Methods for the determination and adjustment of prolactin daily rhythms

• US 5,585,347 A
• Filed: 12/22/1992
• Issued: 12/17/1996
• Est. Priority Date: 05/10/1988
• Status: Expired due to Term

• Current Assignee: Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System), VeroScience, LLC
• Original Assignee: Ergo Science Incorporated, Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Inventors: Cincotta, Anthony H., Meier, Albert H.
• Primary Examiner(s): Czaja, Donald E.
• Assistant Examiner(s): TRAN, LIEN THUY
• Application Number:
  US07/995,292
• Time in Patent Office: 1,456 Days
• Field of Search: 436/71, 436/87, 436/811, 514/250, 514/288, 514/866, 514/338, 514/12
• US Class Current: 514/6.9
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/221 with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4515 having a butyrophenone group in position 1, e.g. haloperidol pipamperone A61K31/4545
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/4985 : Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/54 : having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/5415 : ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/55 : having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 : having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 : 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/695 : Silicon compounds
• CPC Class Codes: A61K 38/2257 : Prolactin
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: Y10S 436/811 : Test for named disease, body condition or organ function

Abstract

Disclosed are methods for detecting abnormalities in prolactin daily rhythms. The methods involve comparing a prolactin profile of a vertebrate (including a human) subject being tested that has been compiled over a predetermined period to a predetermined standard prolactin profile for healthy subjects. The method also involves determining whether the vertebrate subject has an abnormal daily prolactin rhythm by ascertaining whether (i) at any point during waking hours the prolactin level of the subject being tested is greater than 1 SEM above the normal prolactin profile of said healthy subjects, and/or (ii) at any point during sleeptime the prolactin level of the subject being tested is at least 1 SEM lower than the normal prolactin profile of said healthy subjects. Also provided are methods for determining adjustments needed to an abnormal prolactin profile (or daily rhythm) to cause it to conform to the prolactin profile (or rhythm) of a healthy subject, and methods for effecting such adjustments.

Claims

1. A method for determining whether a vertebrate subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises the steps of:

a. measuring the prolactin blood level of the subject at spaced apart intervals during the vertebrate subject'"'"'s waking hours and during the vertebrate subject'"'"'s sleeptime over a time period of at least about 24 hours to generate a prolactin profile for said vertebrate subject;

b. comparing said prolactin profile to a predetermined standard prolactin profile of healthy subjects of the same sex and species; and

c. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime.

2. The method of claim 1 wherein it is determined that said subject should be administered a prolactin stimulator.

3. The method of claim 1 wherein it is determined that said subject should be administered a prolactin inhibitor.

4. A method for determining whether a vertebrate subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises the steps of:

a. measuring the prolactin blood level of the subject at spaced apart intervals during the subject'"'"'s waking hours and during the subject'"'"'s sleeptime over a time period of at least about 24 hours to generate a prolactin profile for said subject;

b. comparing the prolactin profile to a predetermined standard prolactin profile for healthy subjects of the same sex; and

c. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime.

5. The method of claim 4 wherein said subject suffers from Type II diabetes.

6. The method of claim 4 wherein said subject suffers from obesity.

7. The method of claim 4 wherein said subject suffers from hyperlipidemia.

8. The method of claim 4 wherein it is determined that said subject should be administered a prolactin stimulator.

9. The method of claim 4 wherein it is determined that said subject should be administered a prolactin inhibitor.

10. The method of claim 4 wherein it is determined that said subject should be administered both a prolactin stimulator and a prolactin inhibitor.

11. A method for determining whether a vertebrate subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises the steps of:

a. comparing a prolactin profile of said subjects being tested that has been compiled over a predetermined period of about 24 hours to a predetermined standard prolactin profile for healthy human subjects; and

b. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime.

12. The method of claim 11 wherein said subject suffers from Type II diabetes.

13. The method of claim 11 wherein said subject suffers from obesity.

14. The method of claim 11 wherein said subject suffers from hyperlipidemia.

15. A method for determining whether a vertebrate subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises the steps of:

comparing a prolactin profile of said subject being tested, said profile having been determined within a period of time of about 24 hours, to a predetermined standard prolactin profile for healthy individuals; and

b. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime.

16. The method of claim 15 wherein said subject suffers from Type II diabetes.

17. The method of claim 15 wherein said subject suffers from obesity.

18. The method of claim 15 wherein said subject suffers from hyperlipidemia.

19. A method for normalizing the daily prolactin rhythm in a subject having an abnormal prolactin daily rhythm which comprises the steps of:

comparing the prolactin profile of said subject to the prolactin profile of healthy subjects of the same species and sex; and

adjusting the prolactin profile of said subject having an abnormal prolactin daily rhythm to generally approach or conform said abnormal rhythm to the prolactin profile of said healthy subjects;

wherein said adjusting step comprises at least one of;

administering to said subject having an abnormal prolactin daily rhythm a predetermined amount of a prolactin inhibitor at a first predetermined time prior to a time at which said subject'"'"'s daytime prolactin level is higher than said healthy subjects'"'"' prolactin level by more than 1 standard error of the mean; and

administering to said subject having an abnormal prolactin daily rhythm a predetermined amount of a prolactin stimulator at a second predetermined time prior to a time at which said subject'"'"'s sleeptime prolactin level is lower than said healthy human subjects'"'"' prolactin level by at least 1 standard error of the mean.

