FR2601245A1 - NEW USE OF BROMOCRIPTINE. - Google Patents

Abstract

AIM OF THE INVENTION IS THE USE OF BROMOCRIPTINE OR ITS SALTS WITH PHARMACEUTICALLY ACCEPTABLE ACIDS FOR THE TREATMENT OF SEVERE MYASTHENIA, ENDOCRINOUS OPHTHALMOPATHY, BASEDOW-GRAVES DISEASE, JUVENILE DIABETE, , ACUTE LITUS ERITHEMATUS DISSEMINATED, AUTOIMMUNE HEMOPATHY, MULTIPLE SCLEROSIS, INFLAMMATORY INTESTINAL AUTOIMMUNE CONDITIONS.

Description

The present invention relates to new therapeutic means, in

  especially immunosuppressive therapy to treat an autoimmune disease. More particularly, the present invention relates to new therapeutic means as above and which consist in administering Bromocriptine to treat; diseases

specific autoimmunes.

  Bromocriptine, also known as 210 bromo-12'-hydroxy2 '- (methylethyl) -5' - (2-methylpropyl) -ergotaman-3 ', 6', 18-trione and 2bromo-a-ergocryptine ( cf. MERCK INDEX, 10th edition (1983), article 1386) is a known compound having advantageous pharmaceutical properties, in particular an activity of inhibition of pro15 lactine. It is found on the market in the form of an addition salt with a pharmaceutically acceptable acid, namely in the form of methane sulfonate, under the registered trademarks PARLODEI and PRAVIDETÈ, which is used in the

  treatment of hyperprolactinaemia, Par20 kinson disease and acromegaly, for example.

  According to the present invention, it has now surprisingly been discovered that, among the many diverse autoimmune diseases known in the literature, an effective and advantageous treatment can be carried out for specific diseases: a) myasthenia gravis; b) endocrine ophthalmopathy; c) Graves-Graves' disease; d) juvenile diabetes (type I diabetes mellitus); e) glomerulonephritis (with or without nephrotic syndrome); f) systemic lupus erythematosus; g) autoimmune hemopathy; h) multiple sclerosis; and

  i) autoimmune inflammatory bowel conditions

  munes; using Bromocriptine as a single agent. For

  these specific diseases, Bromocriptine alone, administered at appropriate dose rates, or according to an appropriate dosing regimen or technique, provides adequate and surprisingly beneficial medication.

  This finding can be considered to provide an exceptional advantage in the long-term treatment of subjects suffering from the particular diseases 10 a) to i) indicated above, or in the treatment of these diseases in subjects "resistant" to treatment with cyclosporine or considered "at risk" with regard to potential organ damage induced by cyclosporine, for example for the treatment of these diseases in infants and children or in patients already suffering from a lesion or dysfunction of an organ,

for example kidney or liver.

  Thus, for the specific autoimmune diseases a) to i) indicated above, it can be expected that the use of a bromocriptine monotherapeutic will be particularly beneficial to subjects belonging, for example, to the "resistant" or "at risk" categories. "indicated above following a preliminary cyclosporine monotherapeutic or a combined cyclosporine / Bromocriptine therapy, for example usable in the remission phase of the disease or as maintenance treatment which reduces the need

  long-term continuous treatment with cyclosporine.

  According to the above, the present invention relates to the treatment of a disease chosen from the group consisting of: a) myasthenia gravis; b) endocrine ophthalmopathy; c) Graves-Graves' disease; d) juvenile diabetes (type I diabetes mellitus);

  e) glomerulonephritis (with or without nephro-

  tick); f) systemic lupus erythematosus; g) autoimmune hemopathy; h) multiple sclerosis; and i) inflammatory intestinal autoimmune conditions; in a subject in need of such treatment, this method comprising administering to the subject an effective amount of Bromocriptine. Among the subgroups of specific diseases to which the invention applies include: e1) idiopathic nephrotic syndrome or lipoid nephrosis; gl) hemolytic anemia; g2) aplastic anemia; g3) congenital hypoplastic anemia; g4) idiopathic thrombocytopenia; i1) Crohn's disease; and

i2) ulcerative colitis.

  As indicated above, Bromocriptine exists both in free form and in the form of an addition salt with an acid. In general, the pharmaceutically acceptable acid addition salts of Bromocriptine, for example Bromocriptine mesylate available on the market, have been found to have the same level or the same

  order of tolerance and efficacy as the free compound.

