USE OF ANABOLIC STEROID DERIVATIVES IN THE TREATMENT OF CHRONIC HEART FAILURE

Abstract: A method of preventing or reducing muscle loss or weakness associated with chronic heart failure which comprises administering to a patient having chronic heart failure a therapeutically effective amount of dehydroepiandrosterone (DHEA) or an analogue thereof.

Description: SE OF ANABOLIC STEROID DERIVATIVES IN THE TREATMENT OF CHRONIC HEART FAILURE The present invention relates to a method of treatment of patients with chronic heart failure. Chronic heart failure, also called congestive heart failure, (hereinafter referred to as CHF) is a progressive disease in which the heart is increasingly unable to pump an adequate volume of blood. When the heart starts to fail, the rest of the body compensates and such mechanisms eventually result in CHF. CHF is currently suffered by 1-2% of the population of Western countries. Conventionally treatments have centered on the heart and related systems. For example, improvement of the heart's pumping capacity by administration of an inotropic agent, such as digitalis and urethane-containing aminosteroid compounds as mentioned in WO95/08559; reduction of the heart's workload by rest and/or by administration of vasodilators such as captopril; and controlling sodium and water retention by a low sodium diet or administration of a diuretic such as thiazide. We have taken a different approach and have looked at peripheral muscle mass. This approach provides a number of advantages. According to a first aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for increasing peak VO 2 in a patient with CHF. In other words the present invention relates to a method of increasing peak VO 2 in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. CHF is associated with lack of blood and nutrients to parts of the body, i.e. reduced peripheral blood flow at rest and impaired cardiac output during exercise. We have found that this triggers secondary effects which then lead to muscle loss. This reduction in muscle itself leads to less O 2 consumption. Whilst not wishing to be bound by any theory it is believed that by building up peripheral muscles, not only does one improve the lifestyle of the patient, but that one also increases O 2 consumption. Any increase in O 2 consumption may lead to a mortality benefit. Details of exercise testing for use in measuring peak VO 2 can be found in Chaitman B, "Exercise Stress Testing", Ch 6, in "Heart Disease: A Textbook of Cardiovascular Medicine", Ed Braunwald E, 4th Edn. (1992) WB Saunders Company. According to a second aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for preventing or reducing peripheral muscle loss or weakness in a patient with CHF. In other words the present invention relates to a method of preventing or reducing peripheral muscle loss or weakness in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. This is particularly advantageous as there has previously been no specific treatment for the muscle wasting in chronic heart failure. By "peripheral muscle" we mean muscle outside of heart muscle. Prevention of reduction in peripheral muscle loss can be determined by comparing muscle mass (size) before treatment with that after treatment. Urinary nitrogen levels may also be monitored as a decrease in urinary nitrogen level is indicative of a decrease in muscle mass loss. Body water levels may also be determined to confirm that there is a true prevention or reduction of muscle loss. According to a third aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for reducing VENCO 2 in a patient with CHF. In other words the present invention relates to a method of reducing VENCO 2 in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. VENCO 2 indicates the total amount of ventilated air relative to exhaled CO 2 . An increase in VENCO 2 is a strong marker of impaired survival in CHF (Chua TP et al, Clinical correlates and prognostic significance of the ventilatory response to exercise in CHF, J Am Coll Cardiol, 1997, 29, 1585-1590). Details of testing for VE/CO 2 can be found in this reference. According to a fourth aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for reducing catabolic/anabolic imbalance in a patient with CHF. In other words the present invention relates to a method of reducing catabolic/anabolic imbalance in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. We have found that CHF, particularly cachetic CHF, is more closely associated with a catabolic/anabolic imbalance than conventional measures of severity of CHF (Anker SD et al Hormonal changes and catabolic/anabolic imbalance in CHF, Circulation, 1997, 96, 526-534). Changes in the catabolic/anabolic imbalance can be measured using the tests