Treatment of systemic lupus erythematosus with dehydroepiandrosterone

FIELD: medicine.

SUBSTANCE: a patient with systemic lupus erythematosus (SLE) should be prescribed to apply efficient quantity of pharmaceutically active form of dehydroepiandrosterone (DHEA) and then, after prescription it is necessary to detect the values for disease activity and total symptoms of the process that characterizes SLE-patient's state, such as: index of SLE activity (IASLE), degree of SLE activity (DSLE), patient's visual analog scale (VAS) and coefficient of Krupp's severity degree (CSDK) to determine the difference between these above-mentioned values obtained before treatment and those taken during therapy, moreover, the decrease of three out of these four values or either the decrease of stabilization or the increase being not higher than by 5% in the fourth value shows that patients reacts to the intake of DHEA.

EFFECT: higher efficiency of therapy.

13 cl, 1 dwg, 8 tbl

 

LINKS TO the APPLICATION THAT are relevant TO THIS APPLICATION

The present application describes the effect of the invention in the provisional application U.S. No. 60/165, 108, which was filed 12.11.1999, entitled “Treatment of SLE with DHEA and in which Kenneth Schwartz (Kenneth Schwartz) is listed as the inventor. This previous application, so fully entered into the present description by reference.

The SCOPE of the INVENTION

The invention relates to improvements in the treatment of systemic lupus erythematosus (SLE).

BACKGROUND of INVENTION

Links

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Gutierrez-Ramos et al “Nach” (“Nature”), 346:27, (1990).

Hines D. and others “Steroids Lip Pec.” (“Steroids Lip Res.”), 5(4):216, (1974).

Jungers and other “Arthritis room.” (“Arthritis Rheum.”), 25:454, (1982).

Krupp, L.P. and other “Arch Neurol” (“Arch Neurol”), 46:1121, (1989).

Lahita and other “Arthritis room.” (“Arthritis Rheum.”), 26:1517, (1983).

Liang and other “Arthritis room.” (“Arthritis Rheum.”), 32:1517, (1989).

Linker-Israeli and other “Immunol” (“J. Immunol.”), 130:2651, (1983).

Lucas and others). The wedge. Invest.” (“J. Clin. Invest.”), 75:2091, (1985).

Murakami and other “Immunol” (“J. Immunol.”), 134:187, (1985).

Rubinyan and other “Arthritis room.” (“Arthritis Rheum.”), 22:1399, (1979).

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Vande Ville and other “Recent Prog. The Gorm. Pec.” (“Recent Prog. Horm. Res.”), 19:75, (1963).

BRIEF description of the INVENTION

This invention provides a method of treatment of systemic lupus erythematosus (SLE). The method includes receiving an effective amount of pharmaceutically active form of DHEA in a patient with SLE and at least 4 weeks after administration of DHEA, the definition of the following indicators of disease activity and General symptoms of the process, which characterize the condition of the patient with SLE: activity index for SLE (IASCF), the degree of activity of systemic lupus erythematosus (SASW), visual analogue scale patient (YOUR patient), and the ratio of the severity of Krupp (XTC). Then determines the difference between the values of IASCP, XTC, and YOUR SASW after the appointment of taking DHEA and preliminary values of IASCP, XTC, and YOUR SASW prior to the appointment taking DHEA. The lower three of the four indicators and either a decline or stabilization or increase of no more than 5% from the initial value of the fourth value indicates that the patient responds to the acceptance of the above DHEA. Preference is given to a patient who is ill SLE, and moreover, the patient, the value of IASCF above 2.

Polymorphic forms of DHEA, also known as form I and II are mainly used in the method of treatment, which is a complement to the ohms of the present invention. Thus, in the best embodiment, at least 85% or preferably at least 95% accept DHEA is present in polymorphic form I polymorph form II or combinations thereof.

In one application of DHEA taken doses of a certain period of time sufficient to reduce three of the four measures of disease activity and symptoms of the process, which characterize the condition of the patient with SLE or to reduce or stabilize, or increase no more than 3% of the initial value of the fourth metric. In another application of DHEA taken doses, which can reduce the risk of outbreaks of SLE approximately 200 days of receiving DHEA by at least 5%. Preference is given to receive daily internal dose of at least 100 mg, and preferably about 200 mg, pharmaceutically active DHEA. The first application of DHEA take not less than 40 weeks.

One of the advantages of this method of treatment that is the subject of this invention is the fact that it can be combined with other therapies. For example, the treatment can be performed with the patient with SLE, which is also orally takes such medications, as a glucocorticoid, a non-steroidal anti-inflammatory agents, immunosuppressants or anti-malarial drugs. In this case, the method of treatment in the cancel further taking the drug while taking DHEA.

This invention also provides a drug used for the treatment of systemic lupus erythematosus (SLE) person. This pharmaceutical product includes a large number of doses of pharmaceutically active form of DHEA and instructions for carrying out the method of treatment that is the subject of this invention.

This invention involves the use of a pharmaceutical preparation for the treatment of systemic lupus erythematosus (SLE) person.

