HK1139038A - Composition useful for the prevention of adverse effect due to the use of ppar-gamma agonists - Google Patents

Description

Composition for preventing adverse effects due to PPAR-gamma agonist

The present invention relates to the use of acetyl L-carnitine (acetyl L-carnitine) or a salt thereof for the preparation of a medicament for the prevention of the harmful effects due to PPAR-gamma agonists.

Background

PPAR-gamma agonists are agents useful for reducing insulin resistance in prediabetic obese patients and for treating type II diabetes.

Insulin resistance is a silent condition that increases the likelihood of developing type 2 diabetes. In the case of insulin resistance, muscle, fat, and liver cells cannot properly utilize insulin. The pancreas attempts to meet the demand for insulin by producing more insulin. Too much weight also contributes to insulin resistance because too much fat hinders the ability of the muscle to utilize insulin. Lack of exercise further reduces the ability of the muscle to utilize insulin.

According to the American Diabetes Association, pre-Diabetes may be defined as a condition that exists when a person's blood glucose levels are higher than normal but not high enough to diagnose Diabetes. Of the patients with pre-Diabetes in Diabetes mellitus standards and control groups, approximately 11% of the individuals develop type 2 Diabetes mellitus annually during an average 3-year follow-up. Other studies have shown that many people with pre-diabetes develop type 2 diabetes within 10 years.

Prediabetes have previously been referred to as Impaired Glucose Tolerance (IGT) and are also known as borderline or chemical diabetes.

Obesity associated with insulin resistance and prediabetes may be an increased risk factor for hypertension, one of the most important risk factors for cardiovascular disease, which may lead to heart attack or stroke. Hypertension, if untreated, can also lead to a variety of other life-threatening conditions such as kidney damage and congestive heart failure.

Thus, people with obesity and insulin resistance have a higher risk of cardiovascular disease. People with pre-diabetes are at a 1.5-fold increased risk of cardiovascular disease as compared to people with normal blood glucose, while people with diabetes are at a 2-4-fold increased risk of cardiovascular disease. Always according to the american diabetes association, people with pre-diabetes can delay or prevent the onset of type 2 diabetes. This can be done through lifestyle changes.

In the united states, it is estimated that 2000 million people have pre-diabetes, and this number is rapidly increasing. 50% of people with pre-diabetes are likely to develop type 2 diabetes.

Early diagnosis is important. In the early years of pre-diabetes or diabetes, β -cells are progressively destroyed by hyperglycemia. Usually by the time diabetes is diagnosed, half of the beta cells are not functional. This cannot be reversed because the beta cells can be traced back to insulin production. However, near 100% of β -cells are functional when early diagnosis of prediabetes is performed. If lifestyle changes are made and some diabetes medications are used immediately, many beta cells will remain healthy and make glycemic control easier.

Diabetes or pre-diabetes can be detected and differentially diagnosed using one of the following tests:

fasting glucose test, which measures blood glucose after not eating overnight. This test is most reliable when performed in the morning. Fasting glucose levels of 100-125mg/dL are above normal, but not high enough to be termed diabetes. This condition is known as prediabetes or Impaired Fasting Glucose (IFG) and suggests that the patient may have developed insulin resistance for some time. IFG is considered a pre-diabetic state, meaning that the patient is likely to develop diabetes but has not yet suffered from diabetes. Levels at or above 126mg/dL are commonly associated with diabetes.

Glucose tolerance test, which measures blood glucose after an overnight fast and 2 hours after the patient drinks a sweet liquid provided by a doctor or laboratory. If the patient's blood glucose falls to 140-199mg/dL 2 hours after drinking the fluid, the patient's glucose tolerance is greater than normal, but not high enough to be diabetic. This condition is also a form of pre-diabetes, known as Impaired Glucose Tolerance (IGT), which, like IFG, indicates a history of insulin resistance and a risk of developing diabetes.

Levels at or above 200mg/dL are commonly associated with diabetes.

Insulin resistance can be assessed using measurements of fasting insulin.

If routine testing indicates that the patient has IFG or IGT, the physician may recommend dietary changes and exercise in order to reduce the risk of developing diabetes.

Diabetes is a disease that is widespread throughout the world and is associated with major clinical complications including microvascular complications such as diabetic retinopathy, diabetic neuropathy and nephropathy, and macrovascular complications such as atherosclerosis, peripheral vascular disease, obesity, hypertension, myocardial infarction, stroke, polycystic ovary syndrome and syndrome X (j.am. osteopath.assoc., 2000 oct., 100 (10): 621-34; Jama, 2002 nov., 27; 288 (20): 2579-88).

The complications constitute a serious threat to the life and health of the individual.

The use of acetyl L-carnitine in the medical field is known.

For example, WO98/01128 discloses the use of acetyl L-carnitine, isovaleryl L-carnitine, propionyl L-carnitine for increasing the level of IGF-1. Osteoporosis is included in the list of pathologies mentioned in WO 98/01128.

