JP5685362B2 - Acetyl L-carnitine for the prevention of painful peripheral diabetic neuropathy - Google Patents

Description

  The present invention relates to the use of acetyl L-carnitine (ALC) for the preparation of a medicament useful for the prevention of painful peripheral neuropathy characterized by pain, abnormal sensation or hypersensitivity in patients with type 2 diabetes.

  Diabetic neuropathy is the most frequent peripheral neuropathy in the West, including various forms of neuropathy, the most common of which is diabetic polyneuropathy.

  The anatomical-pathological picture of diabetic peripheral neuropathy is localized or pervasive non-specific fiber loss, showing demyelination associated with structural or endoneuronal abnormalities of connective tissue or small blood vessels. Accompany.

  Various metabolic abnormalities and biochemical changes have been documented in both experimental models of diabetes and diabetic patients, including increased glucose metabolism and decreased myo-inositol.

  A characteristic symptom of diabetic polyneuropathy is the presence of burning or electric shock associated with clinical signs of symmetric sensitivity, motility, and / or deep tendon reflexes, such symptoms appear in the distal part of the lower limbs Mainly exists.

  Diabetic peripheral neuropathy is caused by hyperglycemia, and metabolic imbalance and neurotrophic ischemia due to hyperglycemia are the best known pathogenic mechanisms.

  Many variables generally can accelerate or slow the onset of characteristic symptoms of diabetic peripheral neuropathy, particularly painful peripheral neuropathy; for example, good metabolic control of serum glucose levels ensures the onset of the symptoms Can be late.

  The use of acetyl L-carnitine for the prevention of painful peripheral neuropathy in patients with type 2 diabetes has not been described previously.

  In the literature you can find many publications aimed at demonstrating or elucidating the therapeutic role of acetyl L-carnitine in the treatment of numerous symptoms in the course of diabetic neuropathy, for example neuropathic pain Such publications do not disclose or suggest that acetyl L-carnitine is a useful compound for the prevention of painful peripheral neuropathy in patients suffering from type 2 diabetes.

  Diabetes Care, 2005; Jan; 28 (1): 89-94, reported that treatment with ALC is useful for alleviating pain symptoms and regenerating nerve fibers in patients with stabilized diabetic neuropathy. ing.

  “Giornale Italiano di Diabetologia, 1998, V.18, 30-31” describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with sensorimotor polyneuropathy.

  Drugs in Research and Development 2002, Vol 3 (4), pp 223-31 describes the use of acetyl L-carnitine for the treatment of neuropathic pain in diabetic neuropathy patients.

  Diabetologia 1995, VOL / ISS / PG. 38/1 (123) describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with diabetic neuropathy.

  “IL GIORNALE DEI CONGRESSI MEDICI, 5, 14-19,1993” describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with diabetic neuropathy being treated with insulin or oral antidiabetic drugs. Use is described.

  J. of the American Diabetes Association June 2002, Vol 51, Supplement 2, describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with diabetic neuropathy.

  CONGRESSO NAZIONALE DELLA SOCIETA ITALIANA DI NEUROFISIOLOGIA CLINICA, ABSTR ACTS, PERUGIA 1-4 June, 1994, p 98 describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with diabetic neuropathy. Yes.

  Clin. Drug. Invest, Vol 10 (6), pp 317-22 1995 describes the use of acetyl L-carnitine for the treatment of neuropathic pain in diabetic neuropathy patients.

  Int. J. Clin. Pharm. Res. XV (1): 9-15; 995 describes the use of acetyl L-carnitine for the treatment of pain in patients with diabetic neuropathy.

  In the Journal of the Neurological Sciences, 1997, Suppl. To Vol 150, it is reported that acetyl L-carnitine improves nerve conduction velocity in diabetic patients suffering from polyneuropathy.

  IX CONGRESSO NAZIONALE SOCIETA 'ITALIANA DI FARMACOLOGIA CLINICA; II CONGRESS MEDITERRANEAN SOCIETY CLINICAL PHARMACOLOGY "THERAPEUTIC ADVANCES AND NEW HEALTH PROBLEMS", VENICE, 8-10 / 10/1991 ABS The effect of acetyl L-carnitine treatment on patients is described.

  Drugs 1997 Sept: 54 (3) 414-421 reports that acetyl L-carnitine improves nerve conduction velocity in diabetic patients suffering from neuropathy.

  US Pat. No. 4,751,242 describes the use of acetyl L-carnitine for the treatment of neuropathic pain in patients with peripheral neuropathies of various origins, such as diabetic peripheral neuropathy.

  WO 02096409 refers to the use of acetyl L-carnitine for the preparation of a medicament having “pre-emptive-type” analgesic activity. “Prophylactic” analgesia involves the initial administration of a substance to a painful event, which can inhibit the central nervous system input of pain stimuli and thus promote responses to the spinal cord elicited by nociceptive stimuli It is a therapeutic strategy that includes preventing this. The efficacy of “prophylactic” analgesics as described in WO 02096409 not only depends on the time to start treatment for painful events, but also on the effective ability of drugs to prevent changes in the central pain sensitization mechanism Also depends.

  WO 02096409 shows prevention of pain that occurs after surgery as an example of preventive pain therapy.

  In these studies, there is no disclosure or suggestion of the use of ALC for the prevention of painful peripheral neuropathy in patients with type 2 diabetes.

  In the pharmaceutical field, there are no drugs known to be useful for the prevention of painful peripheral neuropathy in patients with type 2 diabetes.

  It has now been found that acetyl L-carnitine can be used as a useful drug for the preparation of a medicament for the prevention of painful peripheral neuropathy in patients with type 2 diabetes.