Another aspect of the invention concerns the use of pharmaceutically active acid, salt or ester form of DHEA (dehydroepiandrosterone) in the manufacture of drugs in tablet form for the treatment of systemic lupus erythematosus (SLE) person with the expectation of more than 50% on the achievement of improvements measured values of at least three of the indicators of disease activity and symptoms of the process, which characterize the condition of the patient with SLE, including IASCF, XTC, and YOUR SASW, and to increase the initial value of the fourth metric is not greater than 5%, where the change of each indicator is determined by the difference between the initial values and values at the time of treatment, when the patient's initial level of IASCF greater than 2, and when the patient was given for oral administration, the dose of DHEA is not less than 100 mg per day. This VA is iante treatment the patient was given a dose of at least 200 mg of DHEA per day for at least 40 weeks.

The drawing shows the results of the clinical studies conducted to determine the effect of treatment with DHEA to outbreaks of SLE, which are described below in connection with tables 6-8. Patients were given 200 mg of DHEA per day for oral administration in capsules or capsules, which contain no drug (placebo). The drawing shows a graph of the percentage of patients in whom there were no outbreaks of the indicated duration of the research.

DETAILED description of the INVENTION

This invention concerns a method for the treatment of systemic lupus erythematosus (SLE) using dehydroepiandrosterone (DHEA). In the best embodiments of the method uses 4 criteria of SLE: the activity index of SLE (IASCF), the degree of activity of systemic lupus erythematosus (SASW), visual analogue scale patient (YOUR patient), and the ratio of the severity of Krupp (XTC). In the selection of patients for treatment with DHEA preference is given to those who value IASCF above 2.0. Moreover, the method of treatment involves the comparison of the values of these indicators of disease activity and General symptoms of the process before and after the appointment of taking DHEA for determining response to receiving DHEA.

Evaluation criteria for SLE

A. the Rate of activity of SLE

The activity index of SLE (IASCF) was developed as a clinical indicator for what serenia disease activity (Bombardier). It consists of a weighted index of 24 questions that deal with disease activity in 9 bodies. Table 1 presents a questionnaire to determine the value of IASCP, which was used in the conduct of these studies. As can be seen, the value of IASCF weighted: 8 points allocated to the Central nervous system and vascular system, 4 points - renal and muscular-skeletal, 2 points - serous, cutaneous and immunological and 1 point for constitutional and hematologic data. All systems are marked as present or absent during the ten-day period prior to the day of evaluation and assessment day. Thus, IASCF as a quantitative indicator of the activity of SLE evaluates only the recent activity of SLE, which must be present during the previous 10 days, indicating the current status of the disease.

C. the Degree of activity of systemic lupus erythematosus

The degree of activity of systemic lupus erythematosus (SASW) includes symptoms, which took place last month, and consists of 24 clinical manifestations and 8 laboratory parameters (Liang). Clinical and laboratory parameters shows not only the activity but also the severity of the disease. Manifestation or symptom is defined as either active or passive, the degree of severity is used to increase the gradation of the scale, and is determined by the need to use during treatment immunosuppressants, the need to monitor patients more closely or functional or prognostic implications manifestations” (Liang). Table 2 is a questionnaire that was used when conducting these studies, to determine the value SASW. Theoretically, the value of SASW ranges from 0 to 86, where the value for patients with SLE usually varies from 5 to 20.

C. Visual analogue scale patient

When defining values for a visual analogue scale patient (YOUR patient) overall (or global) assessment of the patient based on the visual analogue scale whose values range from a mark of “absolutely no problems” (0) to the level of “worst state” (100). The scale shown below (question 2) in table 3. Patients are asked to mark on the scale how they felt last week. To determine the value, the distance is measured in millimeters from “0”.

D. the Ratio of the severity of Krupp

The coefficient severity Krupp (XTK) is a composite indicator is the average of 9 questions, the value of which ranges from 1 to 7, where the higher the value, the heavier the disease (Krupp), as shown above (question 1) in table 3. Theoretically, the value XTC ranges from 0 to 7, where the value for patients with SLE usually varies from 4 to 7.

That is, the Change of values criter the EB estimates

For all four indicators increase measured or defined value indicates a more severe condition or evaluation, and the reduction in the value means improvement or assessment.

For each activity indicators (IASCF and SASW) and symptoms of the process (YOUR patient and XTC) score for each patient is determined as the difference between the initial value taken before treatment DHEA, and values taken during treatment, calculated as the average of all values obtained during scheduled visits during the treatment, i.e. at 13, 26, 39 and 52 week treatment.

For all indicators improved value means either (a) no change in the indicator or (b) the lower values of the index. Thus, for example, improving the initial value of the index of IASCF equal to 5.0, will be the acceptance of a value of 5.0 or below. Change indicator, which indicates the deterioration evident in the increasing values of the index.

Successful patient in clinical studies conducted in accordance with the invention, is a patient who shows improvement in three of the four indicators (i.e., IASCF, SASW, YOUR patient and XTC) and increasing the value of the fourth index of not more than 5% from the initial values (before treatment). Thus, if the social value of IASCF is 5.0 plus 3%, the maximum permitted increase in the value of IASCF when tested 3% is 0.15.