WO 98/41113 describes a therapeutic nutritional composition for diabetic patients comprising gamma linoleic acid, acetyl L-carnitine, inorganic salts and vitamins.

US 4362719 describes the use of L-carnitine and acyl L-carnitine for the treatment of juvenile onset diabetes.

US 5430065 describes the use of L-carnitine and acyl L-carnitines for the long-term treatment of non-insulin dependent diabetic patients.

The addition of acetyl L-carnitine to the culture medium has been reported in Journal of Cellular Physiology, 203, 2005, 439-.

None of the above publications describes the use of acetyl L-carnitine for the preparation of a medicament for the prevention of the harmful effects due to PPAR-gamma agonists.

PPAR-gamma agonists include, but are not limited to: spirolaxine and glitazone derivatives are known classes of drugs that can be used to prevent or reduce insulin resistance in obese patients and for the treatment of type II diabetes.

PPAR-gamma agonists act as transcriptional regulators of genes involved in glucose and lipid metabolism (Diabetes 47 (4): 507-April 14, 1998). PPAR-gamma is expressed in many tissues, increasing the likelihood that a drug interacting with it may induce a clinical effect other than insulin sensitization. Among the tissues expressing PPAR- γ is bone. In bone tissue, PPAR- γ functions as a molecular switch that regulates the fate of pluripotent mesenchymal stem cells, which are capable of differentiating into adipocytes or osteoblasts. In vitro, PPAR-gamma agonists promote adipocyte differentiation in preference to osteoblast differentiation.

It is known in the art that PPAR-gamma agonists, an antidiabetic compound, have several deleterious effects.

Indeed, in j.endocrinol.2004 Oct; 183(1): 203-16 report that Thiazolidinediones (TZD) used for the treatment of type 2 diabetes increase the risk of osteoporosis.

In Endocrinology, 2005 Mar, 146 (3): 1226-35, Epub 2004 Dec reported that peroxisome proliferator activated receptor gamma isoform activation is a negative regulator of bone mass, and suggested that the production of oxidized fatty acids with increasing age could in fact be an important mechanism for the development of age-related osteoporosis in humans.

A study published in the Journal of Clinical Endocrinology and Metabolism, 2007, jan, 30 found that short-term treatment with a commonly prescribed PPAR-gamma agonist inhibited bone formation and accelerated bone loss in an experiment conducted in 50 healthy postmenopausal women.

Studies conducted on more than 4,000 patients with type 2 diabetes have unexpectedly found that the use of rosiglitazone in women gives rise to a higher rate of fracture (most commonly involving fractures of the humerus (homerous), hand and spine) than the use of metformin or glyburide (glyburide) (scrip no 3216, p 18).

In contrast, non-diabetic postmenopausal women with osteoporosis exhibit a higher rate of fracture of the femur and lower extremities.

To date, there has been no explanation for osteoporosis-related major fractures in different body parts in postmenopausal non-diabetic patients due to osteoporosis caused by rosiglitazone.

The presence of diabetes and treatment with, for example, rosiglitazone, represents a difference between the two groups of patients.

Furthermore, The Annals of Pharmacotherapy 2001, January, Vol35 reported that patients treated with rosiglitazone showed significant pulmonary and peripheral edema, and this may be a thiazolidinedione effect.

Patients treated with rosiglitazone were reported to exhibit increased weight gain and fluid retention with edema in the Journal of Clinical Endocrinology & Metabolism, Vol 86, N ° 1, 2001 and Diabetes Care, Volume 24, N ° 7, July 2001.

There remains a clear need in the medical field for compounds that can be used to reduce or prevent the deleterious effects caused by the use of PPAR-gamma agonists.

Disclosure of Invention

It has now surprisingly been found that acetyl L-carnitine, or a pharmaceutically acceptable salt thereof, can be used for the preparation of a medicament for the prevention of the harmful effects caused by the use of PPAR-gamma agonists. Pharmaceutically acceptable salts of acetyl L-carnitine refer to any salt of acetyl L-carnitine with an acid that does not cause toxic or side effects.

These acids are well known to those skilled in the art of pharmacologists and pharmaceutics. Non-limiting examples of such salts are: chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate (acid sulfate), glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate (mucate), magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate, and trifluoroacetate.

Pharmaceutically acceptable salts of L-carnitine also represent salts approved by the FDA and listed in publications, which are incorporated herein by reference. J.of pharm.33(1986), 201-217, which is incorporated herein by reference.

Accordingly, one object of the present invention is the use of acetyl L-carnitine or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of the harmful effects due to the use of a PPAR-gamma agonist selected from the group consisting of spirolaxine of formula (I)

Or a glitazone derivative selected from troglitazone (roglitazone), pioglitazone, or rosiglitazone;

wherein: the adverse effects due to the use of PPAR-gamma agonists are selected from osteoporosis, weight gain, and edema.

Another object of the present invention is a pharmaceutical composition comprising as active ingredients acetyl L-carnitine and a PPAR-gamma agonist, optionally together with one or more pharmaceutically acceptable diluents and/or excipients.