outlined in this reference. According to a fifth aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for increasing protein metabolism in a patient with CHF. In other words the present invention relates to a method of increasing protein metabolism in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. It has been found that patients with wasting as a result of CHF, have in general dramatically reduced adipose tissue, and moderately to severly reduced lean body mass. This is as a result of downregulated protein metabolism, and maintained or increased reliance on fat as an oxidative fuel. Alterations in body composition are frequently associated with chronic illness. The present invention provides a treatment to improve this situation. Protein metabolism can be measured using the stable isotope L-[l- C] leucine. This is described below in more detail. According to a sixth aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for improving muscle quality in patients with CHF. In other words the present invention relates to a method of improving muscle quality in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. Thus not only is there an increase in muscle bulk but there is also an increase in the strength per unit muscle, i.e. muscle function er se is improved. According to a seventh aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for improving exercise capacity in a patient with CHF. In other words the present invention relates to a method of improving exercise capacity in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. Exercise capacity can be measured using a treadmill test as outlined in Chaitman B ibid. In a eighth aspect of the present invention there is provided use of an anabolic steroid in the preparation of a medicament for improving appetite in a patient with CHF. In other words the present invention relates to a method of improving appetite in a patient with CHF which comprises administering to a patient having CHF a therapeutically effective amount of an anabolic steroid. Appetite can be determined by asking a patient to score on a scale 1-10; 10 = best. The present invention was also found to improve a patient's NYHA functional class (i.e. New York Heart Association functional classification of heart disease according to limitation of exercise by shortness of breath or fatigue), and be safe in the sense that no changes could be observed in kidney function nor were any peripheral oedemas observed; if one were observed the diuretic dose could be adjusted accordingly. The present invention also improves symptoms and quality of life and prognosis in a patient with CHF. These are significant benefits. Whilst not wishing to be bound by any theory, we believe that anabolic steroids by exerting their anabolic effects thereby improve body composition, exercise capacity and functional status of patients with muscle wasting due to CHF. The present invention is particularly useful in relation to patients with cachexia. Patients with severe CHF frequently develop significant wasting, i.e. cardiac cachexia. Cardiac cachexia has been recognised for many centuries and once fully developed is accompanied by a mortality up to 50% per year. Little is known about the natural history of wasting in heart failure and the reasons for its development. However studies by the applicant have indicated that peripheral loss of muscle is a general finding in CHF. The wasting in cardiac cachexia affects muscle, fat and bone tissue and is probably mediated by hormonal and immunological mechanisms. A suggested clinical definition of cardiac cachexia, based on documented non-intentional non-oedematous weight loss of >7.5% over a period of at least 6 months, defines a subgroup of CHF patients with profoundly different body composition linked to neurohormonal and immune activation. The present invention is also particularly useful in relation to patients with a hormonal swing from a predominance of anabolic hormone to catabolic hormone control. As indicated above, patients with wasting as a result of chronic heart disease, continue to rely on fat as a fasting metabolic fuel, despite maredly reduced adipose stores. In contrast protein metabolism, in particular whole body protein degerasdation is reduced, resulting in a relative preservation of lean body mass. It is likely that loss of lean tissue contributes to the high mortality observed usually in such groups of patients. We have now found it possible to improve preservation of protein and lean tissue mass. The present invention is additionally particularly useful in relation to patients with CHF which is related to a non-coronary artery disease, for example due to dilated cardiomyopathy. Anabolic steroids are known to those skilled in the