Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/27—Growth hormone [GH], i.e. somatotropin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• This invention relates to a treatment that prevents or delays the onset of hypertension or high blood pressure in mammals, in particular those predisposed to such conditions.
• hypertension develops from unknown cause.
• This form of hypertension is often referred to as essential or primary hypertension to distinguish it from secondary hypertension that arises from known cause (i.e., due to specific illness or medical treatment) (Kaplan 1998).
• Hypertension or high blood pressure, affects about 50 million Americans and is a major risk factor for coronary heart disease, stroke, and heart failure (Centers for Disease Control and Prevention and National Institutes of Health "Heart Disease and Stroke” Healthy People 2010-Conference Edition, November 1999). Of those with high blood pressure, 36% do not realize they have it; thus, hypertension has been referred to as a "silent killer".
• the prevalence of high blood pressure increases with age. However, in older age groups the disease is usually relatively mild compared to that in young adults where it is often more severe. Treatment of high blood pressure can prolong life.
• the present invention is unexpected given our previous observation that adult offspring from ad-libitum control fed mothers showed no significant change in systolic blood pressure following treatment, and that reduction in systolic blood pressure was most marked in programmed animals already exhibiting symptoms of hypertension (Vickers et al WO 00/30588). Ad-libitum and programmed offspring treated with vehicle only showed no significant change in the systolic blood pressure exhibited (Vickers et al WO 00/30588).
• the present invention provides a method of preventing or delaying the onset of hypertension in a mammal, comprising the step of administering to the mammal an effective amount of, or increasing the effective concentration of, growth hormone, an analog thereof, or a functionally equivalent ligand, prior to onset of hypertension or symptoms thereof.
• the mammal is a pre-pubescent or adult mammal prior to the onset of hypertension or symptoms thereof.
• the mammal is human.
• the mammal is predisposed to essential or primary hypertension.
• the mammal is predisposed to essential or primary hypertension as a consequence of Intrauterine fetal programming or intrauterine growth retardation.
• the effective concentration of growth hormone, an analog thereof or a functionally equivalent ligand in the mammal is increased through administration of an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity.
• the present invention provides the use of growth hormone, an analog thereof, a functionally equivalent ligand or an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity in the preparation of a medicament for preventing or delaying the onset of hypertension in a mammal.
• the medicament is administered or to be administered to a mammal predisposed to essential or primary hypertension.
• the medicament is administered or to be administered to a mammal predisposed to essential or primary hypertension as a consequence of intrauterine fetal programming or intrauterine growth retardation.
• the medicament is administered or to be administered to pre-pubescent or adult mammals prior to the onset of hypertension or the symptoms thereof.
• the effective amount of growth hormone, an analog thereof, a functionally equivalent ligand or an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity is adtninistered in a pharmaceutically acceptable combination with one or more suitable carriers or excipients.
• the effective amount of growth hormone, an analog thereof, a functionally equivalent ligand or an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity is administered in combination with anti-hypertensive agents.
• anti-hypertensive agents are selected from the group including but not limited to ACE inhibitors or angiotensin II antagonists.
• the ACE inhibitor is selected from a group that includes but is not limited to captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril.
• angiotensin II antagonist is selected from a group that includes but is not limited to candesartan, irbesartan, losartan, telmisartan and valsartan.
• administration is by way of injection, implant, or a ⁇ lministration of a replicable vehicle encoding for said growth hormone, an analog thereof, a functionally equivalent ligand or an agent which either stimulates production of growth hormone or which lessens or prevents inhibition of growth hormone activity.
• the administration is through intravenous, oral, rectal, transdermal and/or nasal route.
• the dosage range of administration of growth hormone, an analog thereof, a functionally equivalent ligand prefferably be from about 0.1 microgram/kilogram/day to about 1 milligram/kilogram/day.
• the dosage range of administration of growth hormone, an analog thereof, a functionally equivalent ligand is from about 2 to about 200 microgram/kilogram day.
• the increase in effective concentration of growth hormone, an analog thereof, a functionally equivalent ligand is from about 2 and to about 200 microgram/kilogram/day.
• Figure 1 is a schematic depicting the timeline of the experimental paradigm. Treatment of young female rats with recombinant bovine growth hormone was initiated at postnatal day 25 administered twice daily until postnatal day 55, when growth hormone treatment was terminated. Rats were monitored for an additional 45 days after treatment (up to postnatal day 100). Systolic blood pressure recordings were taken at postnatal day 55, postnatal day 70, and postnatal day 100.
• Figure 2 is a graphical presentation of the change in blood pressure following growth hormone treatment.
• the nomenclature is as follows: ADCBS, female offspring from dams fed ad-libitum and treated with carbonate buffered saline; ADGH, female offspring from dams fed ad-libitum and treated with growth hormone; UNCBS, female offspring from dams fed 30% ad-libitum and treated with carbonate buffered saline; UNGH, female offspring from dams fed 30% ad- libitum and treated with growth hormone.
• ADCBS female offspring from dams fed ad-libitum and treated with carbonate buffered saline
• ADGH female offspring from dams fed ad-libitum and treated with growth hormone
• UNCBS female offspring from dams fed 30% ad-libitum and treated with carbonate buffered saline
• UNGH female offspring from dams fed 30% ad- libitum and treated with growth hormone.