II. These clinical studies

A. Effect of DHEA on IASCF, SASW, YOUR patient and XTC

Table 4 shows the main characteristics of the two groups of patients that were involved in clinical trials. group 1 consisted of 176 patients who were given capsules (placebo), not containing drug, and group 2 consisted of 170 patients who were given medication. The table shows that the two groups are comparable in all characteristics that have been identified, including the average base value of IASCP, SASW, YOUR patient and the degree of fatigue. Average core values represent the average of the two values taken prior to treatment.

Each group, in turn, can be divided into three subgroups: (I) all patients, (II) all patients, the value of IASCF which is higher than 2, and (III) patients, the value of IASCF which is higher than 2 and which simultaneously take prednisone (day dose greater than 200 mg of prednisone), decreasesto patients in each group is designated as N in table 5.

Table 5 shows the results of clinical studies in which 3 groups who were given placebo, and group 3, which was given medication and was treated with DHEA for a long period of time. During treatment, patients were given a daily 200 mg of DHEA orally in the form of ordinary tablets or tablets containing no medicine (placebo). The average duration of treatment of each group was slightly higher for the placebo group (308 days for patients receiving placebo, and 288,4 days for patients receiving DHEA), but the median duration of treatment was almost identical (362 days and 359 days, respectively).

Three columns in the table show data for all three subgroups as for placebo, and group, receiving capsules of DHEA. Three rows represent respondents who have seen improvements (stabilization or decrease) in three of the four indicators and the increase in the fourth figure is not more than 3% (first row), 5% (second row) and 10% (third row) from the original key value.

As can be seen, the patients in subgroup II (the value of IASCF above 2) and III (the amount of IASCF above 2 and a daily intake of prednisone) showed more than 50% of the reaction that determines either 3%or 5%or 10% (percentage), “increasing” the fourth indicator, in comparison with the degree of response of the EIT is sustained fashion below than 50% of the equivalent of two placebo groups.

Thus, according to one side of the invention, the degree of response to treatment with DHEA can be greatly improved as only the treatment with DHEA or in combination with a second drug against SLE, such as prednisone, through (a) determine the magnitude of IASV in patients of SLE patients, (b) selection of patients patients with SLE, with a value of IASCF above 2.0, and (C) treatment of selected patients with daily internal doses of DHEA.

In particular, this method can be practiced with the expectation of more than 50% achieve improvements in at least three of the indicators of disease activity and General symptoms of the process, which characterize the condition of the patient with SLE, namely IASCF, XTC, and YOUR SASW, increasing by no more than 5% of the initial value of the fourth metric, where all changes in each measure is determined by the difference between the initial value taken before treatment, and the average of all values obtained at regular intervals throughout the course of treatment.

C. Effect of treatment with DHEA to outbreaks of SLE

Clinical studies were conducted to determine the effect of treatment with DHEA to outbreaks of SLE. Flash SLE is a significant new clinical manifestation of the disease (i.e. not present in the patient is before or have taken place not so severe) and/or clinical intervention. Table 6 shows the clinical detection or intervention, which are considered in this study as flash. Suppose that the patient has flash, if present, at least one of the data detection or intervention.

Table 7 summarizes the main characteristics of the two groups of patients involved in clinical studies. group 1 consisted of 109 patients who were given capsules (placebo), not containing drug, and group 2 consisted of 189 patients who were given medication. As can be seen, the two groups are comparable in all characteristics that have been identified, including the average base value of IASCP, SASW, YOUR patient and XTC. (This table shows the average value taken prior to treatment.)

To convert DHEA-S in the forefront. weight/l, multiply by 0,027. To translate compliments C3 and C4 in g/l, multiply by 0.01.

The results of clinical studies were analyzed for each group (treatment and placebo DHEA) in General (“aggregate data”), and are divided into three subgroups:

all patients with a value of IASCF above 2 (the active form of SLE and patients with a value of IASCF above 2 and the receiving corticosteroids and/or immunosuppressants (a more severe form of SLE).

In the face 8 shows the results of clinical studies, in which patients were given DHEA or placebo for a long period of time. Patients received daily 200 mg of DHEA orally in the form of ordinary tablets or tablets containing no medicine (placebo). The average duration of treatment of each group was slightly higher for the placebo group (308,4 days for patients receiving placebo, and 288,4 days for patients receiving DHEA), but the median duration of treatment was almost identical (362 days and 359 days, respectively).

In the first column presents the analyzed data of the studied groups and subgroups, in the next three columns present the results of the study for those patients where the treatment took effect, according to the following criteria: (1) Average weighted changes in the initial values for the degree of activity of systemic lupus erythematosus (SASW)<1; for an index, the activity of systemic lupus erythematosus (IASCF)<0.5 to Factor severity Krupp (XTC)<0,5; for General assessment of the patient <10; and (2) no clinical deterioration. The last three columns of the table show the results for patients who had at least one outbreak during the study.

The results show that the response to treatment with DHEA increased during the transition of the disease in a more severe form (i.e., from less severe active SLE to more than agelou form to the form of SLE, where patients were given corticosteroids and/or immunosuppressants). In addition, treatment with DHEA reduced the occurrence of outbreaks, and the size of this activity also increased during the transition of the disease in a more severe form of the disease.

