MXPA06002948A - Enhanced method of treatment of growth disorders - Google Patents

Abstract

The application relates to the treatment of conditions and diseases for which growth hormone is a desirable method of treatment, using free fatty acid regulators in combination with growth hormone. In particular, the present invention discloses an enhanced method of treatment of growth disorders as well as methods to prevent and/or reduce adverse consequences of growth hormone treatment.

Description

IMPROVED METHOD OF TREATMENT OF GROWTH DISORDERS FIELD OF THE INVENTION The invention relates to disease states and diseases for which growth hormone is a desirable treatment procedure. In particular, the present invention describes an improved method of treating growth disorders.

BACKGROUND OF THE INVENTION Growth hormone (GH) therapy is used in the treatment of a variety of disease states. However, conventional therapy with GH is subject to the presence of harmful side effects. Side effects of GH therapy include impaired glucose tolerance and / or diabetes, edema, benign intracranial hypertension, arthralgia, myalgia, impaired glycemic control in diabetic patients, paresthesia, and carpal tunnel syndrome. Edema is defined as an accumulation of an excessive amount of aqueous fluid in cells, tissues or serous cavities (such as the abdomen). Symptoms include swelling of the face around the eyes, or on the feet, ankles and legs. The retention of salt and water induced by GH can cause benign intracranial hypertension. Benign intracranial hypertension is characterized by increased intracranial fluid pressure in the absence of a space-occupying lesion. It can present with headaches, visual loss, nausea, vomiting and papilloedema. Arthralgia is pain in one or more joints. Myalgia is pain or discomfort when moving any muscle. Paresthesia is a term that refers to an abnormal burning or stinging sensation that is normally felt in the hands, arms, legs, or feet, but can occur anywhere on the body. Carpal tunnel syndrome occurs when tendons or ligaments in the wrist become enlarged, often because of inflammation. The narrow tunnel of bones and ligaments in the wrist punctures the nerves that reach the fingers and the muscles at the base of the thumb. Symptoms vary from burning, tingling and numbness in the fingers, especially the thumb and forefinger and heart, to difficulty catching things or opening and closing the hand or dropping things. There has been some concern about the possibility of "promoting the growth of cancer" with growth hormone therapy, based on a few cases of leukemia described in children treated with growth hormone therapy. Growth hormone is known to have an antagonistic effect on the actions of insulin in several stages in the insulin signaling cascade. GH therapy has been shown to prevent the suppression of insulin-mediated hepatic glucose generation and increase peripheral glucose utilization (Sugimoto et al 1998). Some of the antagonistic effects on GH insulin are thought to be due to increased lipolysis and subsequent elevation of free fatty acids in plasma (FFA) leading to an inhibition of glucose uptake (Moller et al 1987). An increase in circulating FFA is associated with a reduction in insulin sensitivity since FFAs are known to impede insulin-mediated glucose uptake in skeletal muscle (Felber et al. 1964, Reaven et al. 1988, Randle et al. 1963). The diabetogenic effects of GH therapy during childhood have recently been determined. A higher incidence of type 2 diabetes mellitus has been found in children and adolescents during GH therapy in populations at higher risk of disease (Cutfield et al 2000). Adult males born with low weight have a higher incidence of type 2 diabetes mellitus, dyslipidemia and hypertension (Barker et al 1993, Barker 1994, Law et al 1991). It has been shown that children with short stature in prepubertal period who have intrauterine growth retardation (IUGR) have a very reduced insulin sensitivity, that is, they are insulin resistant., when compared with children of short stature with normal birth weight (Hofman et al 1997). Girls with Turner syndrome have also been shown to have lower insulin sensitivity when compared to normal girls (Caprio et al 1991). Reduced insulin sensitivity or secondary hyperinsulinemia has been associated with the pathogenesis of all the disorders mentioned above (Reaven et al 1991). It has been found that insulin resistance is a marker of type 2 diabetes mellitus in those at risk of type 2 diabetes (Martin et al 1992). In humans and non-diabetic euglycemic animals fasting hyperinsulinemia reflects a generalized increase in insulin secretion that is a compensatory response to a reduction in insulin sensitivity (Kahn et al 1993). In addition, insulin resistance has been linked to the pathogenesis of hypertension. Insulin resistance and secondary hyperinsulinemia are important in the pathogenesis of hypertension that occurs most commonly in low birth weight adults (Barker et al 1993, Law et al 1991). Insulin has an important vasodilatory function that is mediated by the release of nitric oxide (McNally et al 1995, Steinberg et al 1994). Insulin-induced vasodilation is limited in disorders characterized by insulin resistance (Laakso et al 1992, Laakso et al 1993, Feldman ef a / 1993). Applicants have previously observed that in IUGR children the pronounced reduction in insulin sensitivity that occurs during GH therapy was present even 3 months after stopping treatment (Cutfield, et al 2000 (2)). In view of the above observations, it is clearly advantageous to establish a method for eliminating or, at least alleviating, the side effects of GH treatment of growth disorders. It would be particularly advantageous to establish a method that combines GH replacement therapy with a compound that produces synergy in the somatological effects of conventional GH therapy, but reduces its undesirable side effects.

SUMMARY OF THE INVENTION This invention relates to the use of a combination therapy comprising growth hormone (GH) and at least one free fatty acid regulator (FAA) in the treatment of disease states that require or have the potential to require treatment with GH. In particular, the invention relates to methods of treatment with GH, in which the somatological effects of treatment with GH are improved and some of the metabolic or lactogenic side effects of treatment with hGH are reduced. More particularly, the invention relates to the treatment of young patients in need of growth hormone replacement therapy. In one embodiment, the invention provides a method for treating a growth disorder in an animal, said method comprising administering to said mammal an effective amount of at least one FFA regulator in combination with growth hormone. In a preferred embodiment, said mammal is a human being. In another preferred embodiment, said mammal is a juvenile, more preferably a child or adolescent. In another embodiment, the invention provides a method for increasing the growth promoting effects of growth hormone therapy in a mammal, said method comprising administering to said mammal an effective amount of at least one FFA regulator in combination with growth hormone. . In a preferred embodiment, said mammal is a human being. In another preferred embodiment, said mammal is a juvenile, more preferably a child or adolescent. In another embodiment, the invention provides a method for preventing or treating an adverse consequence of treatment with growth hormone, preferably a growth disorder, in a mammal, which comprises administering an effective amount of at least one FFA regulator in combination with hormone. of growth. In a preferred embodiment, said adverse consequence of treatment with GH is edema. In another preferred embodiment, said adverse consequence of GH treatment is loss of trabecular bone. In another additional preferred embodiment, said mammal is a human being, in another more preferred embodiment, said mammal is a young, more preferably a child or adolescent. In yet another embodiment, the invention relates to the use of a combination of growth hormone and at least one FFA regulator in the preparation of a medicament or composition for treating growth disorders in a mammal. In a preferred embodiment, said mammal is a human being. In another preferred embodiment, said mammal is a juvenile, more preferably a child or adolescent. In yet another embodiment, the invention relates to the use of at least one FFA regulator in the preparation of a medicament for increasing the growth promoting effects of growth hormone therapy in a mammal. In a preferred embodiment, said mammal is a human being. In another preferred embodiment, said mammal is a juvenile, more preferably a child or adolescent. In yet another embodiment, said medicament is a combination of growth hormone and said regulator (s) of FFA. In another embodiment, the invention relates to the use of at least one FFA regulator in the preparation of a medicament for preventing or treating an adverse consequence of treatment with growth hormone in a mammal, preferably in a mammal suffering from a disorder of the increase. In a preferred embodiment, said adverse consequence of treatment with GH is edema. In another preferred embodiment said adverse consequence of treatment with GH is loss of trabecular bone. In yet another preferred embodiment, said mammal is a human being. In yet another preferred embodiment, said mammal is a juvenile, more preferably a child or adolescent. In yet another embodiment, said medicament comprises a combination of said growth hormone and said FFA regulator (s). In other embodiments, this invention includes compositions suitable for practicing the methods and uses of the invention. In particular, the invention provides a composition or medicament for treating growth disorders and / or preventing or treating the adverse consequences of treatment with growth hormone, said composition or medicament comprising growth hormone and at least one FFA regulator. In one embodiment of the invention said FFA regulator is fibric acid or a fibric acid derivative, preferably fenofibrate. In another embodiment of the invention, said FFA is nicotinic acid or a nicotinic acid derivative, preferably acipimox. In any of the methods, uses or compositions of the invention, the administration of said FFA regulator (s) may occur before, combined with, or after administration of growth hormone.