art and any suitable anabolic steroid may be used, including precursors and metabolites thereof. Steroids are organic compounds and contain a characteristic ring system: The system may include further rings, may be substituted, contain double bonds and may contain heteroatoms. Also included in the present invention are compounds which do not contain the entire above ring system. Also included are so-called fused ring systems, for example where the ring is not closed between positions 16 and 17. Also included in the present invention are mimics, i.e. compounds having a different structure but having an equivalent functional effect. Such compounds may not be steroidal. Various preferred featureas and embodiments of the present invention will now be described by way of non-limiting example. Illustrative of anabolic steroids useful in the present invention are compounds of the following formula: wherein Z is CHR 7 or N, S or O; Y is CHR'. X, CR l l R 12 R 1 is =O, OH, -C(O)CH 3 , or C(O)CH 2 OH; R 2 , R 3 , R 7 , R 1 ' and R are each independently H, OH, =O, halogen, alkyl, alkynyl or haloalkyl; R is H when the dashed line B is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R is H when the dashed line A is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R 6 is =O, OH, sulfamate, -O-SO 3 H, a sulfatide group of formula (II) a phosphatide group of formula (III) 0 q wherein each of R and R is independently alkyl, a glucuronide group of formula (IV) a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, (X) n -phenyl-alkenyl or -CO- R 10 , wherein each X is independently halogen, alkyl, alkenyl, alkoxy, carboxy, nitro, sulfate, sulfonyl, carboxylester or sulfate ester, n is 0, 1, 2 or 3 and R is H, a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, or (X) n -phenyl-alkenyl; or R and R together form a ring which may contain N, S or O; R is H when dashed line C is a double bond; and H or alkyl when the dashed line is a single bond; and R is H or alkyl. The H atom at position 5 may present in the alpha or beta configuration or the compound comprise a mixture of both configurations. The term "sulfamate" as used herein includes an ester of sulfamic acid, or an ester of an N-substituted derivative of sulfamic acid, or a salt thereof. Further details of sulfamate compounds can be found in our patent publication No. WO93/05064. Preferably the anabolic steroid is dehydroepiandrosterone, testosterone or an analogue thereof. Dehydroepiandosterone (hereinafter referred to as DHEA) is produced by the adrenal gland and circulates largely as its water soluble sulfate. DHEA is thought to be sulfated by human sulfotransferases or sulfatases. Such sulfated compounds or DHEA-S may be employed in the present invention. Little is known of DHEA's physiological functions. Many claims have been made for DHEA, including having anti-obesity, anti-cancer and anti-ageing properties. It has also been claimed that taking a DHEA supplement may expand your lifespan and make you more youthful. Additionally it has been claimed that DHEA may have an important role in cognitive memory, and that it protects the brain from Alzheimer's disease and other degenerative nerve disorders. Nestler et al (J. Clin. Endocrinol. Metab. (1988) 66(1), 57-61) and US4920115 mentions the use of DHEA in relation to atherosclerosis, angina, diabetes, obesity and CHF. Separately it is alleged that it reduces body fat mass and increases muscle mass, lowers serum LDL cholesterol levels, lowers serum apoB levels and does not affect tissue sensitivity to insulin; however the only details are in relation to reducing cholesterol and apolipoprotein B in a 25 year old man and insulin resistant women, no reliable indicators of increased muscle mass are given as there is no indication of whether body water content increased instead and they use a very high dose of DHEA (1600mg/d) which is likely to to cause fluid retention at this dose the increased deurinating androgenic effect of DHEA. GB1246639 relates to a C 1-1 carboxylic acid ester of DHEA. Among other things they are mentioned as being suitable for treatment of heart diseases. No further details are given. WO93/16704 relates to a method of combatting cancer comprising administering DHEA at high doses up to 3600mg/kg body weight. It is indicated that it is also necessary to administer ubiquinone to combat heart failure induced by DHEA pointing to the fact that the benfits provided by the present invention are particularly surprising. Illustrative of DHEA and its analogues useful in the present invention are compounds of formula (I): wherein R 1 is =O or OH; R 2 , R 3 , R 5 and R 7 are each independently H, OH, halogen, alkyl or haloalkyl; R 4 is H when the dashed line