic substances in which the dose of an SSRI is 0.1-500 mg/day, preferably 1-200 mg/day, more pre is respectfully 20-50 mg/day. However, such use is in combination with estrogen. Thus, in General it can be noted that, as a rule, antidepressant therapeutic dose of an SSRI, or the specified range is so wide that not actually given an explanation of any private dose.

It is recognized that in a typical antidepressant therapeutic dose of an SSRI s (including paroxetine) have significant side effects that the patient may not survive. Women with menopausal sensations of heat may not be ready to receive antidepressant doses timolepticheskoe funds because of side effects, and because of the reluctance to be treated, which is typical for depression. In addition, patients that are several other medicinal therapies, in particular cancer therapy or have maintained a cancer, usually do not wish to deal with other medical problems. Simple side effects for most patients who are willing to endure the side effects in other situations, can be an insuperable obstacle for patients dealing with multiple medications for other conditions. Thus, there remains a need for tools to combat disorders of thermoregulation in terms of the tides and the sensation of heat and other vasomotor disturbances t is samoreguljacii while minimizing side effects and risks associated with the use of therapeutic agents mentioned above.

Paroxetine is a molecule that is well characterized in the pharmaceutical and patent literature. Chemical methods of its manufacture are described in detail in U.S. patent№№4861893, 6172233, 6326496, 6433179, 6541637, 6686473, 6716985, 6881845, 6900327 and 6956121, among other things. It is known that they exist in different solvate and polymorph forms, including various hydrates, anhydrous forms, isopropylate, utility etc., amorphous forms, as well as various crystalline forms, for example those disclosed in U.S. patents№№4721723, 5039803, 5672612, 5872132, 5900423, 6080759, 6133277, 6436956, 6440459 and 6638948, among other things. Various pharmaceutical dosage forms known from the above-mentioned patents, as well as, for example, from U.S. patent No. 5955475, 6113944, 6645523, 6660298 and 6699882 and Some other derivative of paroxetine disclosed in U.S. patent No. 6063927. In U.S. patent No. 6440459 and [publish] in the application for U.S. patent No. 2004/0143120 disclosed maleate paroxetine and method of manufacturing hydrochloride paroxetine from maleate. In [publications] applications for U.S. patent No. 2002/0193406, 2002/0035130 and 2001/0023253, in particular, reveals mutilata salt, as well as many other salts. In the US 2002/0090394 disclosed compositions paroxetine controlled selection. It was also indicated that paroxetine can be used in a wide range of the method is in treatment, starting from its use as an antidepressant (U.S. patent No. 4007196) to neurological and mental disorders (U.S. patent No. 5470846), disorders of the Central nervous system (U.S. patent No. 5985322) and before treatment with the purpose of getting nicotine, premenstrual symptoms, post-traumatic stress disorder, addiction to heroin, etc. Each of the disclosures of the above patents is included in this document (in its General form) by reference.

Disclosure of inventions

Thus, the aim of the invention is the provision of a patient suffering from disorders of thermoregulation, dosage form paroxetine, suitable for insertion in an amount of from 0.1 mg/day to a dose not exceeding antidepressant effective dose of paroxetine for the day.

Another objective of the invention is the provision of a patient suffering from disorders of thermoregulation, dosage form paroxetine, suitable for administration in an amount of from 0.1 mg/day to a dose of not more than 10 mg/day.

Another objective of the invention is the provision of a patient suffering from disorders of thermoregulation, treatment with paroxetine, which would substantially prevented and/or reduced side effects, which typically occur from antidepressant effective amount of paroxetine.

Furthermore, an additional goal izobreteniya obvious to the ordinary person skilled in the technical field.

The above objective is achieved in that a method of treatment of disorders of thermoregulation with the use of paroxetine in the form of free osnovana or its pharmaceutically acceptable salt in the anhydrous, hydrated or solvated form, non-crystalline form, or in any of the above crystalline polymorphic forms, in the amount of from 0.1 mg/day to a dose not exceeding antidepressant therapeutically effective amount of paroxetine.

The implementation of the invention

The present invention provides a method of treating disorders of thermoregulation with the use of paroxetine in the form of free base or its pharmaceutically acceptable salt in the anhydrous, hydrated or solvated form, non-crystalline form, or in any of the above crystalline polymorphic forms, in the amount of from 0.1 mg/day to a dose not exceeding antidepressant therapeutically effective amount of paroxetine. The invention also provides pharmaceutical form of paroxetine in the form of a dose that does not exceed the effective amount when used as an antidepressant.

In the present invention paroxetine may be in the form of free base or in the form of any pharmaceutically acceptable salt. To pharmaceutically acceptable salts include the I (but the list is not limited to) hydrogenogenic (such as hydrochloride, the hydrobromide, hydroiodide), sulfates (such as sulfate, hydrosulfate), phosphates (such as mono-, two - and trekhosnovnye phosphate, oxalate, mesilate, toilet, pamoate, citrate, carbonate, bicarbonate, maleate, malate, fumarate, and many other salts mentioned in the links to the patents mentioned above. Preferably, paroxetine is in the form of a free base, in the form of cleaners containing hydrochloride or mesilate salt or in the form of their mixtures. Most preferably, when paroxetine is in the form of cleaners containing hydrochloride salt or in the form of mesilate salt. Paroxetine for use in the present invention may be in anhydrous form, in the form of a hemihydrate, monohydrate, or in a more hydrated form. Paroxetine for use in the present invention may be amorphous or crystalline, the choice is made by the developer of formulations depending on the desired composition and solubility. Crystalline forms have the best stability, but amorphous forms have a more rapid solubility profile.