  Throughout the present description and in the claims, it is therefore intended to include, when reference is made to the

  Bromocriptine, both the free compound and its pharmaceutically acceptable acid addition salts, except

otherwise indicated.

  In its use according to the present invention, Bromocriptine is preferably used in the form of a

  addition salt with a pharmaceutically acceptable acid, in particular in the form of Bromocriptine mesylate.

  The present invention is particularly applicable to subjects undergoing maintenance treatment

  or being in the remission phase of diseases a) to i) specified.

  The efficacy of Bromocriptine according to the invention can be demonstrated in standard experimental animal models, as well as in clinical trials, carried out, for example, as follows: [For all experiments and all Following clinical trials, Bromocriptine is administered under the

  form of its mesylate salt (methane-sulfonate)].

1. TYPE I JUVENILE DIABETES

BB / Worcester rat animal model

  The essay is based on the general methodology described by Like et al. , in Am. J. Pathol. 117, 92-97 (1984).

  For experimental purposes, groups of 60-day-old BB / W (and O) rats were used (strain from

  which spontaneously appears autoimmune diabetes comparable to juvenile type I diabetes).

  Experimental treatment involves administering

  Bromocriptine alone, at doses of 3 to 10 mg / kg / day administered continuously throughout the day intramuscularly, for 10 days.

  The control groups receive a placebo of oli25 ve oil in place of the experimental substance. All experimental animals are regularly examined to determine

the appearance of glycosuria.

  In the groups receiving Bromocriptine, there is a significant reduction in the number of animals with diabetes, for example having abnormally high blood glucose levels or glycosuria, when compared with the results obtained with the control groups.

receiving placebo.

2. SERIOUS MYASTHENIA

  Myasthenia Gravis Experimental Allergic (EAMG) The experimentation is carried out according to the general methodology described by V.A. Lennon et al., In J. Exp. Med. 141, 1365-1375 (1975). EAMG is induced in groups of 8 to 12 Lewis rats () weighing approximately 150-200 g, by intradermal injection of a mixture containing part of complete Freund's adjuvant (Difco, 0638-60) and part d a solution comprising 10 μg of purified acetylcholine receptor (obtained on California Torpedo rats). An additional adjuvant (Pertussis, 1 × 1010 units) is administered subcutaneously in the pad of the hind paw. Autoantibody titers are determined

  every week using the ELISA technique.

  The experimental treatment consists of the administration

  of Bromocriptine alone at doses of 1 to 10 mg / kg / day subcutaneously, 5 days a week.

  Treatment begins: either on the day of immunization to determine prophylactic efficacy; either after autoantibodies have already formed (usually about 14 days after immunization) to determine therapeutic efficacy.

  In the groups receiving the above treatment,

  observed significant inhibition of antibody formation using a prophylactic regimen and a reduction in antibody titer using a therapeutic regimen, when compared with the results of the control groups receiving placebo.

3. MULTIPLE SCLEROSIS

  Activity on experimental allergic encephalomyelitis (EAE) established The experiment is carried out according to the general methodology described by Borel et al., In Agents and Action, 6, 468 (1976). EAE is induced in groups of 8 to 12 Wistar (9) or Lewis (9) rats each weighing 150 to 200 g, by intradermal injection, into each pad of the hind paw, of 0.1 ml of an emulsion comprising 2.5 g of bovine spinal cord (lyophilized and reconstituted with 12 ml of H2O), 1.5 ml of Arlacel A, 8.0 ml of Nujol and 0.2 ml of physiological saline containing 20 mg of Mycobacterium

phlei dried and killed.

  The experimental treatment consists of the administration of Bromocriptine alone at doses of 1 to 10 mg / kg / day by the subcutaneous route, administered daily or every

  two days, and continues for approximately 14 days.

  During treatment, the experimental animals are examined daily for symptoms of the disease (paralysis of the hind limbs and tail) and a positive score is assigned to the appearance of the disease when full involvement is observed. both hind legs and tail. Ex-experimental animals are kept under observation for a total period of 25 days. In the groups receiving the above treatment,

  observed a significant reduction in the onset of symptoms of EAE disease, when compared to the results of the 20 control groups receiving placebo.