DETAILED DESCRIPTION OF THE FIGURES Figure 1 represents the body weight gain curves for each treatment subgroup; in the group ad libitum (AD) (Figure la) and for the group of short stature for their gestational age (SGA) (Figure Ib). Figure 2 represents the difference in weight gain for animals treated with GH alone: for animals AD (Figure 2a) and for animals SGA (Figure 2b). Figure 3 depicts the daily changes in body weight (animals AD in Figure 3a, SGA animals in Figure 3b). The lower axis is the day of treatment. Figure 4a represents the change in the length of the tibia as a percentage of the change in the group treated with saline for AD and SGA animals. Figure 4b represents the untied tibia length in all treatment groups. Figure 5 represents the relationship between the total length of the body (nose-anus) and the length of the tibial bone. Figures 6a and 6b show the anus-to-nose length of the groups AD (Figure 6a) and SGA (Figure 6b) post mortem. Figure 7 shows the effects of each treatment in AD and undernourished (UN) groups on blood hematocrit. Figure 8 depicts changes in liver weights in each treatment group as a percentage of a total body weight. Figure 9 depicts retroperitoneal fat mass in each treatment group as a percentage of total body weight. Figure 10 depicts the adrenal weights in each treatment group as a percentage of total body weight. Figure 11 depicts spleen weights in each treatment group as a percentage of total body weight. Figure 12 depicts plasma IGF-I concentrations in each treatment group at the time of sacrifice.

Figure 13 depicts plasma insulin concentrations in each treatment group after an overnight fast. Figure 14 represents the fasting plasma glucose concentrations in each treatment group. Figure 15 represents the concentrations of plasma leptin in each treatment group at the end of the study. Figure 16 represents the plasma levels of free fatty acids (FFA) in each treatment group after fasting overnight. Figure 17 depicts plasma triglycerides in each treatment group after an overnight fast. Figure 18 represents the free glycerol in plasma in each treatment group. Figure 19 represents the systolic blood pressure in each treatment group.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the term "growth hormone" or "GH" includes growth hormone; growth hormone secretagogues (GHS); proteins / growth hormone releasing peptides (GHRP); growth hormone-releasing hormone (GHRH); Somatotropin releasing inhibitory factor (SRIF); compounds that increase the endogenous release of growth hormone or growth hormone secretagogues; a pharmaceutically acceptable salt of GHS; analogues; mimetics; compounds that increase the activity of neural growth hormone receptors; compounds that bind to, or increase the concentration of, compounds that bind to neural growth hormone receptors; compounds that reduce or prevent the inhibition of GH, GHS or ligand activity; or inhibitors of their antagonists. Examples of agents that stimulate growth hormone and production or reduction or prevent its inhibition include, but are not limited to, growth hormone releasing peptides such as GHRP-1, GHRP-2 (also known as KP-102). ), GHRP-6, hexarelin, G-7039, G-7502, L-692,429, L-629,585, L-163,191 (aka MK-0677), ipamorelin, NN703, GHS-25, CP-424.391, ghrelin, SM- 130686 or GHRH or inhibitors of GH antagonists (substances that bind to growth hormone or otherwise prevent the action of GH in the body). These latter compounds exert an indirect effect on effective concentrations of GH by means of the withdrawal of an inhibitory mechanism and include substances such as somatostatin release inhibiting factor (SRIF). The GH can be any GH in a native sequence or in a variant form and of any origin, whether natural, synthetic or recombinant. Examples being human GH, bovine GH, rat GH and porcine GH. However, it is preferred that the GH employed is human GH and more preferably recombinant human GH. Examples of human growth hormone include, but are not limited to, human growth hormone (hGH), which is natural or recombinant GH with the native human sequence (e.g., GENOTROPIN ™, somatotropin or somatropin) and growth hormone recombinant (rGH), which refers to any GH or GH variant produced by means of recombinant DNA technology, including the recombinant human native sequence, mature GH with or without a methionine at its N-terminus, somatrem, somatotropin and somatropin . Another example is methionilated human growth hormone (met-hGH) produced in E. coli, for example, by the process described in U.S. Patent No. 4,755,465 issued July 5, 1998 and Goeddel et al., Nature, 282: 544 (1979). Met-hGH, marketed as PROTROPIN ™ (Genentech, Inc. USA), which is identical to the natural polypeptide, with the exception of the presence of a methionine residue at the N-terminus. Another example is recombinant hGH marketed as NUTROPIN ™ (Genentech, Inc., USA). This last hGH lacks the methionine residue and has an amino acid sequence identical to that of the natural hormone. See Gray et al., Biotechnology 2: 161 (1984). Another example GH is a variant of hGH which is a placental form of GH with pure and non-lactogenic somatic activity as described in the United States patent.

United n ° 4,670,393. GH variants are also included, for example such as those described in W 0 90/04788 and W 0 92/09690.

In a particular embodiment, the GH molecule or its GH variant is modified, preferably pegylated. As used herein, "treatment" of a disease or "therapy" therefor includes preventing the occurrence of the disease in a mammal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease. the disease (prophylactic treatment), inhibit the disease (slow down or stop its development), provide relief of symptoms or side effects of the disease and alleviate the disease (cause regression of the disease). As used herein, "adverse consequence of treatment with growth hormone" refers to any of the side effects or adverse events that arise from a treatment with growth hormone. This term therefore includes, but is not limited to: glucose intolerance, insulin resistance, secondary hyperinsulinemia, diabetes, dyslipidemia, hypertension, obesity, pathological conditions associated with sodium and water retention including edema; trabecular bone loss, benign intracranial hypertension, arthralgia, myalgia, deterioration in glycemic control in diabetic patients, paresthesia and carpal tunnel syndrome. Preferably, the invention relates to the treatment of edema and / or loss of trabecular bone. As used herein, the term "free fatty acid regulator (FFA)" refers to any compound that has a lipid-lowering effect, i.e., that lowers FFA levels. FFA regulators of interest include, but are not limited to, fibric acid and derivatives thereof and nicotinic acid (niacin) and derivatives thereof. The effects of fibrates are mediated by activated receptors of peroxisome proliferators (PPAR). It is believed that PPARa mediate the hypotriglyceridemic effect of fibrates by stimulating the catabolic pathways of fatty acids in the liver. PPARa activators also reduce adipose tissue mass. It has been found that fenofibrate, cipofibrate and GW9578 reduce insulin resistance without adverse effects on body weight and adipose tissue mass in an animal model. PPARa agonists can exert direct actions of insulin sensitization. Bezafibrate has been shown to reduce fatty deposits and improve insulin sensitivity. In adipocytes, nicotinic acid reduces lipolysis by inhibiting adenylyl cyclase, leading to the suppression of hormone-sensitive lipase (Holm et al., (2000) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis.) Annu Rev Nutr 20: 365- 393). The overnight administration of acipimox, a long-acting analog of nicotinic acid, was shown to inhibit lipolysis and reduce plasma levels of FFA, reduce insulin resistance, increase carbohydrate oxidation, improve oral tolerance to the glucose and reduce plasma insulin levels in non-diabetic muscle and obese subjects and subjects with reduced glucose tolerance or type 2 diabetes (Santomauro et al. (1999) Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects.Diabetes 48: 1836-1841). Fibric acid derivatives include, although without being limited to them, fenofibrate, clofibrate, gemfibrozil, bezafibrate and ciprofibrate. Nicotinic acid derivatives (niacin) include, but are not limited to, extended-release niacin; controlled release niacin; niacinamide (nicotinamide); acipimox (5-methylpyrazinecarboxylic acid 4-oxide); and esters of nicotinic acid (methyl nicotinate, hexyl nicotinate), niceritrol, acifran, cyclohexylphenyl nicotinate and nicotinated cyclohexylphenyl oxide. As used herein, the terms "co-administration", "co-administered" and "combined with", which refer to growth hormone and one or more free fatty acid regulators, are intended to indicate, and refers to, and includes the following: - simultaneous administration of said combination of GH and FFA regulator (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases said components substantially at the same time to said patient - practically simultaneous administration of said combination of GH and FFA regulator (s) to a patient in need of treatment, when such components are formulated separately in separate dosage forms that are taken at about the same time by said patient, whereby said components are released practically at the same time in said patient - sequential administration of said combination d and GH and FFA regulator (s) to a patient in need of treatment, when such components are formulated separately in separate dosage forms that are taken at consecutive times by said patient with a significant time interval between each administration, thereby , said components are released practically at different times to said patient; and - sequential administration of said combination of GH and FFA regulator (s) to a patient in need of treatment, when said components are formulated together in a single dosage form that releases said components in a controlled manner, whereby these are administered concurrently, consecutively and / or overlapped at the same time and / or at different times by said patient. "Somathogenic effects" of hGH treatment include, but are not limited to, promoting growth, increasing body weight and osteoanabolic actions. "Lactogenic effects" of treatment with hGH include, but are not limited to, exogenous growth hormone effects that are associated with prolactin receptor signaling (PRLR). These effects include, but are not limited to, the development of mammary glands, changes in osmotic balance, and cell proliferation. "Metabolic effects" of treatment with hGH include, but are not limited to, stimulation of lipolysis, stimulation of IGF-1 secretion and diabetogenic effects.

