JPS6323817A - Novel use of bromocriptin - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to new therapeutic means for the treatment of autoimmune diseases, particularly immunosuppression therapy.

More particularly, the invention comprises administering bromocriptine for the treatment of certain autoimmune diseases.
The present invention relates to the above-mentioned new therapeutic means.

BACKGROUND OF THE INVENTION Bromocriptine is 2-bromo-12°-hydroxy-2°-(methylethyl)-5°-(2-methylpropyl)nylbotaman-3°,6″,18-trione and 2-bromo- Also called α-ergocributine [Merck Index 10th edition (1
983) Item 1386 is a known compound that has useful pharmaceutical properties, particularly an inhibitory effect on prolactin secretion. Honjima is commercially available as a pharmaceutically acceptable acid addition salt, such as methanesulfonic acid, under the trade names Parlodel and Pravidel for the treatment of, for example, perprolacine syndrome, Parkinson's disease, and acromegaly.

[DESCRIPTION OF THE INVENTION] According to this invention, among the various autoimmune diseases known in the literature, the following details: (a) Myasthenia gravis (b) Endocrine eye disorders (c) Graves' disease (d) Juvenile form Diabetes (diabetes mellitus I) (e) Glomerulonephritis (with or without nephrotic syndrome) (f) Systemic lupus erythematosus (g) Autoimmune blood disorders (h) Multiple sclerosis (i) Autoimmunity It has been found that the treatment of certain diseases of inflammatory bowel disease (P) can be effectively achieved through the use of bromocriptine as a monotherapy. For these diseases, administration of bromocriptine alone, at appropriate dosage rates, and according to appropriate administration methods or techniques provides a suitable and surprisingly advantageous therapy.

Based on this finding, Φ with diseases (a) to (i) above.

long-term treatment of children or children who are ``resistant'' to tucrosborin therapy and who are ``at risk'' of cyclosporine-induced 2D organ damage, such as infants, children, or organs such as the kidneys and liver. Significant disadvantages may also arise in the treatment of the above-mentioned diseases in patients with disorders or dysfunctions.

That is, bromocriptine monotherapy for autoimmune diseases (a) to (i) above can be used, for example, in the above-mentioned "resistant" or "risk" patients, after preliminary cyclosporine monotherapy or cyclosporine/bromocriptine combination therapy, , can be expected to be used as a remission or maintenance therapy, thereby alleviating the need for long-term continuous therapy with ricrosvorin.

Accordingly, this invention provides a method for administering an effective amount of bromocriptine to a subject in need of treatment for the following groups in the above-mentioned subjects: (a) Myasthenia Gravis (b) Endocrine Eye Disorders (c) Graves' Disease (d) Juvenile diabetes mellitus (diabetes mellitus type I) (e) Glomerulonephritis (with or without nephrotic syndrome) (f) Systemic lupus erythematosus (g) Autoimmune blood disorders (h) Multiple sclerosis (i) A method for treating diseases selected from autoimmune inflammatory bowel diseases is provided.

Diseases to which the method of this invention is applied include the following specific examples.

(e') Idiopathic nephrotic syndrome or minimal change nephropathy (gl) Hemolytic anemia (g2) Aplastic anemia (g3) Erythroblastic fistula (g4) Idiopathic thrombocytopenia (i') Crohn's disease (12 ) As mentioned above, bromocriptine exists in free form and acid addition salt form. In general, pharmaceutically acceptable filtrate addition salt forms of bromocriptine, such as the commercially available bromocriptine menate, have been found to have similar levels of tolerance and efficacy as the free form. Therefore, as used herein, the term bromocriptine includes both the free form and the acid addition salt form, unless otherwise specified.

When using bromocriptine in accordance with this invention, bromocriptine is preferably used in the form of a pharmaceutically acceptable acid addition salt, most preferably as bromocriptine menate.

The method of the present invention is particularly suitable for patients who are undergoing continual therapy or in remission for the diseases (a) to (1) above.