The results of this study are also shown in the drawing which is a graph showing the relationship of the percentage of patients who did not experience outbreaks, to the specified time period of the study. The drawing shows that treatment with DHEA reduces the risk of flare in patients with active form of SLE after about 85 days of treatment, compared with patients who are given a placebo. After approximately 200 days of treatment, the occurrence of outbreaks by at least 5% lower in patients taking medicines, and from that moment the difference in the occurrence of outbreaks among patients taking the drug, and patients taking placebo, increases at least almost 10%.

Thus, with regard to one side of the invention, treatment with DHEA can significantly reduce the risk of outbreaks, especially in patients with a value of IASCF above 2.0.

III. The method of treatment

The subject of this invention is a method of treating SLE in a patient. Patients could be any animal disease SLE or similar disease is. Typically, the patient is a mammal, preferably a person with a diagnosis of SLE. It is better if the patient is of IASCF above 2.0. According to this method, the patient was given DHEA, and then determine and compare the above four indicators of disease activity and General symptoms of the process with initial values taken prior to the appointment of DHEA. The lower three of the four indicators and either a decline or stabilization or increase of no more than 5% from the initial value of the fourth value indicates that the patient responds to the acceptance of the above DHEA.

A. DHEA

According to the method of treatment of SLE, which is the subject of this invention, the patient SLE give effective amount of pharmaceutically active form of DHEA (dehydroepiandrosterone). Used herein, the term “pharmaceutically active form of DHEA” includes pharmaceutically active acid, salt and ester form of DHEA, such as DHEA sulfate (sulfate alpha-3H-DHEA, for example, Hines).

You can select 6 different polymorphic forms of DHEA, which is described in detail are also in the possession of the inventor of PCT application no PCT/US/00/06987 (international publication number WO 00/54763). Previously it was known, by using analytical techniques such as x-ray diffraction, infrared (IR) spectroscopy and d is ferentially scanning calorimetry (DSC), that DHEA is found in crystalline form some of the various hydrates and dehydrates. Form dehydrates include forms I, II, III, IV and V, although the latter two forms were observed only temporarily using DSC. Hydrates (solvate) include the form S1 (1/4 hydrate), S2 (monohydrate), S3 (monohydrate) and S4 (1/2 methanolate). In PCT application no PCT/US/00/06987 described additional form, form VI, which can be recognized only by using solid-state NMR.

In the best embodiment of the present invention used DHEA has the properties of bioaccumulation and pharmacokinetics, which are achieved with the use of preparations containing polymorphs, which provide the specified properties.

In one aspect, the method of treatment includes the preparation of DHEA, i.e. at least 85%, better than 90%, still better than 95%, preferably 99% in the Polymorphic form I. form I has the following characteristics:

(1) visible x-ray diffraction peaks of the powder in 15,0 (C)16,8 (SL)and 18.0 (cf), 18,7 (cf), 19,1 (CL), and 19.3 (CL), 20,2 (CL), 24,8 (CL), 25,0 (CL), 25,2 (CL) (peak position is shown at 26 degrees; s=strong, cf=moderate, SL=weak); and

(2) the peaks of 13C-TAMR: 14,8,14,1 ppm carbon No. 18, 120,4,118,9 ppm of carbon number 6, where data are measured, as described in PCT application no PCT/US/00/06987.

Drugs DHEA containing the form I show a good absorption through the gastrointestinal tract when ingested, have the give good therapeutic activity and high stability in the environment.

In another aspect, the method of treatment includes the preparation of DHEA at least 85%, better than 90%, better still at 95%, preferably 99% in the form II. Polymorphic form II has the following characteristics:

(1) distinguishable peaks of x-ray diffraction on powder 8.6 (CL), 17,3 (CL), 20,9 (cf), 22,0 (CL), 22,2 (CL), 27,1 (CL) (peak position shows at 2θ degrees; s=strong, cf=moderate, SL=weak); and

(2) the peaks of 13C-TAMR: 13,1 ppm carbon No. 18, 119,9 ppm of carbon number 6, where data are measured, as described in PCT application no PCT/US/00/06987.

Drugs DHEA containing form II, show a good absorption of the gastrointestinal tract in the internal reception, the speed of absorption (higher than the polymorphic form T), show good therapeutic activity and high stability in the environment.

In addition, useful in the treatment of drugs of DHEA may contain a mixture of polymorphic forms I and II. Typically, a mixture of polymorphic forms I and II contains at least 85%, better than 90%, still better than 95%, preferably 99% of DHEA in such preparations. Preparations enriched to form I and/or II, as described herein, provide a more predictable pharmacokinetic parameters than those drugs that contain random polymorphic structures.

DHEA and precursors, such as DHEA acetate, commercially available from various sources (e.g., Sigma chemical Co., Art.-Louis,Missouri; “The Aldrich Chemical Company, Inc.; “Diosynth, Inc.; “Pfalz & Bauer, Inc.; “Schering AG”). The compositions of DHEA, enriched to the selected polymorphs can be produced by crystallization commercially available DHEA in the selected solvents under conditions appropriate cooling or evaporation.