is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R 6 is =O, OH, sulfamate, a sulfatide group of formula (II) a phosphatide group of formula (III) wherein each of R and R is independently alkyl, a glucuronide group of formula (IV) a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, (X) n -phenyl-alkenyl or -CO- R 10 wherein each X is independently halogen, alkyl, alkenyl, alkoxy, carboxy, nitro, sulfate, sulfonyl, carboxylester or sulfate ester, n is 0, 1 , 2 or 3 and R is H, a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, or (X) n -phenyl-alkenyl; R is H, OH or halogen; and the H atom at position 5 is present in the alpha or beta configuration or the compound comprises a mixture of both configurations. A preferred compound is a compound of formula (V) Preferred compounds according to this formula include DHEA wherein are each OH and the double bond is present; 16 alpha-bromoepiandrosterone wherein R is Br, R is OH and the double bond is present; 16 alpha- fluoroepiandrosterone wherein R is F, R is OH and the double bond is present; etiocholanolone wherein R is H and R is OH and the double bond is absent; dehydroepiandrosterone sulfate wherein R is H, R is OSO 2 OM and M is Na, and the double bond is absent; and dehydroepiandrosterone sulfatide wherein R 2 is H, R 6 is OSO 2 OM and M is a sulfatide group as defined above and the double bond is absent. Preferably the DHEA or DHEA analogue is a halogenated analogue according to formula (V) wherein R is Br, F or Cl and R is OH and the double bond is present, and most preferably wherein R is F and R is OH and the double bond is present. DHEA is available as tablets or capsules and is not known to cause serious side effects. DHEA is a generic drug that is inexpensive (1 month full dose, i.e. 75 mg per day, about £70 in the UK (supplied via IDIS World Medicines), but only about $40 in the USA). Further in the USA, the FDA recently confirmed that DHEA is a food supplement and is freely available in any pharmacy. DHEA and DHEAS are adrenal precursor steroids which are transformed into androgens and/or estrogens in peripheral target tissues. DHEA is a direct anabolic hormone, but it is also converted to testosterone. The application of testosterone previously had the major disadvantage of needing to be injected. However, it is now available as a tablet. DHEA is also converted to dihydrotestosterone. Illustrative of testosterone and its analogues useful in the present invention are compounds of formula (VI): wherein R 1 is =O or OH; R 2 , R 3 , R 4 and R 7 are each independently H, OH, halogen, alkyl or haloalkyl; R 5 is H when the dashed line is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R 6 is =O, OH, sulfamate, a sulfatide group of formula (II) a phosphatide group of formula (III) wherein each of R and R is independently alkyl, a glucuronide group of formula (IV) a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, (X) n -phenyl-alkenyl or -CO- R 10 , wherein each X is independently halogen, alkyl, alkenyl, alkoxy, carboxy, nitro, sulfate, sulfonyl, carboxylester or sulfate ester, n is 0, 1 , 2 or 3 and R is H, a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, or (X) n -phenyl-alkenyl; R is H, OH or halogen; and the H atom at position 5 is present in the alpha or beta configuration or the compound comprises a mixture of both configurations. A preferred compound is a compound of formula (VII) Examples of suitable halogens include, Br, Cl, F and I. Examples of preferred substituents for R 3 , R and R 3 include OH and Br. When any of the substituents is alkyl or contains an alkyl moiety it is preferably C 4 , more preferably C t _| 0 , even more preferably C 1 -6 alkyl. C 1-4 alkyl is especially preferred. When it is part of an alkynyl group it is C 2 _ 10 etc. The substituent may be branched or straight chain. Examples of other preferred anabolic steroids for use in the present invention include oxandrolone, androsterone, androstanediol, androstanediol glucuronide, androstenedione, testolactone, stanozolol, mibolerone, tibolone, trenbolone, Org OD 14, metandienon, anabolin and dana ' zol. These compounds are commercially available. The compounds used in the present invention may be made according to procedures known to those skilled in the art and/or are commercially available. The compounds useful in the present invention may be administered er se or in the form of a pharmaceutically acceptable salt. Such salts will be known to those skilled in the art. The anabolic steroids may, of course, be used in combination. Subjects to be treated by the method of the present invention include both human and animal and are preferably mammal, even more preferably human. Whilst it may be possible for the compounds of the present invention to be administered as the raw agent, it is preferable to present them as a pharmaceutical formulation. Such formulations may comprise at least one an anabolic steroid together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous and rectal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, for example using the technology in accordance with The United States Pharmcopeia. All methods include the step of bringing into association a compound of the present invention as herein defined or a pharmacologically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Formulations for inhalation may be presented in any of the ways known to be effective e.g. metered dose inhalers. Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water-for- injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. The overall dose of the anabolic steroid to provide a therapeutically effective amount in accordance with the present invention will depend upon a particular patient and the mode of administration, and may be determined by a skilled person. Preferably the anabolic steroid is administered to the patient daily for about 2 weeks to 6 months. The compounds of the invention may typically be administered orally or via injection at a dose of from 1 to 200 mg per day, preferably 1 to 100 mg per day, more especially less than lOOmg per day, for example 2.5mg to 75mg, 50mg or 25mg per day. Preferred regimes include 25mg bd (twice daily) (50mg/day) or 25mg od (once daily). Another preferred regime is 25mg tds (three times daily), i.e. 75mg/day. A particularly preferred regime is 1 week at 25mg od then 25mg tds for a total of 12 weeks. CHF is a serious medical condition with significant morbidity and mortality. More particularly CHF indicates a progressive disease in which the hemodynamic capacity as well as the structural integrity of the heart is increasingly compromised. The progression of CHF has been classified into four functional classifications by the NYHA: Class I: Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. Class II: Patients with cardiac disease resulting in slight limitations of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. We have found that most heart failure patients experience muscle loss in the legs. Cachectic patients show significant general lean tissue (muscle proteins), fat (energy reserves) and bone tissue loss (also show osteoporosis). The wasting process may be triggered by severe anabolic/catabolic imbalance and detrimental immune activation and development of general metabolic dysregulation. These patients are also characterised by increased fatiguability, reduced maximal strength and reduced strength per unit muscle. We have also shown that cardiac cachexia is an independent risk factor for impaired survival independent of peak VO 2 (i.e. peak oxygen consumption measured during a symptom limited exercise test) , functional NYHA class, ejection fraction (i.e. fraction of blood that the heart ejects into the circulation during each heart beat (in % of the maximal heart chamber volume), assessed by ultrasound or radionucleotide techniques) and age. Cachectic CHF patients (>7.5% documented weight loss) have a 1.5 year mortality of 50%). Cachetic CHF patients with a peak VO 2 <14ml/kg/min have a 1.5 year mortality of 77% (Anker et al, Lancet 349: 1050-1053). We suggest that cachectic CHF patients are characterised by catabolic/anabolic imbalance. This is supported by the following findings: - catabolic stress hormones like nonadrenaline, adrenaline and cortisol are almost only increased in heart failure patients that are wasted (compared to non-cachectic patients and healthy controls); - anabolic hormones are also altered in these patients: decreased DHEA levels, compared to non-cachetic patients insulin levels are lower in cachetics although both patients groups are similarly insulin resistant, development of growth hormone resistance; growth hormone levels are increased (possibly direct catabolic effects), but the peripheral anabolic mediator IGF-I is decreased, and also growth hormone binding proteins and IGF-binding protein-3 are reduced, total testosterone unchanged (free testosterone is expected to be reduced like DHEA); - there is a pattern of general immune activation in cachectic CHF patients. One therapy for CHF patients has been established based on training. Training is an anabolic treatment, but the therapy was established because it was thought to be good for the heart. The use of growth hormone in CHF patients has been suggested to increase cardiac muscle mass and thereby to improve cardiac performance, but not as an anabolic hormone acting on peripheral muscle. Although it may be useful in the present invention it is not particularly preferred because of the high