Detailed Description

Treatment of pre-diabetic obese patients shows the unexpected protective effect of the compounds of the present invention.

Example 1

Six osteoporosis patients were selected in a group of patients treated orally with rosiglitazone at 8 mg/day for 12 months, with osteocalcin (osteopalcine) < 3.5pg/l, IGF1 < 350 ng/ml.

In these 6 patients, serum levels of osteocalcin and IGF1 increased slightly, although not significantly, after a one-month washout period (without treatment with rosiglitazone) (table 1), while Body Weight (BW) and systemic water content (TWB) showed no change (table 2).

TABLE 1

Serum levels of osteocalcin (pg/L) and IGF1(ng/ml) after treatment with rosiglitazone (T0) and a wash out period of 1 month (T1)

TABLE 2

BW and TBW (evaluated using the heavy water system) after treatment with rosiglitazone (T0) and a wash out period of 1 month (T1).

After this washout period, treatment with a combination of rosiglitazone (at the same dose) and acetyl L-carnitine (3 g/tablet, administered o.s.) was initiated.

Serum levels of osteocalcin and IGF1 were monitored after 4 months of treatment with the combination of rosiglitazone and acetyl L-carnitine.

The results obtained are reported in tables 3 and 4, respectively.

TABLE 3

Osteocalcin (pg/L) and IGF1(ng/ml) serum levels at 1 month washout of rosiglitazone (T1) and after 4 months of treatment with rosiglitazone and acetyl L-carnitine (T2)

TABLE 4

Body Weight (BW) and systemic water content (TBW) at 1 month washout of rosiglitazone (T1) and after 4 months of treatment with rosiglitazone and acetyl L-carnitine (T2)

The results reported in Table 3 indicate that osteocalcin and IGF1 were significantly increased (p < 0.02 and p < 0.001).

The results reported in Table 4 show a significant reduction in BW and TBW (p < 0.001).

The results reported above indicate that the compounds of the present invention are useful in the treatment of the deleterious effects caused by the use of PPAR-gamma agonists.

The compositions of the present invention comprise active ingredients known in the medical field and already used in clinical practice. They are therefore very readily available as products already on the market for some time and are of a grade suitable for human or animal administration.

Spirolaxine is a known compound described in EP 1368025B 1.

Glitazones are known compounds available on the market and can be prepared according to the methods described in the literature. The glitazones are administered in an amount of 1mg to 10mg per day, preferably 3 to 9mg per day, most preferably 8mg per day.

Acetyl L-carnitine is a known compound, the preparation of which is described in US4,254,053. Acetyl L-carnitine may be administered in an amount of 0.5-6 g/day, preferably 1-5 g/day, most preferably 3 g/day.

The daily dose to be administered according to the invention depends on the judgment of the attending physician, on the weight, age and general condition of the subject.

The compositions of the invention may have a single form for simultaneous administration, in which the active ingredients are present in a single pharmaceutical composition (tablet, sachet, capsule, vial), or the active ingredients may be administered in a coordinated sequential manner. In the latter case, the pharmaceutical composition may be formulated such that the components are provided in separate containers with instructions for their sequential administration.

The compositions of the invention are entirely conventional and are obtained by methods routinely practiced by the pharmaceutical industry. Depending on the route of administration chosen, the compositions may be in solid or liquid form suitable for oral, parenteral or intravenous administration. The compositions of the invention comprise at least one pharmaceutically acceptable vehicle or excipient together with the active ingredient. Particularly useful may be formulation aids such as, for example, solubilizers, dispersants, suspending agents and emulsifiers. The general reference is Remington's Pharmaceutical Sciences Handbook, latest edition.

Claims (9)

1. Use of acetyl L-carnitine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of the harmful effects due to the use of PPAR-gamma agonists.

2. The use of claim 1, wherein the PPAR-gamma agonist is selected from spirolaxine of formula (I)

Or a glitazone derivative selected from troglitazone, pioglitazone or rosiglitazone.

3. The use of claim 1, wherein the deleterious effects are selected from the group consisting of osteoporosis, weight gain, and edema.

4. The use of claim 1, wherein the pharmaceutically acceptable salt of acetyl L-carnitine is selected from the group consisting of chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate, and trifluoroacetate.

5. A pharmaceutical composition comprising as active ingredients acetyl L-carnitine and a PPAR-gamma agonist, and optionally one or more pharmaceutically acceptable diluents and/or excipients.

6. The pharmaceutical composition of claim 5, wherein the PPAR-gamma agonist is selected from spirolaxine of formula (I) or a glitazone derivative selected from troglitazone, pioglitazone or rosiglitazone.

7. A pharmaceutical composition according to claim 5, wherein the active ingredient is in solid or liquid form suitable for oral or parenteral administration, in the form of tablets, sachets, capsules or vials.

8. The pharmaceutical composition of claim 5, wherein the active ingredients are in a single pharmaceutical form for simultaneous administration.

9. The pharmaceutical composition of claim 5, wherein the active ingredients are in separate containers and are administered in a coordinated sequential manner.