One of the best ways to clean a form I made: (a) crystallization of DHEA of anhydrous 2-propanol (or, alternatively, acetone or acetonitrile) under a nitrogen stream at room temperature for more than 2 days to obtain a crystalline precipitate, which contains mainly form I and a number of form IV, followed by (b) dissolving the precipitate in ethylacetate (about 100 ml/30 g of DHEA) and stirring the resulting suspension at room temperature for approximately one week, followed by filtering. The filtered precipitate is allowed to dry at room temperature overnight. Analysis of the 13C-TYR (solid-state nuclear magnetic resonance of carbon), described below, showed that the product obtained by this method consisted of pure or nearly pure (>99%) form I; in the analysis of 13C-TAMR other forms not identified.

DHEA, strongly enriched to form II can be obtained by rapid crystallization from tetrahydrofuran (THF), dioxane, chloroform or mixture is th chloroform and THF. In example 1 of PCT application no PCT/US/00/06987 described specific procedure crystallization from THF, whereby was obtained a product which, as shown by x-ray diffraction on the powder, is a pure form II.

Century Development of formulation and the purpose of DHEA

DHEA can be taken internally in a variety of ways: orally, parenterally, transdermally, through mucous membranes or through inhalation, although the preference is usually oral method.

Depending on the route of administration can be provided in various dosage forms of DHEA. Dosage forms of DHEA can be represented in various forms, such as granules, tablets, capsules, suppositories, powders, compounds with adjustable selection, suspensions, emulsions, creams, ointments, balms, lotions, aerosols, etc.

The compositions of DHEA used in the invention may include one or more pharmaceutical organic or inorganic carriers, extenders and/or reducers, especially those that are suitable for internal or external use. Such media contain tocopherol, dimethylsulfoxide, etc. For internal use such fillers may include lactose, mannitol, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like.

For from the otopleniya tablets for oral administration of DHEA mix with at least one pharmaceutical excipient, and a solid drug is pressed to obtain the tablets in accordance with known methods for delivery in the gastrointestinal tract. The composition of the tablets usually includes additives such as sugar or cellulose carrier, binder, for example, starch paste or methyl cellulose, a filler, a Ripper or other additives that are commonly used in the production of medical drugs. For the manufacture of capsules for oral administration of DHEA mix with at least one pharmaceutical excipient, and a solid drug is placed in a capsule for delivery to the gastrointestinal tract.

Reducers known in this field include, for example, vegetable and animal oils and fats. Stabilizers, wetting and emulsifying agents, salts for modifying the osmotic pressure, buffers to ensure proper pH level and/or substances that increase the penetration into the skin, can be used as auxiliary agents in the compositions of DHEA. Methods of preparation of various traditional forms of dosages are known and will be obvious to a person skilled in the art; for example, see “Remington''s Pharmaceutical Sciences” (Handbook of pharmaceutical Sciences, edited by Remington, 19th edition, Williams and Wilkins, 1995).

The ratio of pharmaceutically active DHEA and media and/or the other substances may vary from 0.5 to almost 100% (weight percentage). For oral administration the pharmaceutical composition typically will comprise from about 5 to about 100% by weight of the active substance. For other types receive pharmaceutical composition typically will comprise from about 0.5 to about 50% by weight of the active substance.

The compositions of DHEA, according to this invention provide an effective amount of DHEA in the appointment to the patient. As indicated in this context, “effective amount” of DHEA - is a quantity that can improve the symptoms of SLE. This therapeutic effect is usually seen within about 4-6 weeks from the beginning of reception of an effective amount of DHEA.

The compositions better, although it is not necessary to take daily in an amount which will at least 10%, and in most cases at least 25% to increase the level of DHEA in the blood. Typically, the total day dose will be at least about 50 mg, at best - at least about 100 mg, in even the best case is at least about 200 mg and not more than 500 mg per day for oral administration, i.e. not more than 4 capsules or tablets, each containing 50 mg of DHEA. Although, tablets or capsules for oral administration may contain the full daily dose, ie 200 mg or more. When neuroretinal taking DHEA can be taken continue the sustained fashion time for example, 3-10 days, in the quantities that can replace at least the average daily dose, ie 50 mg

Treatment with DHEA is held for a long period of time, usually at least about 20, at least about 40, or at least about 60 weeks, and better up until this treatment brings the patient noticeable benefit.

Better if you take DHEA doses a certain period of time sufficient to reduce three of the four measures of disease activity and symptoms of the process, which characterize the condition of the patient SLE or to reduce or stabilize, or increase no more than 3% of the initial value of the fourth metric. Better if you take DHEA doses, which can reduce the risk of outbreaks of SLE approximately 200 days of receiving DHEA by at least 5%.

The phenomena of outbreaks in at least 5% below the group of patients who are given drugs, compared with patients given placebo. Relevant study groups are groups in which a severe form of the disease agreed with the corresponding patients, i.e. reducing the risk of outbreaks of the patient is determined in terms of the group of patients who are given drugs, and the group of patients who are given a placebo. In these groups of patients are equally t the heavy form of the disease. For this purpose, the severity of the same disease, if the patient and two groups of studied patients fall into one of the groups listed in table 8 above.

Treatment with DHEA can be combined with one or more other medicines that are used in conventional ways to treat SLE, including corticosteroids, such as corticosteroids; non-steroidal anti-inflammatory agents; immunosuppressants and anti-malarial drugs. Examples of such drugs can serve as hydroxychloroquine, prednisone, Akrikhin, azathioprin and immunosuppressants such as anticytokine, including anti-TNF-2, receptor antagonists of TNF-2, anti-IL-1, anti-IL-6 and anti-CD40 ligand. Dose glucocorticoid prednisone, for example, are usually about 1-15, and often 1-12 mg/day and usually more than 2 mg per day. Additional medications may be taken separately or in combination with DHEA and, if desired, can be included in the composition of DHEA.