Pathological states treated using GH Pathological conditions treated using GH include growth disorders such as growth hormone deficiency in adults (aGHD), chronic kidney failure (CKD), AIDS depletion, aging, erectile dysfunction, HIV lipodystrophy, fibromyalgia, osteoporosis, memory disorders, depression, Crohn's disease, traumatic brain injury, subarachnoid hemorrhage, Noonan syndrome, end-stage renal disease (ERET), rescue of bone marrow stem cells, metabolic syndrome and glucocorticoid myopathy. As used herein, the term "growth disorder" refers to any pathological condition that results in a short stature. Such pathological states include, but are not limited to, growth hormone insufficiency, growth hormone deficiency (GHD), intrauterine growth retardation (IUGR), growth retardation in children who were born small for their gestational age ( SGA), very low birth weight (VLBW), skeletal abnormalities including dysplasia, chromosomal variations (Turner syndrome, Down syndrome, Prader-Silli syndrome), growth retardation related to chronic renal failure, constitutional growth delay , growth retardation related to cystic fibrosis, idiopathic short stature (ISS), short stature due to treatment with glucocorticoids in children, inability to achieve compensatory growth for short-term premature infants, or any other pathological state that from place to size low. GH deficiency Diagnosis of growth hormone deficiency requires testing of growth hormone stimulation. The assays used include the insulin hypoglycaemia test or insulin tolerance assay (ITT), L-dopa stimulation assay, arginine infusion assay and arginine / GHRH assay. Maximum growth hormone secretion levels in adults less than 3-5 ng / ml are indicative of GHD. In children, values below 10 ng / ml are considered inadequate. Growth hormone deficiency is treated with recombinant human growth hormone that is usually administered by a daily subcutaneous injection.

There are several causes of GHD in children and most may be related to a problem in the hypothalamus or pituitary gland. In some rare cases, there is a defect in the body's use of growth hormone. In most children with growth hormone deficiency, the defect falls on the hypothalamus. When other hormones of the pituitary gland are not normally secreted either, the child is said to have hypopituitarism. In congenital hypopituitarism, an abnormal formation of the pituitary or hypothalamus occurs during fetal development. Acquired hypopituitarism results from injury to the pituitary gland or hypothalamus that occurs during or after birth. This can be caused by a severe head injury, brain injury due to illness, radiation therapy or a tumor. The global incidence of GHD in children has been estimated to be at least 1 in 10,000 live births and in some countries an incidence of up to 1 in 4,000 live births has been reported. A child with growth hormone deficiency has a growth pattern less than 5.08 cm per year. In many cases, the child will grow normally until the age of 2 or 3 years and then begin to show signs of delayed growth. The trial of growth hormone deficiency will occur when other possibilities of short stature have been ruled out. A weekly dose of up to 0.3 mg / kg body weight divided by daily subcutaneous injections is recommended for children with GHD. In adults, growth hormone deficiency can develop in the following situations; presence of a large pituitary tumor, after surgery or therapy with pituitary tumor radiation or other brain tumors, secondary to disorders of the hypothalamus and the continuation of growth hormone deficiency in childhood in adulthood. The clinical picture of GHD in adults includes; fatigue, muscle weakness, reduced exercise capacity, weight gain, increase in body fat and reduction in muscle mass, increase in LDL cholesterol and triglycerides and decrease in HDL cholesterol, increased risk of heart attack, heart failure and stroke , reduction in muscle mass, anxiety and depression, especially lack of feeling of well-being, social isolation and little energy. In the United States, a total of 35,000 adults are estimated to have GHD and approximately 6,000 new cases of GHD occur each year. For an average male of 70 kg, the recommended dose at the start of treatment is approximately 0.3 mg administered as a daily subcutaneous injection, up to a maximum of 1.75 mg per day in patients younger than 35 years and up to a maximum of 0.875 mg per day in patients older than 35 years. Minor doses may be necessary to minimize the occurrence of adverse events, especially in older or overweight patients.Prader-Willi syndrome Prader-Willi syndrome is a disorder of chromosome 15 characterized by hypotonia, hypogonadism, hyperphagia, cognitive impairment and difficult behavior; morbid obesity being the main medical concern. Growth hormone is typically deficient, causing short stature, lack of growth increase at puberty, and a high proportion of body fat, even in those who have a normal weight. The need for GH therapy will be assessed in children and adults. In children, if the growth rate is reduced or the height is lower than the third percentile, treatment with GH will be considered. The replacement of growth hormone helps normalize height and increases lean body mass; this helps to treat the height. The usual weekly dose is 0.24 mg / kg of body weight; This is divided into 6 or 7 smaller doses during the course of the week.

Turner syndrome Turner syndrome occurs in approximately 1 in 2,500 girls born alive. It is due to abnormalities or absence of an X chromosome and is often associated with a short stature, which can be alleviated with GH treatment. Other features of Turner syndrome may include short neck and, occasionally, short neck, valgus ulna, fourth and fifth metacarpus and short metatarsus, a shield thorax and primary hypogonadism. Growth in height is variable in patients with Turner syndrome so that the decision to treat with GH and the interval of said treatment is made individually. Frequently, treatment begins when the patient's height is below the fifth percentile or when the assessment of the standard deviation decreases to less than 2 standard deviations below the mean. Treatment is often initiated with slightly higher doses of GH than those used in the treatment of GHD; an initial starting dose is 0.375 mg / kg per week divided into daily doses.

Chronic Renal Failure Chronic renal failure (CRI) affects approximately 3,000 children in the United States. It is manifested by a gradual and progressive loss of the ability of the kidneys to excrete waste, concentrated urine and preserved electrolytes. Approximately one third of children with chronic kidney disease have an abnormal growth partially because renal diseases alter the metabolism of growth hormone. Corticosteroid hormones that are often used to treat kidney diseases can also delay growth. Kidney transplants can help a child begin to grow normally again but most children will not make up for the loss of growth prior to transplantation. The age at which kidney disease begins has more impact on growth retardation than the reduction in renal function (ie, the younger the child is when the disease starts, the more their growth is delayed). Treatment with GH can be administered in a dose of 0.35 mg / kg per week administered six or seven times a week.

