Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-24
2001-08-14
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000, C514S012200, C514S178000, C514S179000
Reexamination Certificate
active
06274582
ABSTRACT:
The present invention relates to the prevention and treatment of Metabolic Syndrome. More particularly, the invention relates to medicaments, preparations and treatments comprising cortisol synthesis inhibitors and growth hormone for treating the conditions which comprise the Metabolic Syndrome.
In both men and women, visceral (intra-abdominal) fat accumulation is associated with an increased risk of the development of non-insulin dependent diabetes, myocardial infarction, stroke and other arteriosclerotic diseases and their associated risk factors, including insulin resistance, elevated blood lipids, glucose and hypertension. The clustering of these risk factors has been designated ‘Metabolic Syndrome’, also called ‘Syndrome X’, the ‘Insulin Resistance Syndrome’ or the ‘Deadly Quartet’. This syndrome is also characterised by one or more endocrine disturbances and is therefore also called ‘Neuro-endocrine Syndrome’ (Marin, P. Neuroendocrine News, 21(3) 1996, 2). These disturbances include low serum levels of sex steroids (testosterone in men, and estrogens in women), signs of a decreased action of growth hormone, and an excessive secretion of cortisol. The latter has been shown clinically as a major causative process for the development of Metabolic Syndrome as demonstrated by successful treatment with the cortisol synthesis inhibitor ketoconazole (WO 96/04912).
Conditions related to Metabolic Syndrome include diabetes mellitus type II (IDDM), non-insulin dependent diabetes (NIDDM), myocardial infarction, stroke and other arteriosclerotic diseases as well as the risk factors for these diseases, insulin resistance in general, abdominal obesity caused by accumulation of intra-abdominal fat, elevated serum lipids, and raised diastolic and/or systolic blood pressure.
While cortisol synthesis inhibitors such as ketoconazole are a valuable means for treatment of the aforesaid conditions, there is always scope for further improvement in the prevention and treatment of the conditions generally known as or symptomatic of Metabolic Syndrome. Certain known inhibitors exhibit undesired side-effects at therapeutically effective doses and it is an aim of researchers and doctors alike to improve the efficacy of a treatment and/or lower the amount of an active ingredient which must be administered to achieve a particular effect.
The present invention accordingly seeks to provide an effective method for the prevention and treatment of the conditions commonly known as Metabolic Syndrome.
It has now been found that an effective treatment of Metabolic Syndrome and/or the symptoms or conditions associated therewith can be achieved by co-administration of a cortisol synthesis inhibitor and growth hormone.
Thus, according to one aspect, the present invention provides a method of combatting Metabolic Syndrome in a mammal, which method comprises administering a cortisol synthesis inhibitor and growth hormone to said mammal in amounts effective to combat the clinical manifestations of Metabolic Syndrome.
The term “combatting” as used herein includes both therapeutic treatment and prophylaxis (preventative treatment), and hence methods of treating and preventing Metabolic Syndrome are encompassed by the present invention.
The term “Metabolic Syndrome” is used herein to refer to the accumulation of visceral fat and the risk factors associated therewith, as well as the endocrine disturbances listed above which characterise the Syndrome. The term is also used to refer to the conditions related to Metabolic Syndrome, IDDM, NIDDM etc. as discussed above.
The steroid glucocorticoid hormone cortisol is synthesised in the adrenal glands from pregnenolone via progesterone and is itself involved in the metabolism of proteins, carbohydrates and lipids in most tissues and in the suppression of inflammatory reactions. ‘Cortisol synthesis inhibitors’ should be understood as agents reducing but not completely blocking the synthesis of cortisol by the human body. They are administered with the aim of reducing increased cortisol levels to normal or slightly sub-normal levels.
A large number of agents are known to suppress glucocorticoid production or inhibit their receptor binding in humans: sodium valporate (Aggernaes, H. et al. Acta Psychiatr. Scand. (1988) 77 170-174); Enkephalins and their synthetic analogues (Stubbs, W.A. et al. The Lancet (1978) 1225-1227); Opioids such as loperamide, commercially available under the trademark IMODIUM from Janssen Pharmaceutica N.V.; the antihypertensive drug Clonidine (Slowinska-Srzednicka, J. et al. European Journal of Clinical Pharmacology (1988) 35 115-121); Oxytocin (Legros, J.J. et al. Endocrinologica (1987) 114 345-349) and Mifepristone, known as RU 486 or RU 38486 available from RousselUclaf.
Any of the above agents or any of the large number of cortisol synthesis inhibitors known in the art may be used as cortisol synthesis inhibitors according to the present invention. However, the majority of known cortisol synthesis inhibitors are administered topically to fight infections by fungi; their adverse reactions and/or low absorption in the gastro-intestinal tract, in general, make them less attractive for use in the present invention. The present invention permits the oral administration of a cortisol synthesis inhibitor. Treatments and medicaments comprising the cortisol synthesis inhibitor ketoconazole were found particularly effective in the present invention by virtue, in particular, of its low toxicity and lack of other adverse effects. The particular mechanism of action of s ketoconazole results in the synthesis instead of normal cortisol of a substance known as ‘crippled cortisol’, which lacks the biological function of native cortisol. Derivatives of ketoconazole may also be used.
Other useful cortisol synthesis inhibitors include econazole (Squibb, U.K.) and miconazole (Janssen, Belgium) and their derivatives. Ketoconazole, econazole or miconazole in conjunction with growth hormone thus represent preferred embodiments of the present invention.
Human growth hormone is a protein having 191 amino acids and a molecular weight of 22,000 daltons and is produced in the anterior lobe of the pituitary gland or adenohypophysis. The hormone is synthesised in the form of the precursor and once processed to the active form is secreted from the cell. The mode of action of human Growth Hormone (hGH) is not well understood, but it stimulates the liver to produce somatomedin-1, which in turn causes growth of muscle and bone; stimulation of fat, muscle and cartilage cell differentiation, as well as affecting lipid and carbohydrate metabolism. Analogues of growth hormone are also known in other species, and any mammalian growth hormone (GH) or derivative thereof may be used.
Extracted and purified GH can be used in the. present invention but the use of recombinant GH (rGH) is preferred, especially recombinant human growth hormone (rhGH). Such recombination techniques are known in the art; U.S. Pat. No. 5,268,277 for example, describes a process for producing human growth hormone identical to natural human growth from a transformed
Bacillus subtilis
culture.
The term “growth hormone” includes also, in addition to native sequences, sequence- and chemicallymodified variants of the mammalian peptide, particularly the 191 amino acid hGH. All peptide fragments incorporating amino substitutions, additions and deletions to the full growth hormone are encompassed by the term, provided they retain, preferably all or substantially all, the biological activity of the native growth hormone. Assays for growth hormone activity are known in the art and could be based on the differentiation of pre-adipocytes to adipocytes [Green, H. et al., Differentiation 1985;29: 195-198]. Any recombinant growth hormone peptides should preferably have at least a 65% homology with the native peptide.
The Examples which follow give an indication of the clinically observable symptoms and conditions associated with Metabolic Syndrome which can be combatted or “treated” according to the present invention an
Botts Baker
Cook Rebecca
Cortendo AB
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