The effectiveness of bromocriptine according to the method of this invention is demonstrated, for example, by a targeted animal experimental model or clinical experiment using the method described below.

(In all animal and clinical experiments, bromocriptine was administered in the menlate (methane sulfonate) form.

) 1. Juvenile Diabetes Type I (13B/Walcester Rat Model) This experiment was described in Reich et al. The experiments were conducted based on the general method described in
A strain of spontaneous autoimmune diabetes corresponding to juvenile diabetes type (60 days old) was used.

Study therapy included bromocriptine at doses of 3 to 10 m9/kq/
This was done by administering intramuscularly intramuscularly for 10 consecutive days at a daily dose of 10 days. (All day) The control group received an olive oil bracebo instead of the test substance. All test animals were examined periodically for the development of glycosuria.

There was a substantial reduction in the number of animals exhibiting diabetes, such as abnormally high blood sugar levels and aJ animals exhibiting glycosuria, in the bromocriptine-treated group compared to the bracebo-treated control group.

2. Myasthenia gravis (Experimental Allergic Myasthenia Gravis EAMG) This experiment was carried out by Rennen et al., Journal of Experimental Medicine (f Exp, Med,) Vol. 141.
The procedure was carried out based on the general method described on pages 365-1375 (1975). E A M G weighs approximately 150-20
Freund's Complete Untended (Difco, 0638-60) consisting of 8-12 Lewis rats (female) of 09
) and 1 part of a solution containing 10 μ9 of purified acetylcholine receptor (obtained from Torpedo Force Hornia Lanoto) by intravenous injection. Additional annujuvant (IXI0101-position) was administered subcutaneously to the sole of the hind paw.

Autoantibody titers were measured biweekly by the ELISA method (enzyme-linked immunosorbent assay).

Test therapy consisted of subcutaneous administration of bromocriptine alone at a dose of 1 to 10 times per day for 9 days for 5 days per week.

Therapy was administered either on the day of immunization to determine prophylactic efficacy or after the onset of autoimmunity (usually 14 days after immunization) to determine therapeutic efficacy.

In the treatment group, there was a substantial inhibition of antibody production when prophylaxis was used, or a reduction in autoantibody titers when treatment was used, compared to the control group treated with bracebo.

3. Multiple faecesia (preventive effect on diagnosed allergic brain myelitis (EAE)) This experiment was carried out using the general method described by Borel et al., Agents and Action, Vol. 6, p. 468 (1976). I did it according to the law. EAE was administered to groups of 8 to 12 Wistar (female) or Lewis (female) rats, each weighing 150 to 200 g, with 2.5 g of bovine marrow (reconstituted in frozen rehydrated water 1211Q) and Arlacel A 1.5*12. Nujol 8.0 and dead dried Mycobacterium freyi (Mycobacterium frey)
ium phlei) 20 mg of saline solution containing 0,
It was induced by injecting an emulsion consisting of 2 mQ 0,1 rnQ into the sole of the hind paw.

The test therapy was bromocriptine 1-10 mg/kg/
The doses were administered subcutaneously daily or every second day for approximately 14 days.

During the treatment period, test animals were inspected daily for disease symptoms of paralysis of the hind legs and tail, and a positive disease appearance was recorded when complete manifestation of disease was present in both hind legs and tail. Test animals were kept under observation for a total of 25 days.

In the treatment group, compared to the control group treated with bracebo, the EA
A substantial reduction in the occurrence of E disease symptoms was observed.

4. Systemic lupus erythematosus (lupus erythematosus) [(NZ
I3/NZW) F1 mouse model] This experiment was carried out using the Bretan on the Rheumatic
Diggies (Bulletin on the
Rheumatic D 1seas) 28
Volume 4-5, pages 940-946 (1977-1978) (
Published by Altricis Foundation, Atlanta, Georgia) (NZB/NZ
W) PL was performed based on the mouse system. Females of this strain spontaneously develop characteristics of the SLE syndrome, including the development of anti-DNA and anti-red blood cell autoantibodies and proteinuria, at approximately 5-7.5 months of age. The symptoms eventually lead to death.