IV. Pharmaceutical drug

The subject of this invention is a pharmaceutical drug used for SLE in a patient and includes a number of doses of pharmaceutically active form of DHEA and instructions on carrying out of this method of treatment. In particular, the instructions described in the following:

1) receiving an effective amount of pharmaceutically active form of DHEA in a patient with SLE;

2) determine what their following indicators of disease activity and symptoms of the process, which characterize the condition of the patient with SLE: IASCF, SASW, YOUR patient and XTC at least after the appointment of DHEA; and

3) determining the difference between the values of IASCP, XTC, and YOUR SASW after the appointment of taking DHEA and preliminary values of IASCP, XTC, and YOUR SASW prior to the appointment taking DHEA, where the lower three of the four indicators and either a decline or stabilization or increase of no more than 5% from the initial value of the fourth value indicates that the patient responds to the acceptance of the above DHEA.

Pharmaceutically active form of DHEA can be manufactured, as described above, according to the method of treatment that is the subject of this invention, and packaged in any convenient way.

As a rule, instructions prescribe the intake of DHEA, as described above, according to the method of treatment that is the subject of this invention. Preferred oral administration. The instructions indicated that the preference for treatment with DHEA is given to the patient, the value of IASCF which is above 2.0.

The statement may be attached to the packaging material or may be included as a liner. While the instructions are usually written or printed materials, they do not stop there. Any medium capable of storing such instructions and passing the TB to an end user considered within this invention. This environment includes the electronic medium for storing data (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g. CD-ROM) and the like, but is not limited to this. Used herein, the term “instruction” may include the address of the Internet website for instructions.

The subject of the invention is also the use of the above-described pharmaceutical preparation for the treatment of SLE person.

All publications and patents mentioned in this detailed description, introduced in the present description by reference as if each individual publication or patent application was entered separately by reference.

Although the above invention has been some manner described in detail in the illustrations and examples the purpose of clarity of understanding, for the usual specialists in this area will be quite obvious that it can be made certain changes and modifications without deviating from the scope of the attached claims.

1. A method of treating systemic lupus erythematosus (SLE), including reception of an effective amount of pharmaceutically active form of DHEA (dehydroepiandrosterone) SLE patients, the definition after the appointment of DHEA indicators of disease activity and General symptoms of the process, characterizes the x condition of the patient with SLE: activity index for SLE (IASCF), the degree of activity of systemic lupus erythematosus (SASW), visual analogue scale (VAS) patient and rate the severity of Krupp (XTC), determining the difference between the values of IASCP, SASW, and YOUR XTC obtained before treatment, and the values taken during treatment, and the reduction of three of the four indicators and either a decline or stabilization or increase of no more than 5% of the fourth indicator indicates that the patient responds to the reception of DHEA.

2. The method according to claim 1, in which the patient of SLE is the man.

3. The method according to claim 2, in which the patient SLE has a value of IASCF above 2.

4. The method according to claim 3, in which the take DHEA doses and during the period of time required to reduce three of the four measures of disease activity and General symptoms of the process and either reduce or stabilize, or increase the fourth figure is not more than 3% from the initial values.

5. The method according to claim 3, in which the above-mentioned receiving includes receiving patient with SLE daily oral doses of at least 100 mg of a pharmaceutically active DHEA.

6. The method according to claim 5, in which the dose is at least 200 mg of DHEA per day for at least 40 weeks.

7. The method according to claim 5, in which the patient with SLE takes oral medication from a group including: a glucocorticoid, Nestea who meets an anti-inflammatory agent, immunosuppressant and anti-malaria tool until the appointment of DHEA, and this method includes continuing the above medications during the period of taking DHEA.

8. The method according to claim 7, in which the above medication is prednisone at a daily dose of at least 2 mg

9. A method of treating systemic lupus erythematosus (SLE), including reception of pharmaceutically active form of DHEA (dehydroepiandrosterone) human SLE patients, with a value of IASCF above 2, after determining the destination of DHEA indicators of disease activity and General symptoms of the process of characterizing the condition of the patient with SLE: activity index SLE (IASCF), the degree of activity of systemic lupus erythematosus (SASW), visual analogue scale (VAS) patient and rate the severity of Krupp (XTC), determining the difference between the values of IASCP, SASW, and YOUR XTC obtained before treatment, and the values in the time of treatment, and the reduction of three of the four indicators and either a decline or stabilization or increase of no more than 5% of the fourth indicator indicates that the patient responds to the reception of DHEA, in which at least 85% take DHEA is either in polymorphic form I, characterized by the peaks of the solid-state nuclear magnetic resonance, carbon-13 at 14.1 and 14.8 ppm d is I the carbon atom No. 18 and 118,9 and to 120.4 ppm for carbon atom No. 6, or polymorphic form II, characterized by the peaks of the solid-state nuclear magnetic resonance, carbon-13 at 13.1 ppm for carbon atom No. 18 and 119,9 ppm for carbon atom number 6, or mixtures thereof.