costs ($500-1000 per month), the necessity to inject the hormones and that in cachetic patients much higher doses might be needed to overcome growth hormone resistance. Currently there is no specific therapy for cachetic CHF patients. The prevalence of cachexia is 16% in our CHF population, but seems to lower (about 10%) in unselected CHF populations. It is believed that the present invention will break the anabolic/catabolic imbalance of the simultaneously acting vicious cycles in these patients and may yield significant therapeutic success. A gain of lean tissue, may lead to increased strength and increased oxygen consumption. Secondly this may trigger increased daily physical activity and improve quality of life, leading to further indirect training, as the patient is able to perform more strenuous activities. Examples 3 CHF patients were studied. The study consists of 2 phases of 12 weeks active treatment and 12 weeks follow-up. To qualify for inclusion in the study a candidate must have satisfied the following criteria: • The patient is male and at least 21 years of age. • The patient has clinical evidence of heart failure: a) reduced ejection fraction (<40%) or cardiomegaly on chest X-ray or left ventricular impairment on echocardiography (left ventricular end-diastolic diameter >60mm), b) stable clinical condition and on medication for at least 1 month prior to the study. • The patient has clinical evidence of body wasting due to CHF, i.e. documented non- intentional, non-oedematous weight loss >7.5% of the previous normal weight over a period of at least 6 months, or patients with a body weight < 90% of ideal in comparison to the Metropolitan Life Insurance tables. • No history of unstable angina, myocardial infarction or stroke within 3 months prior to the study; although patient 1 was subsequently found to have had a stroke more than 1 year prior to the study. • The patient is receiving full conventional medical therapy for heart failure (ACE inhibitor or angiotensin II blocker, diuretics, etc.,). Candidates were excluded from the study if they satisfied any one of the following criteria: • The patient has any life-threatening disease, other than heart failure (including patients with known or suspected myocarditis or with automatic implantable cardioverter/defibrillators). • The patient has an active malignancy of any type, or history of a malignancy (patients who have a history of basal cell carconoma that has been surgically removed are acceptable). Patients with a history of other malignancies that have been surgically removed and who have no evidence of recurrence for at least five years prior to study enrolment are also acceptable. • The patient has had a heart transplant. • The patient is known to have prostatic hyperplasia or to have increased PSA (Prostate Specific Antigen) plasma levels (> 1.5 times of upper limit of normal range). • The patient has drug-treated diabetes mellitus, severe renal disease (S-Creatinine > 300μmol/l), severe liver disease (AS AT or ALAT > 3 times of upper limit of normal range). • The patient has evidence of severe neuro-muscular disease. • The patient has received DHEA or testosterone therapy previously. • The patient has an exercise capacity of > 20ml/kg/min (symptom limited treadmill exercise test). 1 1 • The patient is obese with a body mass index (weight height ) >28kg/min . As the study aims for an anabolic effect on the skeletal musculature, a nitrogen providing food supplement was added to the diet of the patient if necessary according to dietary assessment (here in patient 3). This should promote protein synthesis only if there is an additional hormone stimulus. Hyperalimentation has been reported as not improving the exercise capacity of patients with CHF (Broqvist et al Europ Heart J (1994), 15: 1641- 1650). The nitrogen balance is studied by analyses of 24 hour urine collections that, together with resting gas exchange analysis, allow the basal metabolic rate to be determined (Horber et al Eur J Clin Invest (1996), 26: 279-285). To study body composition, patients underwent DEXA-scanning (i.e. Dual Energy X-ray Absorptiometry) and body impedance measurements (T ANITA, TBF-105). Pharmacology: the substance: DHEA, 1 capsule contains 25mg (generic name Prasterone) route of administration: oral frequency: three times daily dosage: 25 mg od for 1 week, then 25mg tds for a total of 12 weeks. Compliance is monitored by collection and count of tablets. The drug can be obtained from IDIS World Medicines. Protein balance studies - Experimental Protocol and Laboratory Methods Each patient attended the metabolic investigation area following an overnight fast. Body weight was measured on an electronic balance with subjects wearing light