Constitutional Growth Delay The constitutional delay in growth is characterized by normal prenatal growth followed by a slowdown in growth during childhood and childhood, and is reflected in the decrease in height percentiles at this time. Between three years and late childhood, growth proceeds at a normal pace. A period of pronounced growth deceleration can be observed immediately preceding the onset of puberty. Children with constitutional delay have a later onset of puberty. Occasionally, the combination of short stature accompanied and exaggerated by constitutional delay of growth and development in adolescents may cause sufficient psychosocial stress in the adolescent to guarantee treatment with GH administered in the same manner and dose as that used to treat GHD.

Cystic Fibrosis Cystic Fibrosis (CF) is the most common fatal genetic disorder in America. It is estimated that 1,000 individuals are born each year with Cystic Fibrosis in the United States. Cystic fibrosis causes dysfunction of the exocrine glands with a higher viscosity of mucous secretions, which leads to lung disease, exocrine pancreatic insufficiency and intestinal obstruction. Diagnosis and early treatment have significantly reduced mortality in children with CF. However, malnutrition and low growth continue to be a significant problem. Low weight gain, weight loss and inadequate nutrition originate from a reduced caloric intake, greater energy loss and higher caloric expenditure. It has been described that 28% of people with CF are below the tenth percentile for height and 34% are below the tenth percentile for weight. Studies have shown that GH therapy improves growth rate, rate of weight gain, lean body mass (LBM) and lung function in patients with cystic fibrosis.

Skeletal dysplasias Skeletal dysplasias associated with a short stature such as achondroplasia can be treated with GH. Achondroplasia is a genetic disorder that affects the lll-type gene of the fibroblast growth factor receptor, which is evident at birth. It affects approximately one in 20,000 children and occurs in all races and both sexes. During fetal development and childhood, cartilage develops normally in the bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, the rate at which the cartilage cells in the cartilage grows from long bones to bone is slow, leading to short bones and reduced height. Achondroplasia is characterized by short stature, short limbs, proximal extremity (upper arm and thigh), head that seems disproportionately large with respect to the body, skeletal abnormalities (limbs), abnormal hand appearance (trident hand) with persistent space between the fingers heart and ring, accented kyphosis and lordosis (curvatures of the spine), mallard gait, arched legs, prominent forehead (prominence of the forehead), hypotonia and polyhydramnios (present when the affected child has already been born). GH has been approved to treat achondroplasia in some countries such as Japan and South Africa, but it has not yet been approved by the FDA.

Delay of Intrauterine Growth (IUGR) and Children with Age Gestational Small (Children with SGA) Treatment with GH may be beneficial in children with interuterine growth retardation or fetuses who are small for their gestational age (a condition also called Russell-Silver syndrome). A definition of interuterine growth retardation is a weight below the tenth percentile for gestational age or a birth weight two deviations below the mean for gestational age. Studies have shown that children who do not have compensatory growth can benefit from GH treatment. The present invention is based on the surprising finding that coadministration of GH and FFA regulators alleviates the deterioration of insulin sensitivity by preventing lipolysis, has less edemic effects compared to GH therapy alone and exerts a synergistic effect to increase linear growth above that of GH alone. The invention provides a new process and composition intended to alleviate pathological conditions associated with GH therapy and enhance the effectiveness of existing procedures in the prior art. On the other hand, the new application described in the invention provides the public with a beneficial alternative to the procedures that exist in the prior art.

Treatment procedures In general terms, the invention relates to the treatment or prophylaxis of consequences of treatment with growth hormone (GH). GH is commonly used to treat pathological conditions that result in a short stature, including, but not limited to, growth hormone insufficiency, growth hormone deficiency, Intrauterine Growth Delay (Silver-Russell syndrome). , skeletal abnormalities, chromosomal variations (Turner syndrome, Down syndrome) or growth retardation related to chronic kidney disease. Treatment with GH has been shown to contribute to a series of pathological conditions such as those described above. It has also been observed that such pathological states extend beyond the immediate treatment with GH. The applicants established that such consequences can at least be mitigated, if not totally prevented, by administration of an FFA regulator, preferably combined with GH treatment. The addition of FFA to GH corrects insulin sensitivity to the state prior to treatment or that of a normal child. When the adverse consequences of treatment with growth hormone have not been observed as symptoms, the incidence of the consequences can at least be mitigated prophylactically. A particular advantage is that although the adverse effects of GH therapy are alleviated, the effect of increasing the growth of GH is enhanced by the use of the FFA regulator. As a result, the combination treatment provides a useful method to treat the pathological condition of short stature (with administration of GH) while at the same time reducing the adverse consequences of the treatment.

Pharmaceutical composition In general, the compounds of this invention can be administered in the form of pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g., transdermal, intranasal, intrapulmonary or suppository), parenteral (e.g. intramuscular, subcutaneous, intraarterial, intraperitoneal or intravenous injection), by implantation and by infusion through devices such as osmotic pumps, transdermal patches and the like. The compositions may take the form of tablets, pills, capsules, seals, tablets, granules, semi-solids, powders, sustained-release formulation, solutions, suspensions, emulsions, elixirs, aerosols or any other suitable composition; and may include pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art and these, and methods for formulating the compositions, can be found in conventional references such as Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, ef al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999; and Gennaro AR: Remington: The Science and Practice of Pharmacy, 20th Ed., Lippincott, Williams and Wilkins, Philadephia, PA (2000). Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution and the like, with isotonic solutions being preferred for intravenous administration. The active compounds (GH and FFA regulator (s)) to be used in the treatment or prophylaxis in the methods of the invention will be formulated and dosed in a manner consistent with good medical practice, taking into account the clinical state of the patient. particular subject (especially the side effects of treatment with GH alone), the site of release of the composition, the administration procedure, the administration schedule and other factors known to the experts. It is understood that the specific dose level of each active compound (GH and FFA regulator (s)) for each patient will depend on a variety of factors including the activity of the specific agents employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, selected combination of active agent, the intensity of the particular pathological states or disorders that are treated and the manner of administration. The "effective amounts" of each component for the purposes of the present specification are thus determined by such considerations and are amounts that achieve the desired effects, including said effects, but without being limited thereto, increasing the growth rates of the subjects and / or reduce and / or prevent the adverse consequences of treatment with GH, especially the deterioration of insulin sensitivity, edema and / or loss of trabecular bone. The appropriate doses can be determined in clinical trials.

Administration of FFA regulators In general, the daily dose of fibrates normally ranges from 0.1 to 100 mg / kg, typically from 0.1 to 20 mg / kg. For example, an intravenous dose may be in the range of 0.01 mg to 0.1 mg / kg, typically 0.01 mg to 10 mg / kg, which can be conveniently administered as an infusion of 0.1. μg at 1 mg per minute. Infusion fluids suitable for this purpose may contain, for example, from 0.01 μg to 0.1 mg per milliliter. The unit doses may contain, for example, from 0.1 μg to 1 g of each component. Thus, ampoules for injection may contain, for example, 0.1 μg to 0.1 g and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, 0.1 mg a 1 g.