20. The method of claim 19 wherein said subject suffers from Type II diabetes.

21. The method of claim 19 wherein said subject suffers from obesity.

22. The method of claim 19 wherein said subject suffers from hyperlipidemia.

23. The method of claim 19 wherein said prolactin inhibitor is bromocriptine.

24. The method of claim 19 wherein said prolactin stimulator is metoclopramide.

25. The method of claim 20 wherein said prolactin inhibitor is bromocriptine.

26. The method of claim 20 wherein said prolactin stimulator is metoclopramide.

27. The method of claim 19 wherein said prolactin stimulator is 5-hydroxytryptophan.

28. The method of claim 20 wherein said prolactin stimulator is 5-hydroxytryptophan.

29. A method for determining administration that will cause an abnormal daily prolactin rhythm of a patient to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises:

a. comparing the prolactin profile of said patient to a predetermined standard prolactin profile for normal subjects;

b. determining that said patient should be administered a prolactin inhibitor in the event that the patient'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

c. selecting a time for administration of said prolactin inhibitor that is no later than the time at which the waking hours prolactin level of said patient reaches the highest waking hours level; and

d. selecting the amount of said prolactin inhibitor to be administered to said patient so that the prolactin level of said patient at any time during waking hours is not greater than 1 standard error of the mean above the prolactin level of said healthy subjects.

30. The method of claim 29 wherein said subject suffers from Type II diabetes.

31. The method of claim 29 wherein said subject suffers from obesity.

32. The method of claim 29 wherein said subject suffers from hyperlipidemia.

33. The method of claim 29 wherein said prolactin inhibitor is bromocriptine.

34. The method of claim 30 wherein said prolactin inhibitor is bromocriptine.

35. A method for determining administration that will cause an abnormal daily prolactin rhythm of a subject to approach or conform to the daily prolactin rhythm of a healthy subject, comprising:

a. comparing the prolactin profile of said subject having an abnormal prolactin rhythm to a predetermined standard prolactin profile for healthy subjects;

b. determining that said subject having an abnormal prolactin rhythm is in need of a prolactin stimulator by ascertaining that the prolactin level of said subject at any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime;

c. selecting the timing of administration of said prolactin stimulator to said subject having an abnormal prolactin rhythm to be prior to the time at which the sleeptime prolactin level reaches its peak in healthy subjects; and

d. selecting an amount of said prolactin stimulator to be administered to said subject having an abnormal prolactin rhythm such that the prolactin level of said subject at any time during sleeptime is no lower than 1 standard error of the mean below the normal prolactin profile of said healthy subjects during sleeptime.

36. The method of claim 35 wherein said subject suffers from Type II diabetes.

37. The method of claim 35 wherein said subject suffers from obesity.

38. The method of claim 35 wherein said subject suffers from hyperlipidemia.

39. The method of claim 35 wherein said prolactin stimulator is metoclopramide.

40. The method of claim 36 wherein said prolactin stimulator is metoclopramide.

41. The method of claim 35 wherein said prolactin stimulator is 5-hydroxytryptophan.

42. The method of claim 36 wherein said prolactin stimulator is 5-hydroxytryptophan.

43. A method for determining whether a human subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, comprising:

a. collecting a plurality of blood samples from said human subject at spaced apart time intervals within a period of time of about 24 hours;

b. measuring the prolactin content of each of said samples;

c. plotting the prolactin content of each of said samples against the time at which said sample was collected during said time period to generate a data point;

d. generating a prolactin profile by connecting each of said data points with the adjacent data point immediately following it;

e. comparing said prolactin profile to a predetermined standard prolactin profile for healthy subjects; and

f. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subjects during sleeptime.

44. The method of claim 43 wherein said subject suffers from Type II diabetes.

45. The method of claim 43 wherein said subject suffers from obesity.

46. The method of claim 43 wherein said subject suffers from hyperlipidemia.

47. A method for determining whether a human subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm, which comprises the steps of:

a. measuring the prolactin blood level of the subject at spaced apart intervals during the subject'"'"'s waking hours and during the subject'"'"'s sleeptime over a time period of at least about 24 hours to generate a prolactin profile for said subject;

b. comparing said prolactin profile to a predetermined standard prolactin profile of healthy subjects of the same sex; and

c. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of the normal control of FIG. 1, if said subject is a male, or the normal control of FIG. 3, if said subject is a female, by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the prolactin level of healthy subjects of the same sex as said subject.

48. A method for determining whether a human subject is in need of administration of a prolactin inhibitor or prolactin stimulator that will cause an abnormal daily prolactin rhythm to approach or conform to a healthy subject'"'"'s daily prolactin rhythm which comprises:

a. determining prolactin levels in blood samples that were taken from said subject over a time period of at least about 24 hours to generate a prolactin profile for said subject;

b. comparing said prolactin profile to a predetermined standard prolactin profile for healthy human subjects;

c. determining that

(i) said subject should be administered a prolactin inhibitor in the event that the subject'"'"'s prolactin level at any time during waking hours exceeds the prolactin level of healthy subjects during waking hours by more than 1 standard error of the mean;

or that

(ii) said subject should be administered a prolactin stimulator in the event that the subject'"'"'s prolactin level any time during sleeptime is at least 1 standard error of the mean lower than the normal prolactin level of said healthy subject during sleeptime.