Diabetes treatment

Details Diabetes treatment Diabetes treatment

1999-02-04

2001-02-06

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S015800, C514S016700, C514S017400, C514S018700, C514S866000

Reexamination Certificate

active

06184209

ABSTRACT:

CROSS-REFERENCES TO RELATED APPLICATIONS
This patent claims priority to International Application Number is PCT/GN97/00795, filed Mar. 21, 1997; which claims priority to GB Patent Application Serial No. 9606076.9, filed Mar. 22, 1996.
BACKGROUND OF THE INVENTION
a. Field of the Invention
This invention relates to diabetes treatment and is more particularly concerned with diabetes mellitus. The present invention is considered to be suitable for the treatment of either type I (insulin-dependent) or type II (non-insulin-dependent) diabetes mellitus.
b. Description of the Related Art
It has been observed by R. L. Reid et al (“&bgr;-endorphin stimulates the secretion of Insulin and Glucagon in Diabetes Mellitus”, Metabolism, Vol 33, No 3 (March), 1984, pages 197-199) that administration of human &bgr;-endorphin (2.5 mg by intravenous bolus injection) to three subjects with non-insulin dependent diabetes mellitus (type II) induced prompt and simultaneous increments in the plasma concentrations of insulin and glucagon lasting up to 90 minutes and that, in contrast to the hyperglycemic response previously observed in normal subjects following administration of &bgr;-endorphin, these diabetics showed a progressive decline in plasma glucose throughout a three hour study period. However, this progressive decline in plasma glucose was substantially unaffected by the administration of &bgr;-endorphin which took place one hour after the start of the study period.
It has been observed by the inventor that, in normal mice, there are only a small number of &bgr;-endorphin receptors on the muscle fibres, whereas in obese (ob/ob) diabetic mice, there is a dramatically higher density of &bgr;-endorphin receptors on the muscles. The obese (ob/ob) mice inherit diabetes mellitus which resembles type II (non-insulin-dependent) diabetes mellitus seen in humans. In both the human and the mouse with this condition, the muscles are insulin-resistant. The present invention is based on the surprising discovery that blood glucose levels can be reduced by administration of &bgr;-endorphin fragments which do not include the opioid (N-terminal) region of &bgr;-endorphin, and that such fragments act by enhancing the uptake of glucose into the muscle by a non-insulin dependent route .
BRIEF SUMMARY OF THE INVENTION
The invention encompasses a method of treating a patient with diabetes mellitus. The patient is administered an effective amount of a an amino acid sequence having one or more amino acid residues in common with a ten amino acid C-terminal fragment of &bgr;-endorphin, and having one or more amino acid residues different than the C-terminal fragment of &bgr;-endorphin. The peptide comprises no more than 10 amino acid residues, and the fragment has X-Y as the final two amino acid residues at the C-terminal end. The X of X-Y is Gly, Sar, AzGly, Ala, D-Ala, D-Ser or Pro; and the Y is Glu or Gin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention resides in the use of a peptide including an amino acid sequence corresponding to that of an active C-terminal fragment of &bgr;-endorphin or an active analogue of a C-terminal fragment of &bgr;-endorphin, in the manufacture of a medicament for the treatment of diabetes mellitus (type I or II).
The present invention also resides in the use of a peptide including an amino acid sequence corresponding to that of an active C-terminal fragment of &bgr;-endorphin or an active analogue of a C-terminal fragment of &bgr;-endorphin, in the manufacture of a medicament for increasing uptake of blood glucose into muscle.
The term “active” refers to the activity for the uses intended in the present invention.