  4. LUPUS ERYTHEMATEUX ACU DISSEMINE

  Mouse model (NZB / NZW) F1 The experiments are based on the mouse strain (NZB / NZW) F1 described and explained by Steinberg et al., In Bulletin on the Rheumatic Diseases'28, n 4-5, 940 - 946 (1977-1978), published by The Art. Ais Foundation, Atlanta, Georgia. In females of this strain, the characteristics of LEAD syndrome, including the formation of anti-DNA and anti-erythrocyte autoantibodies as well as proteinuria, appear spontaneously at about 5 years of age.

  at 7.5 months. Affection ultimately leads to death.

  For the purposes of this experiment, groups of 6 to 8 mice are used.

  The experimental treatment consists of the administration of Bromocriptine at doses of 1 to 10 mg / kg / day by the route.

subcutaneous, 5 times a week.

  The treatment is applied either before the spontaneous appearance of the autoantibodies (for example at the age of approximately 5 months) to determine the prophylactic efficacy, or after the spontaneous appearance of the autoantibodies (for example at the age of approximately 8 to 9 months) to determine the therapeutic efficacy. In each case, treatment is continued for a total of approximately 8-10 weeks. The anti-DNA and anti-erythrocyte antibody titers were measured at regular intervals during the test period, using the ELISA technique, starting approximately one week before the start of treatment. The other parameters subject to control are the appearance of proteinuria (measured a

  times a week) and the lifespan.

  In the groups receiving the above treatment, there is a significant reduction in proteinuria, as well

  than an increase in the average lifespan, either in prophylactic treatment or in therapeutic treatment, when compared with the results of the control groups receiving placebo.

  5. AUTOIMMUNE HEMATOLOGICAL DISEASE (HEMOLYTIC ANEMIA)

  Model of mouse erythrocyte autoantibody induced by rat erythrocyte Experimentation is carried out according to the general methodology described by Naysmith et al., In Immunological Rev. 55, 54-86 (1981). Four injections, each comprising about 108 well-washed rat erythrocytes, were administered to groups of normal healthy young mice on days 0, 7, 14 and 21 of the experiment, the injection being carried out intraperitoneally. From day 21, the animals are bled at fixed intervals of 5 to 7 days in a citrate saline solution and a direct Coombs test is carried out using a broad sheep antiserum

  anti-immunoglobulin spectrum of mice. We generally observe the positive reaction of the Coombs test in animals.

  control ailments not receiving medication from the 3rd to the 4th week approximately of the experiment. We

  continue the experiment for about 10 to 12 weeks.

  The experimental treatment consists of the administration of Bromocriptine alone at doses of 1 to 10 mg / kg / day orally or subcutaneously 5 times a week.

  The treatment is applied either by starting on day 0 of the experiment to determine the prophylactic efficacy, or by starting after the appearance of auto-anti10 bodies (positive reaction to the Coombs test, generally 21 to 28 days after the day 0) to determine the therapeutic efficacy. In both cases, the

  treatment for a total of about 4 to 6 weeks.

  In the groups receiving the above treatment, there is a significant reduction in the number of animals responding positively to the Coombs test after the prophylactic treatment and a significant reduction in the response to the Coombs test after the therapeutic treatment, if one compare with the results of the groups receiving placebo. 20 6. GLOMERULONEPHRITIS / NEPHROTIC SYNDROME Background In hybrid NZB / W female mice renal disease appears spontaneously, which is characterized by the deposition of immunoglobin (Ig) and complement (C ') at the age of 25 3 at 6 months, with histological glomerulonephritis and proteinurea from approximately 6 months; They thus provide an appropriate animal model for the disease of glomerulonephritis as it appears in humans: Method We randomly classify female NZB / W mice into 'control groups and treatment of 10 mice each. We mark

  each mouse on one ear to be able to identify them individually. The experiments are started when the mice are 12, 24 or 36 weeks old and the experimental treatment is continued for 12 weeks.

  The experimental treatment consists of the administration of Bromocriptine alone at doses of 1 to 10 mg / kg / day per

orally, 5 times a week.

  The degree of proteinuria is estimated by staining 10 μl urine stains on filter paper with bromophenol blue. A thin layer chromatography scanner connected to an integration calculator is used to quantify the intensity of the colored urine spots, compared to successive dilutions of bovine serum albumin. Protein levels above 100 mg percent are considered

as abnormal and positive.