Preferably, fibrates, in particular fenofibrate, are administered in an amount of about 50 to 450 mg per day. A total daily dose of nicotinic acid or a nicotinic acid derivative may generally be in the range of about 500 to about 10,000 mg / day in single or divided doses, or from about 1,000 to about 8,000 mg / day, or approximately 3,000 to approximately 6,000 mg / day in single or divided doses. Preferably, nicotinic acid or nicotinic acid derivative is administered orally. Orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from about 50 to about 500 mg, or from about 200 mg to about 1,000 mg, or from about 500 mg to about 3,000 mg, of nicotinic acid or nicotinic acid derivative. The oral delivery of nicotinic acid or nicotinic acid derivative of the present invention may include formulations, as are well known in the art, to provide immediate release or prolonged or sustained release of the drug into the gastrointestinal tract by any number of mechanisms. Immediate-release formulations include, but are not limited to, oral solutions, oral suspensions, tablets or rapidly dissolving capsules, disintegrating tablets and the like. Sustained or sustained release formulations include, but are not limited to, pH sensitive release from the dosage form based on the pH change of the gastrointestinal tract, slow erosion of the tablet or capsule, retention in the stomach in based on the physical properties of the formulation, the bioadhesion of the dosage form to the mucosa that lines the intestinal tract or the enzymatic release of the active drug from the dosage form. The desired effect is to prolong the period of time during which the active drug molecule is released at the site of action by manipulation of the dosage form. Thus, controlled release formulations with enteric coating are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester. Non-limiting formulation examples, including sustained release formulations, such as those found in NIASPAN® tablets (Kos Pharmaceuticals), are described in U.S. Patent No. 6,080,428 and U.S. Patent No. 6,129,930, both incorporated herein by reference.

Administration of GH Preferably, the effective amount of GH administered to a subject ranges from about 0.001 mg / kg / day to about 0.2 mg / kg / day; more preferably, the effective amount of GH ranges from about 0.01 mg / kg / day to about 0.1 mg / kg / day. In other aspects, the effective amount of GH administered to a subject is at least about 0.2 mg / kg / week. In another aspect, the effective amount of GH is at least about 0.25 mg / kg / week. In another aspect, the effective amount of GH is at least about 0.3 mg / kg / week. In one embodiment, the dose of GH ranges from about 0.3 to 1.0 mg / kg / week and, in another embodiment, from 0.35 to 1.0 mg / kg / week. Preferably, the growth hormone is formulated at a pH of about 7.4 to 7.8. Preferably, GH is administered once a day subcutaneously. In preferred aspects, the dose of GH ranges from about 0.001 to 0.2 mg / kg / day. It is more preferred that the dose of GH ranges from about 0.010 to 0.1 mg / kg / day. GH is suitably administered continuously or non-continuously, such as at particular times (e.g., once a day) in the form of an injection of a particular dose, in which there will be an elevation in the plasma concentration of GH at the time of injection, and then a drop in the plasma concentration of GH until the time of the next injection. Another method of non-continuous administration results from the use of PLGA microspheres and many available implant devices that provide a discontinuous release of the active ingredient, such as an initial burst and then a lapse before releasing the active ingredient. See, for example, U.S. Patent No. 4,767,628. GH can also be administered so that it has a continuous presence in the blood that is maintained for the duration of GH administration. This is most preferably carried out by means of a continuous infusion path, for example, minipump, such as an osmotic minipump. Alternatively, it is carried out appropriately using frequent injections of GH (ie, more than once a day, for example, two or three times a day). In yet another embodiment, GH can be administered using long-acting GH formulations that delay the clearance of GH in the blood or cause a slow release of GH from, for example, the injection site. The long-acting formulation that prolongs GH clearance in plasma may be in the form of complexed or covalently conjugated GH (by reversible or irreversible linkage) to a macromolecule such as one or more of its binding proteins (WO 92 / 08985) or a water-soluble polymer selected from PEG and polypropylene glycol homopolymers and polyoxyethylene polyols, ie, those which are soluble in water at room temperature. Alternatively, GH can be complexed or bound to a polymer to increase its circulating half-life. Examples of polyethylene glycols and polyoxyethylene polyols useful for these purposes include polyoxyethylene glycerol, polyethylene glycol, polyoxyethylene sorbitol, polyoxyethylene glycol or the like. The structure of polyoxyethylene glycerol glycerol is the same structure that occurs, for example, in animals and humans in mono-, di- and triglycerides. The polymer does not have to have a particular molecular weight, but it is preferred that the molecular weight varies from about 3,500 to 100,000, more preferably 5,000 to 40,000. Preferably, the PEG homopolymer is unsubstituted, but may be substituted at one end with an alkyl group. Preferably, the alkyl group is a C 1 -C 4 alkyl group, and most preferably a methyl group. Most preferably, the polymer is an unsubstituted homopolymer of PEG, a homopolymer substituted with monomethyl PEG (mPEG) or polyoxyethylene glycerol (POG) and has a molecular weight of about 5,000 to 40,000. Specific procedures for producing GH conjugated with PEG include the procedures described in U.S. Patent No. 4,179,337 on PEG-GH and in U.S. Patent No. 4,935,465, which discloses PEG linked reversibly but covalently to GH, and also PEG-hGH conjugates such as those described in WO99 / 03887, WO03 / 044056 and WO2004 / 22630. GH can also be administered appropriately by sustained release systems. Examples of sustained release compositions useful herein include semipermeable polymer matrices in the form of shaped articles, eg, films or microcapsules. Sustained-release matrices include polylactides (U.S. Patent No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers, 22, 547-556). (1983), poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed, Mater. Res., 15: 167-277 (1981); Langer, Chem. Tech., 12: 98-105 (1982), ethylene vinylacetate (Langer et al., Supra) or poly-D - (-) - 3-hydroxybutyric acid (EP 133,988), or PLGA microspheres. Sustained-release GH compositions also include GH trapped in liposomes. Liposomes containing GH are prepared by methods known per se: DE 3,218,121; Epstein ef al., Proc. Nati Acad. Sci. USA, 82: 3688-3692 (1985); Hwang et al., Proc. Nati Acad. Sci. USA, 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese patent application 83-118008; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324. Typically, the liposomes are small (approximately 200 to 800 Anglestrom) unilamellar in which the liquid content is greater than about 30 mole percent cholesterol, the selected proportion being adjusted to the optimal therapy. In addition, a biologically active sustained release formulation can be prepared from a GH adduct covalently linked to an activated polysaccharide as described in U.S. Patent No. 4,857,505. In addition, U.S. Patent No. 4,837,381 describes a composition of fat or wax microspheres or one of their mixtures and GH for slow release. For parenteral administration, in one embodiment, GH is generally formulated by mixing the GH to the desired degree of purity, in a unit dose injectable form (solution, suspension or emulsion) with a pharmaceutically acceptable carrier, i.e., one that does not. It is toxic for the receptors in the dosages and concentrations used and is compatible with the rest of the ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be detrimental to polypeptides. In general, the formulations are prepared by contacting the GH with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably, the vehicle is a parenteral vehicle, more preferably, a solution that is isotonic with the blood of the recipient. Examples of such liquid carriers include water, saline, Ringer's solution and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes. The vehicle suitably contains minor amounts of additives such as substances that improve isotonicity and chemical stability. Such materials are non-toxic to the recipients at the doses and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts buffers; antioxidants such as ascorbic acid; low molecular weight polypeptides (less than about ten residues), eg, polyarginine or tripeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid or arginine; monosaccharides, disaccharides and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; complementary ions such as sodium; and / or nonionic surfactants such as polysorbates, polymers or PEG. Typically, GH is formulated individually in such vehicles at a concentration of about 0.1 mg / ml to 100 mg / ml, preferably 1 to 10 mg / ml, at a pH of about 4.5 to 8. The GH preferably has a pH of 7.4 to 7.8. It is understood that the use of certain excipients, vehicles or foreign stabilizers will result in the formation of GH salts. The foregoing describes the invention including its preferred forms. It is intended that the alterations and medications that will be apparent to those skilled in the art are included within the spirit and scope of the disclosed invention.

STUDY PHARMACOLOGY01 A study to determine the efficacy of a combination therapy comprising GH and FFA regulators to improve linear growth and reduce the metabolic abnormalities associated with GH therapy. Study design This study used a well-characterized rodent model of short stature due to fetal growth retardation (Woodall et al., 1996). Below is a diagram of the general experimental design.