The peptide preferably has &bgr;-endorphin 31 (Glu or Gin) as the C-terminal amino acid residue. More preferably, the peptide includes or consists of at least &bgr;-endorphin 30-31 (Gly-Glu or Gly-Gln), even more preferably &bgr;-endorphin 29-31 (Lys-Gly-Glu or Lys-Gly-Gln), and most preferably &bgr;-endorphin 28-31 (Lys-Lys-Gly-Glu (SEQ ID NO:2) or Lys-Lys-Gly-Gln (SEQ ID NO:1)). However, it is within the scope of the present invention for the peptide to include further amino acid residues in its N-terminal region. For example, the peptide may be &bgr;-endorphin 22-31, 23-31, 24-31, 25-31, 26-31 or 27-31.
The peptide preferably has no more than 10 amino acid residues, but more preferably has less, eg up to nine, eight, seven, six or five amino acid residues; or even more preferably, less than six amino acid residues, Thus, most preferably, the peptide is a di-, tri-, tetra- or penta-peptide.
The use of active analogues of the above-mentioned peptides is also within the scope of the present invention. In particular, stabilised analogues thereof are preferred wherein one or more of the following substitutions may be made:
Amino Acid
Substituting moiety
28 (Lys)
Orn, MeLys, des-NH
2
, Nle or D-Lys
29 (Lys)
Orn, D-Lys, MeLys or Nle
30 (Gly)
Sar, AzGly, Ala, D-Ala, D-Ser or Pro
31 (Glu)
Gln
(wherein 28 to 31 relate to the numbering for the corresponding amino acids in the &bgr;-endorphin amino acid sequence).
One of hydrogen atoms at the N-terminal end of the peptide (preferably the 28-N-terminal end of &bgr;-endorphin 28-31) may be substituted by P-Ala, HOOC(CH
2
)
2
CO—, Tyr, benzylcarbonyl, maionyl, acetyl, fatty acid acyl or other acyl group. Hereinafter, these acyl groups will be referred to as Ac.
Of such analogues, those where amino acid 30 (Gly) is replaced by Sar, those where amino acid 29 (Lys) is replaced by D-Lys, and those where the N-terminal (28) end of the fragment is Ac-Lys, are preferred. Particularly preferred is the stabilised analogue in which all three substitutions have been made, i.e. Ac-Lys-D-Lys-Sar-Glu, most preferably CH
3
CO-Lys-D-Lys-Sar-Glu or CH
3
CO-Lys-D-Lys-Sar-Gln.
Furthermore, the above peptides are small molecules compared to insulin (or &bgr;-endorphin). The stabilised analogues include those which are stable to proteolytic digestion and therefore have a relatively long half-life in the blood enabling their actions to be long lasting. Their resistance to proteolytic digestion may also make them effective via oral administration. In addition, the peptides usable in the present invention do not contain the opioid amino acid sequence and therefore are not likely to have those side effects of &bgr;-endorphin which are due to its opioid actions.
&bgr;-endorphin 28-31 is a per se known compound and is sometimes referred to as melanotrophin-potentiating factor (MPF). It is a putative neurotrophic agent. Stabilised analogues of MPF, such as Ac-Lys-D-Lys-SarGlu, are also known, see for example J. S. Morley et al in “MPF analogue with high stability to proteolysis”, Neuropeptides 2:109-114, 1981 and D. M. Ensor et al, Brain Research, 610 (1993), pages 166-168. The latter report MPF and Ac-Lys-D-Lys-Sar-Glu as causing significant reductions on the turning response of dopamine-depleted rats to D-amphetamine. MPF and certain analogues thereof are also reported as promoting urodele limb regeneration (see J. S. Morley et al, Life Sciences, Vol. 45, pages 1341-1347).
The peptides used in the present invention can be administered intravenously, subcutaneously or intramuscularly, although stabilised analogues, such as Ac-Lys-D-Lys-Sar-Glu, may possibly be administered orally.
The peptides used in the present invention can be synthesised in a per se known manner, for example by use of the solid-phase method of R. Bruce Merrifield where amino acids are added stepwise to a growing peptide chain linked to an insoluble resin matrix, using (i) dicyclohexylcarbodiimide to activate the carboxyl groups to be subjected to peptidisation at the appropriate stages, and (ii) a t-butyloxycarbonyl group and trifluoroacetic acid respectively to block and deblock the amino groups to be protected at the appropriate stages during synthesis.
In the case of the N-substituted peptides noted above, N-substitution may also be effected in a manner known per se by a simple peptidisation reaction with appropriate blocking, if necessary, depending upon the nature of the subst

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