  The mice are sacrificed at the end of each experiment and the kidneys are prepared in the usual manner for histological examination. Direct immunofluorescence studies have been carried out using antisera directed against mouse Ig and C3 (Nordic). We classify it

  glomerulonephritis in (i) benign endothelial-mesangial lesions, (ii) more serious segmental proliferative type and (iii) particularly serious membranoproliferative type. The 20 scores range from no injury to serious injury.

  Immunofluorescence scores range from zero to high.

  The results are compared with a control group receiving only placebo. If an animal dies having proteinuria during the experiment, it is considered positive.

  In the groups receiving the above treatment, there is a significant reduction in the deposition of immunoreagents

  and histological evidence of glomerulonephritis, when compared with the results of the control groups receiving placebo.

  The efficacy of Bromocriptine according to the process of the invention will also be demonstrated in clinical trials, carried out for example in the following manner:

  CLINICAL TRIAL: JUVENILE DIABETES TYPE I

  The test is carried out using diabetics willing

  silent, insulin dependent, having been diagnosed as having juvenile type I diabetes. The diagnosis is established on a clinical basis on non obese subjects with confirmed hyperglycemia [National Diabetes Data Group, Diabetes 28, 1039 (1979)]. We determine the basic level of clearance of the

  creatinine, urine exam, serum creatinine, blood urea nitrogen, serum oxaloacetic glutamic transaminase (SGOT), and alkaline phosphat10ase levels, to make sure they are normal.

  Each subject is administered medication according to the

dosing schedule below.

  After discharge, patients are examined weekly for two weeks and then monthly. At each of their clinic visits, blood is taken to measure the levels of the substances studied, the concentrations of creatinine and electrolyte and for haematological tests and liver function tests; after a month and then every three months, the plasma levels of peptide C are measured, at the basic level

and after glucagon stimulation.

  During the course of the trial, all patients are treated with insulin and encouraged to take twice a day and measure blood glucose concentrations using visual compatibility or reference device methods, with test paper. They are asked to follow an appropriate diabetic diet to maintain normal body weight and normal activity. The insulin dose is adjusted as much as possible to cause an average blood sugar of 7.8 mmol / liter before the main meals and supper. The insulin dose is reduced when blood sugar control is consistent with these goals, or to avoid hypoglycemia. People in whom insulin is completely suppressed for at least

  at least one week without loss of expected balance or pairing

  tion of ketonuria and who do not need to resume insulin treatment during the course of the study are classified as "more insulin requirements" (PBI) and are considered to be "in remission". When subjects who become PBI then see hyperglycaemia appearing beyond the objectives of the treatment, the application of insulin or glybenclamide, the agent, is started.

oral hypoglycemic.

TEST DOSAGE

  Bromocriptine alone is administered: i) initially in doses of 1, 25 mg, orally, at bedtime, for approximately 3 to 4 days; increasing to ii) 1.25 mg / day, oral, in the morning, plus 1.25 mg, oral, at bedtime, for approximately 3 to 4 days (total 2.5 15 mg / day); increasing to iii) 1.25 mg orally in the morning and 2.5 mg orally at bedtime for approximately 3 to 4 days (total 3.75 mg / day); with iv) another possible increase in daily intake

  about 1.25 to 2.5 mg / day every 3 to 4 days, up to 20 a maximum daily dose of 10 mg / day in total.

RESULTS

  The results indicate a noticeable and significant increase in PBI remission in subjects receiving the above medication, compared to the remission (i.e., 25 spontaneous PBI remissions) recorded for groups of juvenile diabetics for whom did not try any treatment, or in comparison to PBI remissions recorded in groups of juvenile diabetics receiving other intervention therapy. The results indicate the efficacy of a Bromocriptine monotherapy according to

the present invention.

  The results also indicate that the medication is well tolerated, as shown for example by measuring other physiological parameters during the course of the trial. 35 Results equivalent to the above may be obtained in similarly designed clinical trials in subjects with glomerulonephritis (with or without nephrotic syndrome), myasthenia gravis, autoimmune hemopathy (including aplastic anemia) , congenital hypoplastic anemia, idiopathic thrombocytopenia and, in particular, hemolytic anemia), systemic lupus erythematosus, autoimmune inflammatory disease (including ulcerative colitis and, in particular, Crohn's disease), ophthalmopathy endo10 crine, Graves-Graves disease or sclerosis in

  plaques, using a Bromocriptine monotherapy.

  Doses of Bromocriptine, for example in the form of

  its mesylate, to be administered according to the present invention, will of course vary according to, for example, the mode of administration and the particular pathology to be treated.