• intrauterine programming or growth retardation means disordered fetal growth with causes including but not limited to maternal undernutrition, placental insufficiency, endocrine abnormalities and substance abuse.
• analog means a protein which is a variant of growth hormone.
• the growth hormone variants may be produced by insertion, deletion or substitution of one or more amino acids but which retains at least substantial functional equivalency.
• analog includes synthetic analogs of growth hormone.
• the term "functionally equivalent ligand” means an agent that binds to and activates the receptors which growth hormone binds to and activates to give the anti-hypertensive effect.
• the focus of the invention is on a form of treatment that prevents or delays the onset of hypertension.
• the surprising finding, which underlies the present invention, is that in a rodent model of intrauterine programming, administration of growth hormone of fixed duration to a pre-pubescent rat, prior to onset of symptoms, prevents or delays hypertension. More importantly, the prevention or delay of hypertension occurs regardless of whether there has been intrauterine programming or not.
• the benefits of administering growth hormone continue well after treatment has terminated and act to prevent and/or delay the onset of hypertension.
• Such a finding is applicable towards a preventative course of treatment for individuals predisposed to essential ox primary hypertension (i.e., due to family history); towards those individuals who may acquire hypertension due to adverse gestational conditions while still in the womb, known as "fetal or intrauterine programming"; or towards hypertension in general.
• the invention broadly speaking, therefore provides a method of preventing or delaying the onset of hypertension in a mammal. That mammal may be predisposed to essential or primary hypertension or be one who has experienced intrauterine programming or growth retardation. It is however envisaged that the invention will have application in preventing or delaying mammalian hypertension caused by other etiologies, risk factors and environmental effects.
• the principal application of the method of the invention will be to pre-pubescent or adult humans prior to onset of hypertension, although treatment of non- human mammals is in no way excluded.
• the method of the present invention involves administering to a mammal an effective amount of growth hormone, an analog thereof or a functionally equivalent ligand prior to onset of the symptoms of hypertension, to prevent or delay onset of those symptoms.
• growth hormone itself is administered to the mammal.
• the growth hormone can be any mammalian growth hormone that will be known to a person skilled in this art, 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.
• 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.
• 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, i.e. to the administration of growth hormone agonists or secretagogues (substances which effect a direct increase in production of growth hormone).
• agents that stimulate growth hormone and production or lessen or prevent its inhibition include, but are not limited to, 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 hormone within the body).
• GHRP growth hormone releasing peptides
• SRIF somatostatin release inhibitory factor
• 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.
• angiotensin-converting enzyme inhibitors such as quinapriL or angiotensin II antagonists, such as losartan
• the ACE inhibitor may be selected from a group that includes but is not limited to captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril.
• the angiotensin II antagonist may be selected from a group that includes but is not limited to candesartan, irbesartan, losartan, telmisartan and valsartan.
• a replicable vehicle encoding the growth hormone/analog/ligand to the patient.
• a vehicle which may be a modified cell line or virus that expresses growth hormone/analog/ligand within the patient
• Such a vehicle 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 about 0.1 microgram/kilogram/day to about 1 milligram/kilogram/day. A preferred dosage rate would be from approximately about 2 to about 200 microgram/kilogram/day.
• the method of the present invention will be effective in preventing or delaying the onset of hypertension, particularly in individuals predisposed towards this condition.
• the possibility of effective hormonal therapy for the hypertensive population is of immense public health significance.
• Day 1 of pregnancy was determined by the presence of spermatozoa after a vaginal smear. After confirmation of mating, rats were housed individually in standard rat cages containing wood shavings as bedding and with free access to water. All rats were kept in the same room with a constant temperature maintained at 25°C and a 12-h light: 12-h darkness cycle.
• the diet composition was protein 18%, fat 4%, fibre 3%, ash 7%, and carbohydrate 58% (Diet 86, Skellerup Stock Foods, Auckland, New Zealand). Food intake and body weights were recorded daily.
• rbGH bovine growth hormone
• Treatment with recombinant bovine growth hormone (rbGH) commenced on postnatal day 25 and was administered at a dose of 10 microgram/gram bodyweight/day by twice daily subcutaneous injections (8am and 5pm) over a period of 30 days ( Figure 1). Growth hormone treatment was terminated on postnatal day 55 and the animals were monitored until postnatal day 100. Control animals were treated with carbonate buffered saline (CBS, pH 9.4) in place of growth hormone using an identical protocol.
• CBS carbonate buffered saline
• Systolic blood pressures were recorded by tail cuff plethysmography according to the manufacturer's instructions (Blood pressure analyzer IITC, Life Science, Woodland Hills, CA USA). Systolic blood pressures was measured on postnatal days 55, 70, and 100 respectively. Rats were restrained in a clear plastic tube in a warmed room (25-28°C). After the rats had acclimatized (10-15min) the cuff was placed on the tail and inflated to 240 mmHg. Pulses were recorded during deflation at a rate of 3mmHg/sec and reappearance of a pulse was used to determine systolic blood pressure. A minimum of 3 clear systolic blood pressure recordings were taken per animal. Coefficient of variation for repeated measurements was ⁇ 5%.
• Woodall SM Breier BH, Johnston BM, Bassett NS, Barnard R, Gluckman PD (1999) Administration of growth hormone or IGF-1 to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring. J Endocrinol 163: 69-77.

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• 2002
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