Groups of 6-8 female mice were used in the experiment.

The study therapy was bromocriptine 1-10R9/9/
The drug was administered subcutaneously at a daily dose of 5 times a week.

The treatment will reduce the spontaneous generation of autoantibodies to measure the preventive effect.
11 (eg, at about 5 months of age) or after the natural development of autoantibodies (eg, at about 8-9 months of age) to determine therapeutic efficacy. Anti-DNA and anti-erythrocyte antibody titers were measured by ELISA at regular intervals during the study period, starting approximately one week before the start of treatment. Other parameters for control are proteinuria (measured once a week) and survival time.

In the treatment group, a substantial reduction in proteinuria and an increase in mean life span were observed in both the prevention and treatment groups compared to the placebo control group.

5. Autoimmune blood disorder (hemolytic anemia) (rat red blood cell-induced anti-mouse red blood cell autoantibody model) This experiment was carried out by Naismith et al.
(Immunological Rev.) 5
The procedure was carried out according to the general method described in Vol. 5, pp. 54-86 (1981). Four injections containing thoroughly washed rat erythrocyte cells were given to young normal healthy mice on study days 0.7, I4 and 21. Injections were given intraperitoneally. Animals were bled in citrated saline at fixed intervals of 7 days and directly subjected to Coombs test using a broad spectrum sheep anti-mouse immunoglobulin antiserum.Positive Coombs test responses occurred approximately 3 to 1 days after the experiment.
Commonly seen in control animals not receiving medication from 1 week. The experiment lasted approximately 10-12 weeks.

Study therapy consisted of single oral or subcutaneous administration of bromocriptine at a dose of 1-1 on/9/day, 5 times per week.

Treatment may begin on day 0 of the experiment to determine prophylactic efficacy, or after the development of autoantibodies (positive Coombs test, generally approximately 21-28 days after day 0) to determine therapeutic efficacy. Ta. In each case, treatment lasted a total of approximately 4-6 weeks.

There was a substantial reduction in the number of Coombs test positive animals following pre-treatment or a substantial reduction in Coombs test responses following therapeutic treatment in the treatment group compared to the Bracepo-administered control group.

6. Glomerulonephritis/Nephrotic Syndrome (Background) Female NZ B/W hybrid mice naturally develop kidney disease characterized by immunoglobulin (Tg) and complement (e') precipitation at 3 to 6 months of age. The patient developed symptoms and histological findings showed glomerulonephritis and proteinuria from approximately 6 months of age. Therefore, this animal represents a suitable animal model for human glomerulonephritis.

(Method) Female NZ B/W mice were randomly distributed into control and treatment groups of 10 each. A mark was placed on the ear of each mouse for individual identification. Experiments began when mice were 12.24 or 36 weeks old, and treatment continued for 12 weeks.

The study therapy consisted of single oral administration of bromocriptine at a dose of 1-101119/9/day, 5 times per week.

Evaluation of proteinuria was carried out by staining an IOμ urine spot on a filter paper with bromophenol blue.

The staining intensity of urine spots was compared with serial dilutions of bovine serum albumin using a thin layer chromatography scanner coupled to an integrating computer. A protein level of approximately 100η% was considered abnormal/positive.

At the end of each experiment, mice were sacrificed and kidneys were subjected to histological examination using standard methods. Direct immunofluorescence was performed using anti-mount 1 serum against mouse Ig and C3 (Nordic). Glomerulonephritis is caused by (1) mild endothelial glomerular damage, (
11) more severe segmental proliferation and (iii) most severe membranous proliferation type. Ratings ranged from no damage to severe damage. Immunofluorescence ranged from none to strong. Results were compared to controls treated with placebo. If an animal with proteinuria died during the experiment, it was considered positive.