The dosage is from about 0.1 mg/day and up to a dose not exceeding antidepressant effective amount of paroxetine (calculated as free base, anhydrous form), preferably, up to 9.5 mg/day. Preferably, paroxetine may be introduced to implement izaberete the Oia in quantities at least 0.5 mg/day, more preferably at least 1 mg/day, even more preferably at least 2 mg/day, and most preferably at least 4 mg/day and preferably to a dose of 9 mg/day, more preferably not more than 8.5 mg/day, more preferably not more than 8 mg/day. Other permissive dosages, which are particularly suitable for the present invention include 2 mg/day, 2.5 mg/day 3 mg/day, 3.5 mg/day 4 mg/day 4.5 mg/day 5 mg/day to 5.5 mg/day, 6 mg/day, about 6.5 mg/day, 7 mg/day, 7.5 mg/day 8 mg/day and 8.5 mg/day.

The present invention is applicable for the treatment of disorders of thermoregulation and in particular to such conditions (without limitation)as hot flashes, hot flashes, night sweats, etc. that may be associated with menopause (female or male), perimenopause, hormone ablative therapy (including, but not limited to, an antiestrogen and antiandrogennoe therapy), a treatment other chemical or therapeutic agents that are anti-estrogenic or antiaterogennami or affect thermoregulation, hirurgicheskie procedures such as castration, removal of the uterus, ovary, etc. without restrictions) and painful conditions affecting in normal thermoregulation. Most preferably, the present invention direction is divided into the treatment preclimacteric and post-menopausal sensations of heat, tides and night sweats in women due to aging, treatment-induced menopause or menopause caused by surgery. The invention also is directed, preferably, the hot flashes or flushes, or night sweats in men who have such symptoms occur due to aging, chemical castration, hormonal ablative therapy or surgical castration.

Examples

The following non-limiting examples are presented only to illustrate various embodiments of the invention and not limit it in any way.

Example 1

Women with hot flashes associated with menopause, enter paroxetine (calculated as free base resolutionyou anhydrous form) as follows:

Table 1
FormDoseFormDose
paroxetineparoxetine
Hydrochloride1,0Mesilate1,0
Hydrochloride/td> 2,0Mesilate2,0
Hydrochloride3,0Mesilate3,0
Hydrochloride4,0Mesilate4,0
Hydrochloride5,0Mesilate5,0
Hydrochloride6,0Mesilate6,0
Hydrochloride7,0Mesilate7,0
Hydrochloride8,0Mesilate8,0
Hydrochloride9,0Mesilate9,0
Hydrochloride9,5Mesilate9,5

After a few days-weeks, the symptoms improve.

Example 2

Women with hot flashes, links the data with menopause, enter paroxetine (calculated as free base resolutionyou anhydrous form) as follows:

/tr>
Table 2
Form of paroxetine hydrochlorideDoseForm of paroxetine hydrochlorideDoseForm of paroxetine hydrochlorideDose
Anhydrous1,0Hemihydrate1,0Monohydrate1,0
Anhydrous2,0Hemihydrate2,0Monohydrate2,0
Anhydrous3,0Hemihydrate3,0Monohydrate3,0
Anhydrous4,0Hemihydrate4,0Monohydrate4,0
Anhydrous5,0Hemihydrate5,0Monohydrate5,0
Anhydrous6,0Hemihydrate6,0Monohydrate6,0
Anhydrous7,0Hemihydrate7,0Monohydrate7,0
Anhydrous8,0Hemihydrate8,0Monohydrate8,0
Anhydrous9,0Hemihydrate9,0Monohydrate9,0
Anhydrous9,5Hemihydrate9,5Monohydrate9,5

After a few days-weeks, the symptoms improve.

1. Methods for the treatment of the patient, suffering from disorders of thermoregulation, including the introduction of a specified patient paroxetine in number per paroxetinebuy component, 7.5 mg/day.

2. The method according to claim 1, in which the specified disorder of thermoregulation caused by a condition selected from female hormonal changes associated with menopause, male hormonal changes associated with menopause, hormonal changes caused by chemical way, hormonal changes caused by surgically, medical conditions that cause hormonal disorder, and any combination of these conditions.

3. The method according to claim 1, in which the specified disorder of thermoregulation is a state selected from hot flashes, flushes, night sweats and combinations thereof.

4. The method according to claim 1, in which paroxetine is administered in the form of free base.

5. The method according to claim 1, in which paroxetine is administered in the form of a pharmaceutically acceptable salt of paroxetine.

6. The method according to claim 5, in which the specified pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride.

7. The method according to claim 5, in which the specified pharmaceutically acceptable salt of paroxetine is a paroxetine mesilate.

8. The method according to claim 1, in which paroxetine is administered in crystalline form.

9. The method according to claim 1, in which paroxetine and injected into Orfei form.



 

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FIELD: medicine.

SUBSTANCE: group of inventions relates to field of medicine. Diagnostics of subject, which is in condition of transient cerebral hypoxia and/or ischemia, including those caused by brain trauma, is performed. Not later, than after 16 hours after development of said condition, therapeutically efficient quantity of methamphetamine is introduced to subject.

EFFECT: application of claimed group of inventions makes it possible to efficiently reduce frequency of damage to nervous cells, caused by transient cerebral hypoxia and/or ischemia.

15 cl, 5 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely pulmonology, and concerns treating chronic obstructive pulmonary disease accompanied by bronchiectasia. That is ensured by the endotracheal introduction of berodual 2 ml, 0.25% novocaine 5 ml, 1% diphenylhydramine 1 ml, and 1% dioxidine 15 ml; the procedure is performed for 15-20 min; the therapeutic course makes 10-15 daily instillations.

EFFECT: endotracheal introduction of such complex of the therapeutic preparations provides the effective treatment with no side effects, particularly antibiotic-induced bronchial spasm.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

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