  Bromocriptine is preferably administered at dosage levels and / or according to a daily administration schedule and / or in a form allowing reduction over 24 hours, that is to say continuous, of serum levels regular prolactin. In normal subjects, serum prolactin levels, determined for example by radioimmunoassay (RIA), exhibit cyclical variations during any 24-hour period, with average levels of

  around 3 to 5 ng / ml (RIA) during the day, rising to around 15-20 ng / ml (RIA) in the evening and at night.

  Preferably, when carrying out the process of the present invention, the dosage of Bromocriptine will be determined so as to ensure that the serum prolactin levels do not rise above about 5, preferably 30 '' about 3, better still about 2 ng / ml (RIA) at any time during any 24 hour period. Advantageously administration will be performed to ensure that mean serum prolactin levels during

  any period of 24 hours, do not exceed 3, preferably 2 or even 1 ng / ml (RIA).

  In order to achieve a continuous reduction in regular serum prolactin levels, as described above, administration can be done either enterally (e.g. oral) or parenterally (e.g. muscle intra5) divided for example twice a day or more, preferably three times a day

  day or more, or by using an appropriate delay preparation.

  A suitable daily oral intake of Bromocriptine 10 is generally of the order of 2.5 (preferably approximately.

  3.75) to approximately 15 mg (preferably approximately 10 mg), - administered in divided doses, for example 2 to 4 times a day, preferably 2 times a day, for example with 1/3 of

  taken in the morning and 2/3 of the taken in the evening.

  The treatment with Bromocriptine is advantageously introduced gradually, with an increase in stages of the daily intake over a period of 3 to 5

  weeks, for example, or more, until the desired final dose is reached, for example as described above for the clinical trial method.

  Both oral parenteral preparations of Bromocriptine which can be used in carrying out the process of the invention are known in the art and are available on the market. Thus, Bromocriptine 25 mesylate is commercially available under the registered trademarks PARLODEDI and PRAVIDE, in 2.5 mg tablets (divisible to provide, for example, 1.25 mg intake) as well as

5 mg and 10 mg capsules.

  The present invention also relates to the use of Bromocriptine to treat a disease chosen from the group of diseases a) to i) indicated above, as well as the use of Bromocriptine for the manufacture of a pharmaceutical composition used to treat

  a disease chosen from the group mentioned above.

  The present invention further relates to a composition

  2601245 14 pharmaceutical sition which contains Bromocriptine as active agent, usable in the treatment of a disease

  chosen from the group mentioned above.

15 20 25 30

Claims (5)

  1.Use of Bromocriptine or its pharmaceutically acceptable salts to treat a common disease in the group consisting of: a) myasthenia gravis; b) endocrine ophthalmopathy; c) Graves-Graves' disease; d) juvenile diabetes (type I diabetes mellitus); e) glomerulonephritis (with or without nephrotic syndrome); 1 0 -f) acute systemic lupus erythematosus; g) autoimmune hemopathy; h) multiple sclerosis; and   i) inflammatory intestinal autoimmune conditions.   2.Use of Bromocriptine or its salts pharmaceutically. acceptable for manufacturing a pharmaceutical composition for treating a disease selected from the group consisting of: a) myasthenia gravis; b) endocrine ophthalmopathy; c) Graves-Graves' disease; d) juvenile diabetes (type I diabetes mellitus); e) glomerulonephritis (with or without nephrotic syndrome): f) disseminated acute lupus erythematosus; g) autoimmune hemopathy; h) multiple sclerosis; and   i) inflammatory intestinal autoimmune conditions.   3. Pharmaceutical composition containing Bromocriptine or its pharmaceutically acceptable salts as an active agent for the treatment of a disease chosen from the group consisting of: a) myasthenia gravis; b) endocrine ophthalmopathy; c) Graves-Graves' disease; d) juvenile diabetes (type I diabetes mellitus); e) glomerulonephritis (with or without nephrotic syndrome); f) systemic lupus erythematosus; g) autoimmune hemopathy; h) multiple sclerosis; and   i) inflammatory intestinal autoimmune conditions.   4. Pharmaceutical composition according to claim 3, 10 characterized in that Bromocriptine is Bromocriptine mesylate. 5. Pharmaceutical composition according to claim 3   characterized in that it contains 2.5 to 10 mg of Bromocriptine per unit dose.