clothes and without shoes. Height was assessed using a stadiometer. Bioelectrical impedance analysis was performed in the erect position after urinary voiding using a body fat analyzer TBF-105 (Tanita Coφoration, IL, USA). Lean body mass and fat mass were calculated using equations supplied by the manufacturer of the equipment that were based upon a comparison of densitometric data in a healthy population. Using local anaesthetic an intravenous cannula was inserted into an antecubital fossa vein on each arm. Following the taking of baseline blood and breath samples, a primed, constant intravenous infusion of L-[1-' 3 C] leucine (1 mg/kg, 1 mg/kg/hr, Mass Trace, Somerville, USA) was administered for 180 minutes. The bicarbonate pool was primed with an intravenous bolus of sodium 13 bicarbonate (0.2 mg/kg). Blood and breath samples were taken at 0, 150, 155, 160, 165, 170 & 180 minutes for the measurement of the enrichment of α-ketoisocaproic acid (α-KIC), the concentration of amino acids, insulin, glucose, FFA, cortisol, IGF-I, and the enrichment of expired CO 2 . Respiratory gas exchange and resting energy expenditure (REE), were measured by indirect calorimetry using a computerized open loop gas analyzer system (Medical Graphics Coφoration, Minnesota, USA), during the last 30 minutes of the study. α-KIC enrichment was measured as the quinoxalinol-trimethylsilyl derivative under selected ion monitoring by gas chromatography (Hewlett Packard 5890, Chester, UK) mass spectrometry (VG Trio II, Biotech. Chesire, UK) at m/z 232 and 233. Plasma α- KIC enrichment is a measure of intracellular leucine enrichment (ref, Matthews). 13 C enrichment of expired CO2 was measured on a VG Sira series II isotope ratio mass spectrometer (VG Isotech, Cheshire, UK). Measurements of leucine metabolism were calculated using standard isotope dilution equations, as previously described (Carroll, 1997). Asuming that 580 μmol of leucine are oxidised per gram of protein oxidation the rates of protein , fat and carbhohydrate oxidation were calculated using standard equations. All blood samples were centrifuged within 30 minutes of collection and plasma stored at -70 °C until analysis. Plasma amino acids were measured by ion exchange chromatography using an Alpha plus II (Pharmacia, Cambridge, UK) automated amino acid analyser. Plasma total IGF-I was measured by radioimmunoassay (RIA) after an ethanol-hydrocholric acid extraction (within-assay CV 7%, Teale & Marks, 1990). Insulin was assayed using a double anibody RIA with an interassay CV<9% and intra- assay <6% (Sδnksen). Cortisol, testosterone, SHBG, androstenedione, free T3,and DHEA were measured. The results are shown in Table 1. Table Treatment with DHEA (dose: 1 week 25mg od, then 25 mg tds for a total of 12 weeks) Patient before 12 weeks 12 weeks before 12 weeks 12 wee DHEA DHEA DHEA DHEA DHEA after c right leg muscle strength (N) creatinine (μ mol/1) r- m 1 355.6 404.7 198 203 σ» 2 337.2 410.8 325 155 140 3 173.8 205.9 196.2 125 130 total body lean (DEXA scan) sodium (mol/1) 1 61.532 63.165 140 140 2 42.778 45.336 43.034 139 138 3 45.404 46.439 44.959 141 140 Table 1 (cont.) right leg lean tissue (kg)(DEXA sacn) protein synthesis, whole body (μmol/kg/min) 1 9.093 9.410 1.87 1.84 2 7.216 7.605 7.402 1.37 1.86 3 6.735 6.997 6.558 1.34 1.70 cO 03 CO H H strenj gth/unit muscle (N/kg) protein synthesis, lean tissure (μmol/kg/min) C H m 1 39.11 43.01 2.18 2.14 CO X 2 46.73 54.02 43.91 1.70 2.41 m HI m 3 25.81 29.43 29.92 1.40 1.76 c r* m peak O 2 consumption (ml kg/min) treadmill leucin oxidation, whole body (μmol/kg/min) 1 0.25 0.22 2 14.6 18.6 20.5 0.25 0.11 3 18.5 16.3 13.3 0.34 0.17 Table 1 (cont.) exercise time (s) treadmill leucin oxidation, lean tissure (μmol/kg/min) 0.29 0.26 2 443 550 560 0.25 0.15 O 3 88 259 113 0.35 0.17 c σ co -» c NE VC O 2 slope) leucin breakdown, whole body H 171 (μmol/kg/min) CO X rπ 2.12 2.06 m 1 -i 2 37.24 31.93 29.01 1.57 1.97 a r m 3 87.80 55.10 82.16 1.68 1.87 N) NYHA class leucin breadkdown, lean tissue (μmol/kg/min) 3 3 2.47 2.39 3 2 3 1.95 2.56 3 2 3 1.75 1.94 Table 1 (cont.) protein balance, whole body & protein balance lean tisure (protein synthesis - luecin breakdown (μmol/kg/min) 1 -0.25 -0.22 -0.29 -0.26 -0.20 -0.11 -0.25 -0.15 o c CD -0.34 -0.17 -0.35 -0.17 CO H C H rπ co x m rπ H c r- m ro σ> The results confirm that the present invention provides a significant beneficial effect. The treatment is confirmed as being anabolic (from lean tissue assessment and from metabolic assessment; it improves strength and quality of muscle; it generally improves the NYHA classification; increases exercise time; it reduces the VENCO 2 slope; it reduces the catabolic/anabolic balance; it is safe and the appetite score was increased.