There was a substantial reduction in the precipitation of immunoreactive components and histological findings of glomerulonephritis in the treated group compared to the control group treated with Blacevo.

The effect of bromocriptine according to the method of this invention was also confirmed, for example, in clinical experiments using the method described below.

Clinical experiments: Juvenile diabetes type I experiments were conducted using inulin-dependent diabetic volunteers diagnosed with juvenile diabetes type I. Diagnosis was based on Jλ based on clinical criteria in non-obese patients with confirmed hyperlipidemia.

Baseline creatinine clearance, nW, serum creatinine, blood urea nitrogen, serum glutamate-oxaloacetate transaminase (SGOT), and alkaline phosphatase values were measured and confirmed to be normal values.

Test medication was administered to each child according to the following dosing method.

After discharge from the hospital, Kawane was observed weekly for two weeks and for m months thereafter. Blood was collected at each outpatient visit to measure the test substance concentration, creatinine, and electrolyte level 6, and an In fluid test and liver function test were performed. Thereafter, baseline and glucagon-stimulated plasma C-peptide concentrations were measured at 1 month and 3 column intervals.

During the experiment, all patients were treated with insulin, blood glucose concentration was monitored by reference meter method or visual contrast using 102 doses and reagent strips, and blood glucose concentration was monitored using target body weight and activity maintenance. I was instructed to follow a diabetic diet. The intulin dose was adjusted as much as possible before meals and before evening snacks to obtain a sugar concentration of 7.8 mmol/liter. Intuulin dosage can be reduced when sugar control does not move from the target value or to avoid low sugar levels. complete withdrawal of insulin for at least 1 week without loss of target control or development of ketonuria;
No intuulin re-administration was required during the experimental period)-I
The patient is classified as having lost intuurin requirement (NIR) and is considered to be in "remission." When patients with NIR became hyperglycemic beyond treatment targets, insulin or the oral hypoglycemic agent glibenclamide was administered.

(Test dosing method) Bromocriptine was administered alone.

(1) Initially, an oral dose of 1.25Q caused sleepiness for 3 to 4 days. Then increase f1 (below) (ii) l, 25ff9/day orally administered in the morning, 1
．． 25+9 was orally administered at bedtime for about 3 to 4 days (total of 2
, 5 mgZ day), further increasing the dose (see below) (iii) Orally administering 1.25 R9 in the morning and orally administering 2.5 R9 at bedtime for about 3 to 4 days (total 375 R9/day) (iv) Furthermore, the daily dose is approximately 1.25 to 2.5 m?
/ day increase m for each 3 to 4 days depending on the case, total maximum of 10
up to filozg/day.

(Results) As a result, compared to remission (i.e., spontaneous N1fl) in the juvenile diabetes group not receiving treatment or NIR remission in the juvenile diabetes group receiving other interventional treatments, patients eligible for the above drug regimen 6 showed lower remission. Remission increased markedly and chromatically. This result demonstrated the effectiveness of administering bromocriptine alone according to the present invention.

Additionally, as a result, measurements of other physiological parameters during the experiment revealed that the above dosage regimen was well tolerated.

Similar results are seen in glomerulonephritis (with or without nephrotic syndrome), myasthenia gravis, autoimmune blood disorders (aplastic anemia, erythroblastic fistula, idiopathic thrombocytopenia and especially hemolytic anemia). (including ulcerative colitis, especially Crohn's disease), endocrine eye disorders, Grages' disease or multiple sclerosis. obtained in a clinical trial of bromocriptine monotherapy.

The dose of bromocriptine (eg, menlate form) to be administered according to this invention will, of course, vary depending on, for example, the method of administration and the condition to be treated.

Bromocriptine is administered at dose levels and/or 1
Preferably, it is administered according to a daily dosing regimen and/or in a form that allows for a 24 hour (ie continuous) reduction in daily serum prolacdine levels.