Test groups - 10 animals per group Experimental procedure - analytical methods and procedures Animal model The rodent model of maternal undernutrition used to induce SGA was initially characterized at the Liggins Institute, Faculty of Sciences Medical and Health, University of Auckland by Woodall et al. (nineteen ninety six). This model has already been published in several international evaluation journals (Woodall et al 1996, 1998, Vickers et al 2000, 2001). This experimental technique to induce SGA results in a growth retardation of 30 to 35% in fetuses of 22 days and insufficient growth after persistent birth and without evidence of compensatory growth up to at least 90 days. These animals develop hypertension, insulin resistance and truncal obesity as adults.

Animal protocol to generate offspring with SGA We grouped by age Wistar Virgin rats (75-100 days) using a monitor of the estrual cycle (Fine Science Tools INC., North Vancouver, BC, Canada) to determine the stage of estrus of the animals before introducing the male. Day 1 of pregnancy was determined by the presence of spermatozoa in the vaginal smear. After confirming the mating, the rats were housed individually in conventional rat cages containing wood chips and bed with free access to water. The animal room was kept at 25 ° C with a cycle of 12 hours of light: 12 hours of darkness. Breeding females were randomly assigned to receive either ad-libitum feed (AD group and breeding females for cross-breeding) or to receive 30% ad-libitum (UN group, determined by measurement of food intake the previous day). of a breeding female fed ad libitum). The composition of the diet was 18% protein, 4% fat, 3% fiber, 7% ash and 58% carbohydrate (Diet 86, Skellerup Stock Foods, Auckland, New Zealand). Food intake and body weight were recorded daily. After birth, crossbreeding was performed on mothers fed ad libitum. Cross breeding is necessary due to insufficient milk in breeding mothers with limited food. The size of the bait was adjusted to 8 pups per bait to ensure adequate and normalized nutrition. The body weights of all the offspring were recorded daily. At the time of weaning (at 21 days) the pups were sexed and grouped by weight and lodged in pairs in conventional cages. All animals were fed ad libitum for the remainder of the study. The breeding females were sacrificed by asphyxiation with CO2 and the excess offspring by decapitation. All animals received approval by the Animal Ethics Committee at the University of Auckland. In this experiment only male offspring were used. The use of power calculations determined that a group size of 10 was necessary to demonstrate statistically significant anticipated differences in body length and fasting insulin concentration.

Test compounds Recombinant bovine growth hormone (rbGH) Many studies in rodents use treatment with human GH hGH) due to their relative ease of availability for experimental use. However, hGH possesses lactogenic and somatological properties in the rat due to the binding of hGH to the prolactin receptors and to the GH receptors. This has been clearly demonstrated in binding studies using hGH, bGH, oPRL and rat growth hormone (rGH) and rat prolactin (rPRL). Rat epatocytes contain two types of binding sites that bind to hGH. The first, somathogenic binding sites, are specific for the hormones that promote the growth of bGH and rGH. The second, lactogenic, are specific for lactogenic hormones, oPRL and rPRL. Human GH has shown that it binds to both sites (Ranke et al., 1976). Recombinant rat GH was not available in sufficient amounts for large-scale animal experiments. SoIn the study, bGH was used, a pure somatogen in the rat and an agent that is not a ligand for the rat prolactin receptor (Yamada et al., 1984). The animals were treated with bGH by subcutaneous injection at a dose of 5 mg / kg / day and a volume of 100 ul. This was administered as a divided dose (2 x 2.5 mg / kg / day) at 8:00 AM and 5:00 PM using a thin-gauge insulin syringe. Control animals were given saline using an identical treatment protocol.

Fibrates Fenofibrate belongs to the class of fibrates (drugs derived from fibric acid). Fibrates are lipid-lowering agents that effectively reduce serum triglyceride levels through the mediation of peroxisome proliferator-activated receptor (PPAR-a). In addition, it is known that fibrates reduce serum cholesterol levels. Fenofibrate was administered by oral gavage (8:00 h) in a dose of 30 mg / kg body weight / day.

Acipimox Acipimox is a long-acting analogue of nicotinic acid (AN). As an acipimox hypolipidemic agent it reduces the serum concentrations of triglycerides and non-esterified fatty acids. Acipimox has been shown to partially prevent insulin resistance induced by GH by inhibiting lipolysis (Segerlantz et al., 2001). Acipimox (Pharmacia) was administered by daily gastric tube (8:00 h) in a dose of 20 mg / kg body weight / day (Blachere et al., 2001).

Observations Body weight The animals were weighed between 8-9 a.m. every day for the duration of the experiment. Individual animals were observed every day for signs of clinical changes, reaction to treatment or disease. There were no indications of any adverse response and related symptoms in any of the treatment groups. Food consumption Food consumption was measured daily. The relative food intake per rat (grams consumed per gram of body weight per day) was calculated using the amount of food supplied with respect to the amount of uneaten food left by each pair in each group. Water consumption Water consumption was calculated by weighing the water bottles at the same time of each day of the study. Body lengths Body lengths (nose-anus and nose-tail) and bone length (length of the tibia, femur) were determined post mortem using quantitative computerized peripheral tomography analysis (pQC, Stratec). Bone density was also determined by pQCT. Blood pressure The systolic and diastolic blood pressure and heart rate were recorded by a tail cuff plethysmograph according to the manufacturer's instructions (Blood Pressure Analyzer IITC, Life Science, Woodland Hills, CA, United States). The rats were confined in a transparent plastic tube in a heated room (25-28 ° C). After 10 to 15 minutes of acclimation, the cuff was placed on the tail and inflated to 240 mmHg. The pulses were recorded during deflation at a rate of 3 mmHg / s and the reappearance of a pulse was used to determine the systolic blood pressure. A minimum of 3 clear systolic blood pressure measurements were taken per animal. The previous observations indicate that the coefficient of variation for repeated measures is < 5%. Plasma analysis Blood samples were obtained after fasting overnight. Samples were obtained from the vein of the tail and at the end after decapitation under halothane anesthesia. The blood samples were obtained in heparinized tubes and centrifuged to collect the plasma. Next, the samples were analyzed to determine insulin, glucose, FFA, leptin, IGF-I, glycerol, triglycerides, cholesterol, corticosterone, markers of liver function (ALAT, ASAT, ALAP) and markers of protein synthesis. FFA, triglycerides and glycerol in plasma were measured by a diagnostic kit (Boehringer-Mannheim No. 1383175 and Sigma No. 337, respectively). Leptin, plasma insulin were measured using commercially available kits (Lineo, St Charles, MO, United States). Plasma IGF-I was measured by RIA as described above (Vickers et al., 2000). Plasma glucose concentrations were measured using a colorimetric plate assay. The rest of plasmatic analytes (liver enzymes, electrolytes and the like) were measured with a BM / Hitach¡ 737 analyzer by Agriquality Laboratory Services (Auckland, New Zealand). Tissue studies At the end, the animals were sacrificed by decapitation by halothane anesthesia. The tissues (heart, liver, muscle and adipose (subcutaneous and visceral)) were collected, weighed and frozen rapidly in liquid nitrogen for further analysis. An aliquot of liver tissue was also frozen at -20 ° C for growth hormone receptor testing using ligand binding assay. Data analysis Data were analyzed using a multivariate or factorial ANOVA / ANCOVA regression analysis with post hoc correction (influences after birth and treatment effects after birth) when considered appropriate. The statistical package used was StatView (Version 5, SAS Institute). The previous data provided the basis for the power calculations for the proposed studies (assuming a = 0.05). For insulin sensitivity, an n of 10 with a power of 80% detected a change of 0.2 and 95% a change of 0.26 ng / ml with a DT of 0.15 ng / ml. For the length of the body, an n of 10 with a power of 80% detected a change of 6.88 mm and to 95% a change of 7.97 mm with a DT of 5.2 mm.