Claims: Claims 1. Use of an anabolic steroid in the preparation of a medicament for increasing peak VO 2 in a patient with CHF. 2. Use of an anabolic steroid in the preparation of a medicament for preventing or reducing peripheral muscle loss or weakness in a patient with CHF. 3. Use of an anabolic steroid in the preparation of a medicament for reducing VENCO 2 in a patient with CHF. 4. Use of an anabolic steroid in the preparation of a medicament for reducing catabolic/anabolic imbalance in a patient with CHF. 5. Use of an anabolic steroid in the preparation of a medicament for increasing protein metabolism in a patient with CHF. 6. Use of an anabolic steroid in the preparation of a medicament for improving muscle quality in a patient with CHF. 7. Use of an anabolic steroid in the preparation of a medicament for improving exercise capacity in a patient with CHF. 8. Use of an anabolic steroid in the preparation of a medicament for improving appetite in a patient with CHF. 9. Use according to any preceding claim wherein the patient has cachexia associated with CHF. 10. Use according to any preceding claim in which the anabolic steroid is represented by the formula wherein Z is CHR 7 or N, S or O; Y is CHR'. X, CR l l R 12 R 1 is =O, OH, -C(O)CH 3 , or C(O)CH 2 OH; R 2 , R 3 , R 7 , R 11 and R 12 are each independently H, OH, =O, halogen, alkyl, alkynyl or haloalkyl; R 4 is H when the dashed line B is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R 5 is H when the dashed line A is a double bond; and =O, H, halogen, alkyl or haloalkyl when the dashed line is a single bond; R 6 is =O, OH, sulfamate, -O-SO 3 H, a sulfatide group of formula (II) a phosphatide group of formula (III) O -O— P I I— OCH, 2C , HChL 2OCOR 0 O OCOR M (III) wherein each of R and R 9 i .s independently alkyl a glucuronide group of formula (IV) a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, (X) n -phenyl-alkenyl or -CO- R 10 , wherein each X is independently halogen, alkyl, alkenyl, alkoxy, carboxy, nitro, sulfate, sulfonyl, carboxylester or sulfate ester, n is 0, 1, 2 or 3 and R is H, a fatty acid, alkyl, alkenyl, acetylenic, (X) n -phenyl-alkyl, or (X) n -phenyl-alkenyl; or R and R together form a ring which may contain N, S or O; R is H when dashed line C is a double bond; and H or alkyl when the dashed line is a single bond; and R 9 is H or alkyl. 11. Use according to claim 10 in which the compound is DHEA, testosterone, oxandrolone, androsterone, androstanediol, androstanediol glucuronide, androstenedione, testolactone, stanozolol, mibolerone, danazol or an analogue thereof.

Inventors: ANKER STEFAN, COATS ANDREW, ANKER, STEFAN, COATS, ANDREW
Applicants: ANKER STEFAN, COATS ANDREW, IMPERIAL COLLEGE, ANKER, STEFAN, COATS, ANDREW, IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY & MEDECINE
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P43