WO2000054776A1

WO2000054776A1 - Use of prolactin inhibitors for the treatment of fertility problems in animal species

Info

Publication number: WO2000054776A1
Application number: PCT/IB1999/000448
Authority: WO
Inventors: Eugen Eigenmann
Original assignee: Individual
Current assignee: Individual
Priority date: 1999-03-17
Filing date: 1999-03-17
Publication date: 2000-09-21
Anticipated expiration: 2001-09-17
Also published as: AU2635599A

Abstract

The present invention is concerned with the treatment of fertility problems using a prolactin inhibitor in animals species, especially in cows. Further objects of the present invention are a method for a treatment of fertility problems and a method for the preparation of a medicament with said prolactin inhibitor.

Description

USE OF PROLACTIN INHIBITORS FOR THE TREATMENT OF FERTILITY PROBLEMS IN ANIMAL SPECIES

The present invention is concerned with the use of a medicament in the treatment of fertility problems in various animal species. Furthermore the invention is concerned with a method for a treatment of fertility problems with said medicament.

The postpartum period (PP) is associated with fertility problems in many species (1) . In the cow the problem has been highlighted some time ago (2) . Allusion has been made at that time to under- nutrition. However undernutrition is not specific for the postpartum period. In the cow the problem is referred to as lacta- tional anoestrus (Eigenmann, J.E.). Such cows on rectal palpation exhibit a corpus luteum persistens, an ovarian cyst or nothing (Acyclia) .

Anoestrus by a Swiss study has been recognized to be the biggest problem in large animal practice (3) . Current treatment is empiric, cost expensive and not invariably successful. This treatment includes one or two visits by the veterinarian, rectal palpation and administration of Gestagens. Gestagens in this condition are believed to exert a negative influence on pituitary function and thereby induce a rebound phenomenon at the end of their action. Gestagens include intravaginal devices or oral forms. Intravaginal devices often induce vaginitis and oral forms are time consuming.

Moreover, this Gestagen treatment which is also called synchronization method is derived from the synchronization of normal young. animals. In cows undergoing Gestagen treatment a new oestrus should appear approximately 3-10 days after withdrawal. Not uncommonly prostaglandin F2α is administered in order to remove any residual corpus luteum tissue. Hence the treatment is expensive, nonspecific and most likely unsuccessful in many cases. 30 - 40% of premature slaughtering is due to unresolved fertility problems (3) .

At any rate the cause of the problem remains obscure. Epidemio- logic studies have shown that the problem is related to the 60- day milk yield. The higher initial milk secretion the higher the problems (4) suggesting that it must be a metabolic or hormonal factor which on one hand increases milk production but on the other hand decreases fertility. This study estimates the problem up to 15% of the population. It is believed that the common denominator to all problems is an absolute or relative lack of LH secretion.

In addition fertility problems increase in a square function in relation to milk increase (5) . Although prolactin, which is important in the development of the mammary gland, is said by some veterinarians to be of no importance in milk production there are no good data to reject the hypothesis that specifically in the postpartum period prolactin induces and/or maintains a high milk yield. It is strongly believed that it must be Prolactin which inhibits LH-secretion leading to ovarian dysfunction (6, 7, 8) .

Indeed in human prolactinoma there is significant ovarian dysfunction (lack of LH-secretion) . Careful literature search shows that there have been prolactin (besides other hormones) determinations throughout lactation in a high milk yield breed versus a low milk yield breed. Interestingly prolactin concentrations (around 40 days PP) are higher in the high producers versus low producers (9) . Based on the described prior art it has been an object of the present invention to provide a medicament for a treatment of fertility problems in animal species, especially in cows which is, in the first place very effective and specific in its action and shows less side effects than the medicaments known in the art.

A further object of the present invention has been a method for the treatment of said fertility problems which is, due to the characterics of the medicament according to the present invention, less time consuming and which allows an easier application of said mediament.

This object has been achieved by administering a prolactin inhibitor to anovulatory animal species in the PP period.

Due to their specific effect, especially on the nervous system, alkaloids are a well known class of substances widely used in pharmacology. Examples for such alkaloids are, beside others, caffeine, morphine, strychnine, colchicine, and the socalled ergot alkaloids. Ergot (Claviceps purpurea) is a filamentous fungus growing on various types of grain, especially secale. Ergot alkaloids have been used in the past as labour stimulating and uterus contracting agents. Nowadays these substances are applied inter alia in cancer treatment. For example Biller et al. (6) used Cabergoline (Pharmacia, Columbus, OH), an ergotamine derivative specific for the D2 receptor, for the treatment of prolactinomas, the most commonly occuring pituarity tumour in men.

It has been surprisingly found now, that ergot alkaloids, e.g. Cabergoline, can be used as prolactin inhibitor in order to overcome fertility problems in the cow. Example

All animals (n=6) except one were of the Swiss brown breed. The reminder was a Friesian Holstein. The ages varied between 3,5 and 5,5 years. At the commencement of the treatment 60 to 80 days had elapsed post partum without cycle (heat) or with unsuccessful Gestagen treatment (n=3) . All animals were observed by the farmers and by the veterinarian (one initial and one intermediate and one control at the time of ovulation) . As ovarian pathology acyclia was chosen. These animals are the most difficult to treat. Four cows exhibited true acyclia (no function on the ovary upon rectal palpation and one had a follicle (small) which had been controlled several times and found to be unchanged.

