Link:  Pharm/Biotech Resources

Title:  Treatment of hypertension using growth hormone in mammals subjected to fetal programming

United States Patent:  6,933,278

Issued:  August 23, 2005

Inventors:  Vickers; Mark H. (Auckland, NZ); Breier; Bernhard H. H. (Auckland, NZ); Ikenasio; Betina A. (Auckland, NZ)

Assignee:  Auckland Uniservices Limited (Auckland, NZ)

Appl. No.:  856704

Filed:  November 26, 1999

PCT Filed:  November 26, 1999

PCT NO:  PCT/NZ99/00198

371 Date:  July 18, 2001

102(e) Date:  July 18, 2001

PCT PUB.NO.:  WO00/30588

PCT PUB. Date:  June 2, 2000

Embodiments of this invention include methods for decreasing hypertension in mammals subjected to adverse cardiovascular fetal programming or a long-term adverse postnatal environment. Fetal programming can result from adverse intrauterine conditions, including growth retardation or undernutrition. Adverse postnatal environments include either hypocaloric or hypercaloric nutrition. Decreasing hypertension is such mammals can be accomplished by administering an agent that increases the effective amount of a growth hormone. Such agents can include a growth hormone, an agent that increases the effective concentration of a growth hormone in the mammal, or an agent that decreases inhibition of a growth hormone's effects. Such agents can be used either alone, or in combination with other anti-hypertensive agents.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect the present invention provides a method of treating hypertension in a mammal, which has experienced intrauterine under nutrition and/or growth retardation or an adverse post-natal environment, the method comprising the step of administering to the mammal an effective amount of an agent, wherein the agent is a ligand which binds to, and activates, the growth hormone receptor.

In another aspect, the present invention provides a method of treating hypertension in a mammal, which has experienced intrauterine under nutrition and/or growth retardation or an adverse post-natal environment, the method comprising the step of administering to the mammal an effective amount of growth hormone, an analog thereof, or a functionally equivalent ligand.

Generally, the hypertensive state of the mammal will be the result of intrauterine fetal programming, or of an unfavorable/adverse postnatal environment (eg. a hypercaloric diet). However, any mammal with hypertension can be treated in accordance with the above methods.

Preferably, the mammal to be treated is an adult mammal.

As used herein, the term "intrauterine undernutrition or growth retardation" means disordered fetal growth with causes which include maternal undernutrition, placental insufficiency, endocrine abnormalities and substance abuse, as evidenced by a relatively low birth weight.

As used herein, "analog" means a protein which is a variant of growth hormone through insertion, deletion or substitution of one or more amino acids but which retains at least substantial functional equivalency.

The term "functionally equivalent ligand" means an agent which binds to and activates the receptors which growth hormone binds to and activates to give the anti-hypertensive effect.

In a further aspect, the invention provides a method of treating hypertension in a mammal, which has experienced intrauterine under nutrition and/or growth retardation or an adverse post-natal environment, the method comprising the step of increasing the effective concentration of growth hormone, an analog thereof or a functionally equivalent ligand in the mammal.

The method is particularly suitable for treating a mammal which has experienced either an adverse fetal environment, an adverse postnatal environment, or both.

Preferably, the effective concentration of said growth hormone analog or ligand is increased through direct administration.

Preferably, the effective concentration of growth hormone is increased through direct administration of growth hormone.

Alternatively, the effective concentration of growth hormone is increased through administration of an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity.

Preferably, the mammal is an adult human.

In a further aspect, the present invention provides the use of an agent selected from growth hormone, an analog thereof or a functionally equivalent ligand in the preparation of a medicament for treating hypertension in a mammal, which has experienced intrauterine under nutrition and/or growth retardation or an adverse post-natal environment.

In yet a further aspect, the invention provides the use, in the preparation of a medicament for treating hypertension in a mammal, which has experienced intrauterine under nutrition and/or growth retardation or an adverse post-natal environment, of an agent which either stimulates production of growth hormone or which lessons or prevents inhibition of growth hormone activity.

DESCRIPTION OF THE INVENTION

The focus of the invention is on the treatment of hypertension. It is particularly on the treatment of hypertension in a subset of the adult population. The applicant's surprising finding, which underlies the present invention, is that administration of growth hormone to an adult mammal with hypertension can reduce systolic blood pressure. This is particularly true for mammals which have been subject as a fetus to adverse cardiovascular programming during pregnancy or which have undergone intrauterine growth retardation (IUGR), and have therefore been "programmed" to subsequently develop hypertension.