Results There was a slight reduction in maternal body weights compared to day 1 of pregnancy in pregnant SGA group females until day 15 of gestation. From day 15 of pregnancy, the SGA breeding females gained weight and reached pre-matched weights at the time of delivery. The size of the bait was not significantly different between the two groups (AD 13.4 ± 0.4, SGA 12.8 ± 1.1). Maternal undernutrition resulted in growth retardation reflected by a significantly reduced body weight at calving in the litter of SGA reproductive females (males AD 6.1 ± 0.49 g, SGA 4.3 ± 0.6 g, p < 0.0001). Nose-length (NA) and nose-tail (NT) lengths were significantly lower at birth in offspring of SGA when compared to offspring AD (NA: males AD 49.3 ± 2.43 mm, SGA males 44 ± 3.0 mm; NT: males AD 65.9 ± 2.8 mm, males SGA 58 ± 4.1 mm, p <0.0001 for both lengths). From birth to weaning on day 22, body weights remained significantly lower in offspring of SGA. At the start of treatment, the offspring of SGA were significantly lighter than in AD animals (p <0.0001) and the total body weights remained significantly lower in offspring of SGA for the remainder of the study. Weight response The increase in body weight (increase in grams) was significantly lower in the treatment groups (p <0.0001) when compared with saline (Figure 1). There was no significant difference in absolute body weight between animals treated with GH and animals treated with any of the combination therapies. However, animals treated with GH and acipimox had a significantly higher body weight gain when compared to animals treated with GH and fibrate. The SGA animals were significantly less heavy than the AD animals for all treatment groups and no statistical interactions occurred. Compared with GH alone, AD animals treated with GH and acipimox show a gradual divergence of animals with GH alone in the increase in body weight (Figure 1). However, the effect of combination treatments in AD animals seems to decrease approximately on day 57 after birth when compared to treatment with GH alone. In SGA animals, the combination therapy of GH and fenofibrate showed a marked increase in weight gain when compared to animals treated with GH but this effect decreased after approximately 2 weeks of combined treatment and at the end of the study these animals grew to a slightly lower rhythm than the animals treated with GH. However, SGA animals treated with GH and acipimox showed an increase in slow but positive weight gain compared to animals treated with GH that had not weakened at the end of the study (Figure 2). The analysis of the change in weight per day also indicates that there is an acute beneficial effect of combination therapies on body weight gain when compared to GH alone. This is more pronounced in animals treated with GH and acipimox, in particular, in SGA animals (Figure 3).

Bone length Tibias were stored in 10% neutral buffered formalin. The tissue was separated from the bone and the bone length, area and density (cortical and trabecular) were determined using pQCT (Stratec). Tibial lengths were significantly reduced in the SGA descendants. GH significantly increases the length of the tibia in all treated groups. However, the combination therapy of GH and acipimox potentiates the effects induced by GH on tibial growth (p <; 0.0001), Figure 4). The length of the tibia in the animals treated with GH and fenofibrate was not significantly different from that of the GH alone. The tibial length was very correlated with the total body length (nose-anus) (Figure 5). Total tibial area was significantly lower in SGA animals and increased in all treated animals. It should be noted that treatment with GH significantly reduces the trabecular bone mass. However, this trabecular loss was not apparent in the AD and SGA animals treated with the combination therapy (Table 1). Fisher's PLSD for trabecular Effect: treatment Significance level: 5% Table 1 SSI (stress strain index) was significantly reduced in SGA animals and increased in all animals treated with GH / GH combination. Total bone density did not change significantly in any of the treatment groups, although there was a trend (p = 0.056) toward a reduction in total bone density in the GH group that was not observed in the therapy groups. combination. The cortical bone density (cortical and subcortical, mm2) did not change significantly in any of the treatment groups.

Body lengths Nose lengths increased significantly with GH treatment and, on the other hand, were further increased using combination therapy with GH and acipimox (p <0.005 for GH versus GH and acipimox) (Figure 6) .

Body Mass Index (BMl) A BMl was calculated using: body weight / nose-length (cm) 2. The BMl was significantly lower in SGA animals to be compared with AD animals (p <0.05). BMl was significantly reduced in animals treated with GH and acipimox compared to animals treated with saline and GH (p <0.005). The BMl was not significantly different between animals treated with saline and GH. Due to the lack of lipolysis in animals treated with GH and acipimox compared to those treated with GH, alterations in BMl possibly reflect an improvement in linear growth over that of GH alone.

Food intake There was a significant difference in the relative food intake (grams consumed per g of body weight) in any of the treated groups. The SGA animals were hyperphagic with a light food intake but significantly higher than that of the AD animals (p <0.05) that concur with our previous observations.2 Water intake There were no significant differences in water intakes between any of the treatment groups. However, there was a trend (p = 0.09) towards an increase in relative water intake (water consumed per g body weight) in the group treated with GH plus acipimox, in particular, in AD animals. The SGA animals had a slightly but significantly lower relative water intake (p <0.05) compared to the AD animals.

Blood hematocrit A well-characterized effect of GH treatment is a greater plasma volume (Johannsson et al, 2002). The decrease in blood hematocrit is a reliable marker of the increase in plasma volume associated with fluid retention effects of GH therapy. As expected, the hematocrit in blood plasma was significantly reduced in animals treated with GH in the AD and SGA groups. The decrease in hematocrit was also observed in the animals treated with GH and fenofibrate, but, surprisingly, there was no effect of the combination of GH and acipimox in the reduction of the hematocrit. The plasma hematocrit was significantly higher in the animals treated with GH and acipimox when compared with the GH alone and GH and fenofibrate groups and there were no significant differences with respect to the saline solution (Figure 7), although the combination of GH and regulator of FFA derived from fibric acid presented a degree of synergy in the relief of fluid retention induced by GH.

Liver The weight of the liver with respect to body weight was not significantly different between animals AD and SGA. The relative weight of the liver was significantly lower in animals treated with AD and SGA with GH and fenofibrate (Figure 8). GH alone or combined with acipimox had no effect on liver weight.

Retroperitoneal fat deposits There was no significant difference between animals AD and SGA in relative retroperitoneal fat deposits. Treatment with GH or combination of GH and fenofibrate significantly reduced the retroperitoneal fat mass when compared with saline controls (Figure 9). Retroperitoneal fat was significantly reduced with GH therapy but this lipolysis was partially blocked by combination therapy, in particular, in SGA animals given GH combined with acipimox.

Kidneys Kidney weights were significantly lower with respect to body weight in SGA animals compared to AD animals (p < 0.005). The relative weights of the kidneys were significantly higher in the GH + fenofibrate animals when compared to the rest of the treatment groups. The relative weights of the kidneys were reduced in GH animals when compared with controls are saline but the animals treated with GH and acipimox were not significantly different from the controls.

Adrenal glands The weight of the adrenal glands was not significantly different between animals AD and SGA. Adrenal capsule weights increased significantly in all treatment groups when compared with controls with saline. The weights of the adrenal glands increased significantly in the animals treated with GH and fenofibrate, as well as in GH and acipimox when compared with those treated with GH alone (Figure 10).

Spleen The relative weights of the spleens increased significantly in SGA animals when compared with AD animals. Spleen weights increased in all treatment groups with respect to body weight and there was no trend towards greater splenic growth in animals with GH + fenofibrate when compared with controls (p = 0.056) (Figure 11).

IGF-I IGF-I in plasma increased significantly in animals AD and SGA treated with GH and combination of GH and acipimox when compared with controls with saline (Figure 12). However, plasma IGF-I did not rise significantly in animals treated with GH + fenofibrate. The increase in IGF-I in the animals treated with GH was not significantly different from the increase in IGF-I valued and in the animals treated with GH and acipimox.

Fasting Insulin Fasting plasma insulin increased significantly in animals treated with GH and fenofibrate when compared with those treated with saline. Insulin concentrations were not significantly altered with animals treated with GH and acipimox but were significantly lower than those treated with GH alone or combined with fenofibrate (Figure 13). There was no significant difference in insulin levels between animals AD and SGA.