  The object of the present invention is therefore the use of acetyl L-carnitine, or one of its pharmaceutically acceptable salts, for the preparation of a medicament for the prevention of painful peripheral neuropathy in patients suffering from type 2 diabetes, Wherein the painful peripheral neuropathy is characterized by a symptom selected from the group consisting of pain, dysthesia and hypersensitivity.

  By pharmaceutically acceptable salt of acetyl L-carnitine is meant any salt of acetyl L-carnitine and an acid that does not cause undesirable toxic effects. Such acids are well known to pharmacists and those skilled in the pharmaceutical arts.

  Non-limiting examples of such salts include, for example, chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate and acid fumarate, Magnesium fumarate, lactate, maleate and acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulfate, glucose phosphate, tartrate, acid tartaric acid Salts, magnesium tartrate, 2-aminoethanesulfonate, magnesium 2-aminoethanesulfonate, choline tartrate and trichloroacetate.

  The following examples illustrate the invention.

Example 1 (clinical trial BM14329)
A 52-week, multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in type 2 diabetic patients with diabetic peripheral neuropathy.

  Patients were treated with acetyl L-carnitine at a dose of 0.5 g or 1 g three times daily or with placebo for 52 weeks.

  Patients included in the study were male and female 18-70 years old whose diabetes had been diagnosed for more than a year and HbA1c exceeded 5.9%.

  After 12, 26, and 52 weeks of treatment, the presence and intensity of pain, dysthesia and hypersensitivity, among other variables, was associated with painful peripheral neuropathy in patients who did not show such symptoms at the start of the study. Evaluated as characteristic symptoms.

  At the end of the clinical trial, statistical analysis of the results obtained shows that treatment for 26 or 52 weeks with ALC can cure the symptoms of diabetic peripheral neuropathy that already existed at the start of the clinical trial. Indicated. The therapeutic effect was not the same in all treated populations, but was better only in patients with type 2 diabetes.

  Through further processing of experimental data from this clinical trial, surprisingly surprisingly, acetyl L-carnitine can cure symptoms typical of diabetic painful peripheral neuropathy, including pain, hypersensitivity and sensory abnormalities It has been shown that not only can this be prevented in patients who did not show such symptoms at the beginning of the study.

  Even more surprising was the discovery that the prophylactic activity was only shown when the drugs administered in patients with type 2 diabetes were used at high doses.

The results in type 2 diabetic patients treated with 3 g / day dose of ALC are reported in Table 1-3 below.
Table 1

Table 2

Table 3

Example 2 (clinical trial BM14330)
A multicenter randomized, double-blind, placebo-controlled clinical trial was conducted with the same characteristics as the clinical trial described in Example 1.

  The results obtained in type 2 diabetic patients treated with ALC at a dose of 3 g / day are reported in Table 4-6 below.

Table 4

Table 5

Table 6

  When analyzing the results reported in Table 1-6, the compounds according to the present invention are statistically significant to prevent the onset of symptoms associated with diabetic painful peripheral neuropathy, such as pain, dysthesia and hypersensitivity. It is understood that it has shown ability.

  Acetyl L-carnitine is a known compound and its method of preparation is described in US Pat. Nos. 4,439,438 and 4,225,053.

  Acetyl L-carnitine may be in any form suitable for oral or parenteral administration in a human subject.

  Based on various factors such as active ingredient concentration and patient symptoms, the compounds according to the invention can be marketed as health food supplements, nutritional supplements or therapeutic products and can be obtained with or without a doctor's prescription. .

  The daily dose to which the active ingredient should be administered depends on the patient's age, weight and systemic symptoms and is based on expert judgment to prevent diabetic painful peripheral neuropathy in patients with type 2 diabetes However, it has been found that it is necessary to administer an amount of ALC corresponding to at least 3 g / day in multiple doses, or an equimolar amount of one of its pharmaceutically acceptable salts.

  The medicament according to the present invention provides an active ingredient (acetyl L-carnitine inner salt or one of its pharmaceutically acceptable salts) for enteral (particularly oral) or parenteral (particularly intramuscular or intravenous) administration. It can be prepared by mixing with excipients suitable for the formulation of the composition.

  Such excipients are well known to specialists in the pharmaceutical field.

  Pharmaceutically acceptable salts of the active ingredients include any pharmaceutically acceptable salt prepared by addition of an acid to acetyl L-carnitine inner salt that does not cause undesirable toxicity or side effects. Salt formation by acid addition is well known in the pharmaceutical art.

Claims (2)

A pharmaceutical composition comprising one of acetyl L- carnitine or a pharmaceutically acceptable salt thereof for the prevention of painful peripheral neuropathy in patients suffering from type 2 diabetes, is the painful peripheral neuropathy Characterized by a symptom selected from the group consisting of pain, abnormal sensation and / or hypersensitivity , said prevention being a patient suffering from type 2 diabetes and diabetic painful peripheral nerve It means the action of preventing the onset of the above various symptoms for patients who have not developed any of the symptoms of pain, abnormal sensation and hypersensitivity which are characteristic symptoms of the disorder, and the pharmaceutical composition contains acetyl L- A pharmaceutical composition for orally administering carnitine at a dose of at least 3 g / day .   Pharmaceutically acceptable salts of acetyl L-carnitine include chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate and acid fumarate , Magnesium fumarate, lactate, maleate and acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulfate, glucose phosphate, tartrate, acid tartrate, The pharmaceutical composition of claim 1 selected from the group consisting of magnesium tartrate, 2-aminoethane sulfonate, magnesium 2-aminoethane sulfonate, choline tartrate and trichloroacetate.