10. The method according to claim 9, in which at least 95% accept DHEA is a polymorphic form I polymorph form II or mixtures thereof.

11. The method according to claim 10, in which at least 95% accept DHEA is a polymorphic form I.

12. The method according to claim 10, in which at least 95% accept DHEA is a polymorphic form II.

13. A method of treating systemic lupus erythematosus (SLE), including reception of pharmaceutically active form of DHEA (dehydroepiandrosterone) a person who has SLE importance of IASCF above 2, after determining the destination of DHEA indicators of disease activity and General symptoms of the process of characterizing the condition of the patient with SLE: activity index SLE (IASCF), the degree of activity of systemic lupus erythematosus (SASW), visual analogue scale (VAS) patient and rate the severity of Krupp (XTC), determining the difference between the values of IASCP, SASW, and YOUR XTC obtained before treatment, and the values during the treatment, and the reduction of three of the four indicators and either a decline or stabilization or increase of no more than 5% quarter is the first indicator indicates that the patient responds to the reception of DHEA, DHEA take the doses required to reduce the risk of outbreaks of SLE approximately 200 days of taking DHEA at least 5%.



 

Same patents:

FIELD: animal science.

SUBSTANCE: on should apply a 3-fold selenopyran injection of prolonged form containing 300 mg active substance at the age of 6, 12 and 15 mo and per 500 IU vitamin E, 400000 IU vitamin D and 2000000 IU vitamin A/animal, perorally at the same period of time. The innovation enables to increase the values of growth and inspecific resistance.

EFFECT: higher efficiency.

1 ex, 2 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: medicine, phytotherapy, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing agent eliciting immunocorrecting and anti-inflammatory activity. Method for preparing the phytopreparation eliciting immunocorrecting and anti-inflammatory activity involves milling common horse radish fresh roots, extraction of raw by maceration method in the definite ratio of ratio raw : extractant for definite time at room temperature, at periodic stirring, clarification of extract under definite conditions and filtration. Method provides preparing the phytopreparation from common horse radish roots for carrying out pharmacotherapy of immune deficient states and inflammatory diseases.

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

4 tbl, 3 ex

FIELD: medicine, immunology.

SUBSTANCE: invention is designated for treatment and prophylaxis of diseases associated with the immune system insufficiency in chronic relapsing inflammatory diseases, in cases of insufficient effectiveness of antibacterial and anti-inflammatory therapy. Agent eliciting the immunostimulating effect comprises dropwort (Filipendula ulmaria L.) dried, milled, above-ground part, dropwort (Filipendula ulmaria L. Maxim.) dry an aqueous or dry alcoholic extract prepared in the definite ratio of raw : extractant.

EFFECT: valuable medicinal properties of agent.

4 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves taking lavage fluid samples from injured bronchi in preoperative period in making fiber-optic bronchoscopy examination. Microflora colonizing bronchial mucous membrane and its sensitivity to antibiotics is determined. Therapeutic dose of appropriate antibiotic and therapeutic dose of immunomodulator agent like leykinferon is introduced in endolymphatic way 40-60 min before operation. Smears are taken from outlying bronchi in doing operation. Sputum or fluid in retained pleural cavity are taken in 1-2 days after the operation. Prophylaxis effectiveness is determined on basis of bacteriological study data. Therapeutic dose of antibiotics and leykinferon are introduced in 6-8 and 20-24 h after the operation in endolymphatic way. The preparations are introduced at the same doses in endolymphatic way making pauses depending on selected antibiotic elimination half-time once or twice a day until the drains are removed mostly during 48-72 h after operation.

EFFECT: enhanced effectiveness of antibacterial protection; high reliability of antibiotic prophylaxis.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a new complex of N,N-diethyldithiocarbamate with 2-ethyl-6-methyl-3-hydroxypyridine of the formula: . This complex elicits an anti-allergic activity that allows it using for carrying out the pharmacological control of allergic response based on inhibition of function of allergy target-cells.

EFFECT: valuable medicinal properties of complex.

1 cl, 1 tbl, 3 ex

FIELD: medicine, surgery, urology.

SUBSTANCE: one should apply bactisporin probiotic preparation introduced per os at 1-10 x 109 microbial cells twice or thrice for 10-20 d in combination with staphylo-proteic-pyocyanic adsorbed (SPPA) vaccine; moreover, the mentioned combination of preparation should be applied, also, for instillation of wounds, serous cavities, cavities of urinary and biliary ducts at the quantity of 1-5 x 109 microbial cells in isotonic sodium chloride solution. The present innovation provides better humoral and cellular immunity to already developed infectious process, moreover, combined application of SPPA vaccine and bactisporin leads to increased body immune response to antigens of associated vaccine at the background of secondary immunodeficient state induced by infectious process.

EFFECT: higher efficiency of therapy.

1 cl, 5 ex, 3 tbl

FIELD: biotechnology, molecular biology, medicine, genetic engineering, pharmacy.