As Prolactin inhibitor Dostinex (Pharmacia & UpJohn/Cabergoline) (7) was chosen. The compound was pulverized and 2x10, 9, 8 and 3,5 mg were dissolved in 20 ml 0,9%-ige NaCl. The compound was administered into the uterus. Each catheter was rinsed with another 20 ml NaCl.

Results

No obvious side effects could be observed. All animals exhibited a drop in milk secretion by 30 to 40% when Cabergoline was administered AM. A drop in milk secretion was observed already in the evening. The drop lasted for 5 to 6 days. Ovulation occurred in all cows invariably approximately 2 weeks after treatment except the one who had a follicle on the ovary (3 days) . Three animals developed a very pronounced standing heat as observed by the farmers. Two farmers apparently missed the heat. However occurrence of ovulation was substantiated by rectal palpation (ruptured follicle) . At the present already two cows have had their regular second cycle (in acyclia the first heat is usually afertile (lack of proceeding progesterone phase) .

Conclusion

The drop in milk secretion proves 1) that the compound is biologically active in the cow over several days. This is in keeping with findings in human beings were the compound remains active as long as 7 days after administration (7) and 2) that despite the erroneous belief (10) Prolactin must be involved in milk production (immediate effect!)

The invariable and timewise consistent appearance of an ovulation is striking. It supports the belief that inappropriately elevated prolactin levels are the cause of PP anoestrus in the cow. Moreover since the compound was active in the most severe condition it would appear a powerful tool in combating this at the present most economically important condition.

Although only one cow had been tested with a low dose (3,5 mg) it appears that the individual dose can perhaps drastically be reduced.

Although the compound (for human use) is quite expensive it appears, given the large incidence of the problem, that the compound could be marketed at a reasonable, perhaps even high price for veterinary use due to its efficacy (single dose, causal treatment) .

Larger scientific and clinical investigations are necessary to establish the efficacy of Cabergoline in lactational anoestrus. The application also would include repeat breeders. PP anoestrus also could be treated in other species such a sheep, horse and pig. References

1) Mc Neilly, AS; Brit. med. Bull. 35, 151

2) Oxenreider et al., J. Anim. Sci. 3_3, 1026. Jahr der Publik. ?

3) Stark, KDC; Schw. ARCM. Tiermeilk. 139, 8, 343

4) Grohn, YT; AM. J. Vet. Res. 55, No. 11, 1521

5) Lotthammer KH; Zϋchtungskunde 56 (6), 414 (Jahr der Publ.?)

6) Bartosik, D; Endocrinology 81, 186, 1967

7) Minagushi, H., Endocrinology 80, 603, 1967

8) Biller, B MK; J. Clin. Endocrinol. Metab. 81, 2338

9) Hart, IC; J. Endocr. 77, 333, 1978

10) Karg, H; Experientia 15.5, 1972.

Claims

1. Use of a prolactin inhibitor for the preparation of a medicament for a treatment of fertility problems in animal species .

2. Use according to claim 1 in which said prolactin inhibitor is an ergot alkaloid.

3. Use according to claim 2 in which said ergot alkaloid is an ergotamine derivative.

4. Use according to claim 3 in which said ergotamine derivative is Cabergoline.

5. Use according to any of the foregoing claims in which the animal species is a cow.

6. Method for a treatment of fertility problems in animal species by administering the prolactin inhibitor of claims 1 to 4.

7. Method accoding to claim 6, wherein said prolactin inhibitor is administered at an infusion or an injection site.

8. Method accoding to claim 7, wherein said prolactin inhibitor is administered into the uterus.

9. Method according to claim 8 wherein a catheter is used for administering the prolactin inhibitor into the uterus.

10. Method according to any of claims 7 to 9 wherein the prolactin inhibitor is administered in a dosis ranging from 3,5 to 10 mg per animal.

11. Method for a preparation of a medicament for the treatment of fertility problems in animal species wherein the prolactin inhibitor according to claims 1 to 4 is dissolved in a sodium chloride solution.

12. Method according to claim 10, wherein 3,5 to 10 mg of the prolactin inhibitor is dissolved in a sodium chloride solution.

13. Method according to claim 12, wherein the concentration of the sodium solution ranges between 0,9% und 5%.

AMENDED CLAIMS

[received by the International Bureau on 13 July 2000 (13.07.00) ; original claims 1-13 replaced by new claims 1-9 (2 pages)]

1. Use of a prolactin inhibitor for the preparation of a medicament for a treatment of fertility problems in animal species wherein the prolactin inhibitor is Cabergoline.

2. Use of a prolactin inhibitor according to claim 1 wherein the animal species is a cow.

3. Method for a treatment of fertility problems in animal species by administering the ergotamine derivative Cabergoline.

4. Method according to claim 3 wherein said Cabergoline is administered into the uterus or any other infusion or injection site ..

5. Method according to claim 4 wherein a catheter is used for administering said Cabergoline into the uterus.

6. Method according to any of claims 3-5, wherein said Cabergoline is administered in a dosis ranging from 3,5 to 10 mg per animal .

7. Method according to any of claims 3 to 6 wherin said Cabergoline is dissolved in a sodium chloride solution.

8. Method according to claim 7 wherein 3,5 to 10 mg of the inhibtor is dissolved in a sodium chloride solution.

9. Method according to claim 9, wherein the concentration of the sodium chloride solution ranges between 0,9% and 5%.