This finding with respect to growth hormone is unexpected given the previous reports associating an increase in systolic blood pressure with long-term exposure to endogenous growth hormone in acromegalics (Sacca. L., et al., Growth Hormone and the Heart Endocrine Reviews, Vol 15, No. 5, 555-573 [1994]) and low systolic blood pressure after a long-term lack of exposure to endogenous growth hormone in growth hormone deficient adults (Sacca, L., et al., Growth Hormone and the Heart. Endocrine Reviews, Vol 15, No. 5, 555-573 [1994]). In other studies, growth hormone has been reported to decrease diastolic blood pressure (Johannsson, G., et al., Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism and reduces diastolic blood pressure. Journal of Clinical Endocrinology and Metabolism, Vol 82, No. 3 727-734 (1997)), while having no effect on systolic pressure.

The invention therefore provides a method of treating hypertension in a mammal, such as a mammal which has experienced intrauterine growth retardation or under-nutrition or which has experienced a long term adverse postnatal environment such as hypocaloric or hypercaloric nutrition. It is however envisaged that the invention will have application in treating mammalian hypertension caused by other aetiologies, risk factors and environmental effects.

It is also envisaged that the principal application of the method of the invention will be to adult humans although treatment of pre-adult and non-human mammals is in no way excluded.

In a preferred aspect, the method of the present invention involves administering to the mammal an effective amount of growth hormone, an analog thereof or a functionally equivalent ligand. In a preferred embodiment, growth hormone itself is administered to the mammal.

The growth hormone can be any mammalian growth hormone, with examples being human growth hormone, bovine growth hormone, rat growth hormone and porcine growth hormone. It is however preferred that the growth hormone employed be human growth hormone where the mammal is a human.

The growth hormone which is used in this invention can be obtained from any commercial source.

In addition to growth hormone itself, the use of analogs of growth hormone or functionally equivalent ligands of growth hormone is contemplated.

A protein is a functional equivalent of another protein for a specific function if the equivalent protein is immunologically cross-reactive with, and has at least substantially the same function as, the original protein. The equivalent can be, for example, a fragment of the protein, a fusion of the protein with another protein or carrier, or a fusion of a fragment with additional amino acids. For example, it is possible to substitute amino acids in a sequence with equivalent amino acids using conventional techniques. Groups of amino acids normally held to be equivalent are:

It will also be appreciated that the present invention also extends to the administration of an agent which either stimulates production of growth hormone, or which lessens or prevents inhibition of growth hormone activity, ie to the administration of growth hormone agonists or secretagogues (substances which effect a direct increase in production of growth hormone).

Examples of agents which stimulate growth hormone and production or lessen or prevent its inhibition include growth hormone releasing peptides (GHRP) such as GHRP-1, GHRP-2, GHRP-6, hexarelin, G-7039, G-7502, L-692,429, L-692,585, L-163,191 or growth hormone releasing hormone (GHRH) or inhibitors of growth hormone antagonists (substances which bind growth hormone or otherwise prevent or reduce the action of growth homone within the body). These latter compounds exert an indirect effect on effective growth hormone concentrations through the removal of an inhibitory mechanism, and include substances such as somatostatin release inhibitory factor (SRIF).

The active agent can be administered using any suitable route. Where growth hormone is the active compound to be administered, it will generally be administered as an injectable formulation, in combination with one or more suitable carriers or excipients. Those persons skilled in the art will appreciate how suitable formulations can be prepared.

The active agent can also be administered in combination. For example, a combination of growth hormone and other conventional anti-hypertensive agent(s), for example ACE (angiotensin-converting enzyme) inhibitors such as quinapril, is also contemplated.

Another possibility is administration of a replicable vehicle encoding the growth hormone/analog/ligand to the patient. Such a vehicle (which may be a modified cell line or virus which expresses growth hormone/analog/ligand within the patient) could have application in increasing the concentration of the active compound within the patient for a prolonged period. Such a vehicle could well form part of an implant.

Dosage levels will be formulation dependent. However, by way of example, the recommended dosage rate of growth hormone formulated for injection would be in the range of 0.1 ug/kg/day to 1 mg/kg/day. A preferred rate would be from approximately 2 to 200 ug/kg/day.
 

Claim 1 of 17 Claims

1. A method of treating hypertension in a mammal, comprising administering to the mammal an amount of growth hormone sufficient to reduce systolic blood pressure, wherein said mammal has a history of one or more of the following: low birth weight, intrauterine undernutrition, growth retardation, hypercaloric diet, hypocaloric diet, placental insufficiency or substance abuse; wherein said mammal does not have a growth hormone deficiency.

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