In a typical patient, serum prolactin values (measured, for example, by RIA) show cyclical changes during any 24-hour period, with an average level of about 3-5' during the day! On the order of 9/I&(R(A), about 15-20yt9/mO in the evening and night,
cRI A). When implementing this invention,
Bromocriptine administration is preferably carried out such that the serum prolactin level does not rise above about 5, preferably about 3, and more preferably about 2R9/mQcRIA) within any 24 hour period. Suitably, administration is carried out to ensure that the average surface prolactin level does not exceed about 3, preferably 2 or even I m9/yQcRI A) during any 24 hour period.

To achieve continuous reduction in daily serum prolacdine levels, enteral (e.g. oral) or parenteral (e.g. intramuscular)
Administration can be effected by any route, for example, twice or more times a day, preferably three or more times a day, or using a suitable sustained release form.

A suitable oral lobromocriptine daily dose is generally about 2.5
(preferably about 3.75) to about 15 (preferably about 10
)y, for example 2 to 4 times a day, preferably 1
As a split nail twice a day, for example, take 1/3 dose in the morning,
Preferably, two-thirds of the dose is administered in the evening.

Bromocriptine therapy is suitably introduced stepwise, e.g. by increasing the daily dose stepwise over 3-5 or more periods, e.g. as described above for clinical trials, until the final target value is achieved. be.

Nine forms of both oral and parenteral bromocriptine suitable for the practice of this invention are known and commercially available. That is, bromocriptine menlate is available under the trade names Parlodel and Pravidel in 9 tablets of 2.5 capsules (for example, 1.251 tablets).
111? ) and is commercially available as 5 mg tablets and 10m9 capsules.

This invention also provides the use of bromocriptine in the treatment of diseases selected from (a) to (i) above, and the use of bromocriptine in the manufacture of pharmaceutical compositions for the treatment of the above diseases.

The invention further features a pharmaceutical composition for the treatment of a disease selected from the above group, containing bromocriptine as an active ingredient.

Claims (6)

[Claims] (1) administering an effective amount of bromocriptine to a subject in need of treatment of the following groups in the above subjects: (a) myasthenia gravis (b) endocrine eye disorders (c) Graves' disease (d) Juvenile diabetes mellitus (diabetes mellitus type I) (e) Glomerulonephritis (with or without nephrotic syndrome) (f) Systemic lupus erythematosus (g) Autoimmune blood disorders (h) Multiple sclerosis (i) Treatment methods for selected diseases from autoimmune inflammatory bowel diseases. (2) The following groups (a) Myasthenia gravis (b) Endocrine eye disorders (c) Graves' disease (d) Juvenile diabetes mellitus (diabetes mellitus type I) (e) Glomerulonephritis (with nephrotic syndrome or Use of bromocriptine in the treatment of diseases selected from (f) systemic lupus erythematosus (g) autoimmune blood disorders (h) multiple sclerosis (i) autoimmune inflammatory bowel disease. (3) The following groups: (a) Myasthenia gravis (b) Endocrine eye disorders (c) Graves' disease (d) Juvenile diabetes mellitus (diabetes mellitus type I) (e) Glomerulonephritis (with nephrotic syndrome or (f) Systemic lupus erythematosus (g) Autoimmune blood disorders (h) Multiple sclerosis (i) Manufacture of a pharmaceutical composition for the treatment of a disease selected from autoimmune inflammatory bowel disease The use of bromocriptine in. (4) Containing bromocriptine as an active ingredient, the following groups (a) myasthenia gravis (b) endocrine eye disorders (c) Graves' disease (d) juvenile diabetes mellitus (diabetes mellitus type I) (e) glomeruli Treatment of diseases selected from nephritis (with or without nephrotic syndrome) (f) systemic lupus erythematosus (g) autoimmune blood disorders (h) multiple sclerosis (i) autoimmune inflammatory bowel disease A pharmaceutical composition used for. (5) The composition according to claim 4, wherein the bromocriptine is bromocriptine mesylate. (6) Bromocriptine 2.5-10m per unit dose
The composition according to claim 4, containing g.