SUBSTANCE: the hemopoietic protein comprises the amino acid sequence of the formula: R1-L1-R1, R2-L1-R1, R1-R2 or R2-R1 wherein R1 represents the modified ligand flt-3; R2 represents the modified human IL-3, the modified or unmodified colony-stimulating factor. Modification of R1 is carried out by addition of N-end with C-end directly or through linker (L2) that is able to join N-end with C-end to form new C- and N-ends. The modified human IL-3 is prepared by replacing amino acids at positions 17-123. The human G-CSF is modified by exchange of amino acids. The hemopoietic protein is prepared by culturing cells transformed with vector comprising DNA that encodes the hemopoietic protein. The hemopoietic protein stimulates producing hemopoietic cells and this protein is used as a component of pharmaceutical composition used in treatment of humans suffering with tumor, infectious or autoimmune disease. Invention provides preparing multifunctional hemopoietic proteins eliciting the enhanced activity with respect to stimulation of hemopoietic cells and eliciting the improved physical indices. Invention can be used for preparing chimeric multifunctional hemopoietic proteins.

EFFECT: improved preparing and producing method, valuable medicinal properties of protein.

22 cl, 19 dwg, 18 tbl, 117 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new spiroimidazolidine derivatives of the formula (1):

wherein R1 represents hydrogen atom or methyl; R2 represents phenyl or (C1-C4)-alkyl; X represents -CH2-CH2- or -CH2-CH2-CH2-; W represents isopropyl or cyclopropyl; V represents hydrogen atom or methoxy-group; E represents -CO-R3 wherein R3 represents hydroxy-group, (C1-C4)-alkoxy- or amino-group; phenyl represents unsubstituted phenyl residue or phenyl residue substituted with one or some similar or different substitutes taken among the group consisting of (C1-C4)-alkoxy-, methylenedioxy- and ethylenedioxy-group in all its stereoisomeric forms and their mixtures in all ratios, and to its physiologically acceptablesalts. Also, invention relates to a method for preparing compounds of the formula (1) and pharmaceutical composition based on these compounds. Invention provides preparing new compounds eliciting the inhibitory effect with respect o leukocytes adhesion.

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

16 cl, 1 tbl, 41 ex

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

The invention relates to the pharmaceutical industry and relates to improved pharmaceutical preparations containing dehydroepiandrosterone (DHEA), enriched to polymorphic forms I or II, for therapeutic purposes
The invention relates to medicine

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

FIELD: medicine.

SUBSTANCE: a patient with systemic lupus erythematosus (SLE) should be prescribed to apply efficient quantity of pharmaceutically active form of dehydroepiandrosterone (DHEA) and then, after prescription it is necessary to detect the values for disease activity and total symptoms of the process that characterizes SLE-patient's state, such as: index of SLE activity (IASLE), degree of SLE activity (DSLE), patient's visual analog scale (VAS) and coefficient of Krupp's severity degree (CSDK) to determine the difference between these above-mentioned values obtained before treatment and those taken during therapy, moreover, the decrease of three out of these four values or either the decrease of stabilization or the increase being not higher than by 5% in the fourth value shows that patients reacts to the intake of DHEA.

EFFECT: higher efficiency of therapy.

13 cl, 1 dwg, 8 tbl

FIELD: organic chemistry, steroids, medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent exhibiting structure 7β-hydroxyepiandrosterone or 7β-dehydroepiandrosterone, or their pharmaceutically acceptable esters of the structural formula (I) used for protection of neurons against their damages. Compounds elicit high effectiveness and bioavailability.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 dwg, 3 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: disclosed is application of 7-hydroxyepiandrosteron as active agent for protection from acute or chronic neuron damage caused by hypoxia, ischemia, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, or spinal cord damage. 7-Hydroxyepiandrosteron increases number of pyramidal cell survivor after ischemia or hypoxia.

EFFECT: new agent with neuroprotective activity.

6 cl, 1 dwg, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gynaecology and represents the combination for preparing the medical product, containing Anastrozol, Levonorgestrel and Ethynyl Estradiol, the pharmaceutical composition for endometriosis treatment containing Anastrozol, Levonorgestrel and Ethynyl Estradiol and endometriosis treatment method that involves introduction of Anastrozol, Levonorgestrel and Ethynyl Estradiol.

EFFECT: invention provides effective temporary symptom relief in women with severe endometriosis.

3 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention claims compounds of the formula , where R1, R2, R3 and R4 are equal or different, and each element is oxo group, hydroxy group, mercapto group, hydrogen atom, halogen atom, alcoxy group or aryloxy group, and dot line shows possible simple or double link between one or respective hydrogen atom pairs; and their complex ethers, which can be injected transcutaneously.

EFFECT: most efficient application in plaster form, preferably with adhesive substance containing copolymer of 40-60 wt % of metoxyethylacrylate, 30-40 wt % of laurylacrylate or laurylmethylacrylate and 10-25 wt % of polar monomer.

18 cl, 7 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to psychiatry and gynecology, and can be used in treatment of endometriosis in women with anxiety-and-depressive disorders. For this purpose one month after performing laparoscopy at the background of drug hormonal treatment during 6 months phenotropil in dose 100 mg/day is additionally administered for 90 days.

EFFECT: administration of phenotropil in said dose and introduction regimen makes it possible to reduce anxiety-and-depressive symptoms, and has positive impact on functional state of immune and vegetative nervous system.

4 tbl, 3 ex

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