Fasting Glucose Fasting plasma glucose was not significantly different between AD and SGA animals and was not significantly altered by GH therapy (Figure 14). Plasma glucose was significantly lower in animals treated with GH and acipimox when compared to GH alone and there was a general tendency for glucose to be lower than controls in animals treated with GH and acipimox (p = 0.07). Glucose in the groups treated with GH and fenofibrate was significantly higher when compared with animals treated with saline and GH / GH and acipimox. There was no significant difference in glucose levels between animals AD and SGA.

Leptin There was no statistically significant difference in plasma leptin concentrations between animals AD and SGA (Figure 15). Leptin was elevated in animals treated with GH when compared with saline animals and animals that received GH and fibrate. There was no significant difference in leptin concentrations between animals treated with GH and those given GH and acipimox.

Free fatty acids (FFA) Plasma FFAs were not significantly different between animals AD and SGA. Plasma FFA were significantly lower in AD and SGA animals treated with GH and acipimox when compared to animals treated with saline and treated with GH alone (Figure 16). Interestingly, the combination of GH and fibrate did not reduce the concentration of FFA and were significantly higher than those treated with GH and acipimox.

Triglycerides Plasma triglycerides were not significantly different between animals AD and SGA (Figure 17). Triglycerides were significantly lower in animals treated with GH and acipimox when compared with other treatment groups. There was no significant effect of GH treatment on triglycerides when compared to controls treated with saline.

Free glycerol There was no difference in plasma glycerol between animals AD and SGA (Figure 18). Plasma glycerol was significantly lower in animals treated with GH and acipimox when compared to the rest of the treatment groups. (Figure 18).

Systolic blood pressure As our group has shown previously, systolic blood pressure was significantly elevated in SGA animals (Figure 19). The treatment of the offspring of SGA with GH or GH and FFA regulators significantly reduced and normalized the systolic blood pressure (Figure 20). This is consistent with our previous reports on the antihypertensive effects of GH. (Vickers et al., 2002). The systolic blood pressure was normal in AD animals and there was no effect of the treatment.

Discussion The effects of combination therapy on body weight gain were as marked in normal animals as they were in animals born with low birth weight. However, with respect to the combination therapy with GH and acipimox in AD animals, the weight gain remained high during the study when compared with animals treated with GH. This reduction in dose efficacy was not observed in SGA animals in which there was a clear divergence in body weight gain compared to animals treated with GH as the study progressed. It has unexpectedly been found that synergistic combination therapy comprising GH and a nicotinic acid-derived FFA regulator, acipimox, potentiated linear growth significantly over GH alone or GH combined with fenofibrate. Monotherapy with GH and GH combination therapy increased bone length in all treatment groups when compared to controls. It has been found that the combination treatment of GH and acipimox strongly enhances the effects of GH on the growth of the tibia and achieves a greater increase in the length of the tibia than GH in combination with fenofibrate. In addition, it has been found that both combination treatments reduced the loss of trabecular bone associated with GH monotherapy. It has been unexpectedly found that the combination therapy comprising GH and an FFA regulator derived from nicotinic acid, acipimox, has a beneficial effect on plasma volumes in the treatment group, when compared to animals treated with GH or combination of GH with FFA regulator derived from fibric acid. In the group treated with GH and acipimox there was no increase in plasma volume associated with monotherapy with GH. The SGA animals had a high blood pressure when compared to AD animals. The systolic blood pressure was normalized in this group using either GH alone or a combination that was consistent with the authors' previous patented observations. In summary, GH and acipimox therapy potentiates linear growth over that of GH alone and relieves the fluid retention effects normally associated with GH therapy. The combination of GH and fenofibrate was less effective than that of GH and acipimox. The authors have observed metabolic benefits of combined GH and acipimox therapy (including improved insulin sensitivity and blockade of lipolytic effects induced by GH treatment, ie pharmacological antilipolysis) with respect to GH monotherapy.

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Claims (29)

1. CLAIMS 1. A method for treating a growth dier in a young person, said method comprising administering to said youth an effective amount of at least one FFA regulator combined with growth hormone.
2. 2. A method for increasing the growth promoting effects of growth hormone therapy in a young person, said method comprising administering an effective amount of at least one FFA regulator combined with growth hormone.
3. 3. A method for preventing or treating an adverse consequence of treatment with growth hormone in a mammal, which comprises administering an effective amount of at least one FFA regulator combined with said growth hormone treatment.
4. 4. The method according to claim 3, wherein said mammal suffers a growth dier.
5. 5. The method according to claim 3, wherein said adverse consequence is edema.
6. 6. The method according to claim 3, wherein said adverse consequence is trabecular bone loss associated with the first stages of GH therapy.
7. 7. Method according to any of the preceding claims, wherein said young or said mammal is a human being.
8. 8. The method according to any of the preceding claims, wherein said growth dier is selected from a group consisting of growth hormone insufficiency, growth hormone deficiency, intrauterine growth retardation, premature character, growth retardation in children who were born small for their gestational age, very low birth weight, skeletal abnormalities, chromosomal variations, growth retardation related to chronic renal failure, constitutional growth retardation, growth retardation related to cystic fibrosis, idiopathic short stature, short stature due to glucocorticoid treatment in children, compensatory growth retardation for premature infants with short stature or any other pathological condition that results in short stature.
9. 9. Process according to the preceding claims, wherein said FFA regulator is fibric acid, nicotinic acid, a fibric acid derivative or a nicotinic acid derivative.
10. 10. The method according to claim 9, wherein said FFA regulator is nicotinic acid or a nicotinic acid derivative.
11. 11. The process according to claim 10, wherein said FFA regulator is acipimox.
12. 12. The method according to any of the preceding claims, wherein said GH is administered by subcutaneous injection.
13. 13. The method according to any of the preceding claims, wherein said FFA regulator (s) is administered orally.
14. 14. Use of a combination of growth hormone and at least one FFA regulator in the preparation of a medicament or composition for treating growth diers in a young person.
15. 15. Use of at least one FFA regulator in the preparation of a medicament for increasing the growth promoter effects of growth hormone therapy in a young person.
16. 16. Use of at least one FFA regulator in the preparation of a medicament for preventing or treating the adverse consequences of treatment with growth hormone in a mammal.
17. 17. Use according to claim 16, wherein said mammal suffers from a growth dier.
18. 18. Use according to claim 16, wherein said adverse consequence is edema.
19. 19. Use according to claim 16, wherein said adverse consequence is loss of trabecular bone associated with the first stages of GH therapy.
20. 20. Use according to any one of claims 14 to 19, wherein said young or said mammal is a human being.
21. 21. Use according to any of claims 14 to 20, wherein said growth dier is selected from a group consisting of growth hormone insufficiency, growth hormone deficiency, intrauterine growth retardation, prematurity, growth retardation in children who were born small for their gestational age, very low birth weight, skeletal abnormalities, chromosomal variations, growth retardation related to chronic renal failure, delay constitutional growth, growth retardation related to cystic fibrosis, idiopathic short stature, short stature due to treatment with glucocorticoids in children, compensatory growth retardation for premature infants with short stature or any other pathological state that results in short stature.
22. 22. Use according to any one of claims 15 to 21, wherein said medicament comprises a combination of said growth hormone and said FFA regulator (s).
23. 23. Use according to any one of claims 14 to 22, wherein said FFA regulator is fibric acid, nicotinic acid, a fibric acid derivative or a nicotinic acid derivative.
24. 24. Use according to claim 23, wherein said FFA regulator is nicotinic acid or a nicotinic acid derivative.
25. 25. Use according to claim 24, wherein said FFA regulator is acipimox.
26. 26. A composition or medicament for treating growth disorders and / or preventing or treating the adverse consequences of treatment with growth hormone, comprising growth hormone and at least one FFA regulator.
27. 27. A composition according to claim 26, wherein said composition or medicament comprises a vehicle and / or pharmaceutical excipient suitable for said growth hormone and / or said FFA regulator (s).
28. 28. Composition according to claim 26 or 27, wherein said FFA regulator is fibric acid or a fibric acid derivative.
29. 29. Composition according to claim 28, wherein said FFA regulator is fenofibrate.