FR2703248A1 - New compositions with antidiabetic and anti-tissue-degeneration activity based on 4-hydroxybutyric acid - Google Patents

Abstract

The present invention relates to the field of chemotherapy. The subject of the invention is a pharmaceutical composition combining 4-hydroxybutyric acid and nicotinamide. It has a potentiated antidiabetic activity. The compositions according to the invention are furthermore potentially of interest in the treatment of other degenerative tissue pathologies, in human medicine and in veterinary medicine.

Description

NEW COMPOSITIONS WITH ANTIDIABETIC ACTIVITY
AND TISSUE ANTI-DEGENERATION
BASED ON 4-EYDROXY BUTYRIC ACID
The present invention is directed to the field of therapeutic chemistry and more particularly to a new diabetes medicine.

More specifically, it relates to novel pharmaceutical compositions exhibiting an antidiabetic activity potentiated with respect to the eigenfunction of each of the active constituents.

Progress remains to be made in the treatment of degenerative tissue pathologies such as, for example, diabetes (types I and II), pancreatitis, cerebral senescence (memory disorders,
Parkinson, Alzheimer's disease) hypoxia (cerebral, cardiac), cataract, retinitis, osteoarthritis, etc.

The evolution of these pathologies is determined by a set of risk factors such as genetic characteristics, the more or less aggressive influences of the tissue environment (hypoxia, deficiencies, xenobiotics, immunological effects, etc.), the biological reactions to these diseases. influences (inflammation) as well as the psycho-behavioral and organic reactions (neuro-vegetative, neuro-endocrine, vasomotor) of the individual to his environment.

From a metabolic point of view, at the cyto-tissue level, these risk factors cause disturbances which, to varying degrees, can participate in the process of tissue degeneration. The most common known disturbances are - slowing of mitochondrial energy processes (hypoxia) - dysfunction of acid maintenance mechanisms
nucleic acid (DNA, RNA), pyridine nucleotides (NAD, NADP),
phospholipids and membrane receptors - electrolyte and water imbalance, intra and extracellular
(K +, Ca ++, Mg ++) - an increase in harmful free radicals resulting, on the one hand,
increased production (reperfusion after hypoxia or after
hypothermia, catabolism of purine bases and catecholamines)
and, on the other hand, insufficient capacity of the mechanisms
causing their detoxification, particularly under the control of NADPH
and Glutathione.

- alterations of mitochondrial and nuclear DNA - an increase in nitrogen catabolism (proteolysis) and waste which
must be detoxified and eliminated.

The metabolic crisis, linked to these disturbances, decreases the repolarization capacity of the membrane, modifies the cellular exchanges with the environment, exposes the cells to the more or less aggressive fluctuations of this one, modifies the regulations related to the gene expression and alters thus the functional and structural integrity of tissues and organs.

In addition to symptomatic and / or substitutive treatments for the condition, the treatment of a degenerative disease must include means to correct all the risk factors and metabolic disturbances that accompany it, with a view to stopping or to slow down the process of degeneration itself.

In this respect, the object of the present invention constitutes a progress for a better control of the processes of tissue degeneration.

The present invention specifically relates to pharmaceutical compositions in which 4-hydroxybutyric acid or a salt thereof and nicotinamide are mixed with or added to a pharmaceutically acceptable excipient or non-toxic inert carrier.

According to the present invention, 4-hydroxybutyric acid (GHB) and nicotinamide (NCA) mutually enhance their tissue protection and regeneration activity. The potentiated activity results from the synergy of 4-hydroxybutyric acid and nicotinamide at the level of fundamental cyto-tissue mechanisms.

In the following, 4-hydroxybutyric acid is used either in the form of the lactone (gamma-butyrolactone), or in the form of a salt with a mineral or organic, therapeutically-compatible base.

The salts of 4-hydroxybutyric acid with a mineral or organic base may be defined as alkali metal salts, such as sodium, potassium, lithium, ammonium or rubidium; alkaline earth metal salts such as calcium or strontium; magnesium, aluminum or ferrous metals. It may also include salts of alkylamines, cycloalkylamines, arylalkylamines, pyridylalkylamines, furylalkylamines, hydroxyalkylamines, amino acids, desoxy-osamines, cyclitic amino, substituted guanidines, poly peptides or the like.

Preferred examples are alkali metal salts, calcium salts,
Magnesium or even salts with a basic amino acid.

Nicotinamide is used in free form or in salified form, for example with a mineral or organic acid. Nicotinamide ascorbate is one of the preferred salts.

4-hydroxybutyric acid can also be used in the compositions according to the invention in the form of an ester of the hydroxyl function with an inorganic or organic acid or else esters of the carboxylic function with an aliphatic or cycloaliphatic alcohol having 1 to 12 carbon atoms.

The molar proportions of each of the constituents can vary from 1 p. of 0.1% hydroxybutyric acid of nicotinamide at 1 p 10 p
The usual proportions range from 1 part of hydroxybutyric acid to 0.5 part of nicotinamide to 1 part of hydroxybutyric acid to 2 parts of nicotinamide.

The compositions according to the invention are those which are suitable for administration by the digestive route, parenterally or locally.

In therapy, the oral dosage for the 4-hydroxybutyric acid / nicotinamide combinations can be from 0.1 to 20 mmol / day of 4-hydroxybutyric acid and from 0.1 to 20 mmol / day of nicotinamide. Parenterally or locally, doses may be higher or lower.

4-hydroxybutyric acid is a biological substance (LABORIT et al., 1960 - ROTH and GIARMAN, 1969) whose properties have been the subject of general reviews (MUYARD and LABORIT, 1977 - MAMELAK, 1989).

 It is currently used in surgical anesthesia for its hypnotic and muscle relaxant properties as well as in intensive care for its protective tissue properties (brain, intestine).

4-Hydroxybutyric acid has a remarkable protective effect on tissues subjected to hypoxia, posthypoxic reperfusion or free radical generators: cerebral hypoxia (Mc MILLAN, 1978 - DIXON et al, 1989), myocardial hypoxia (BREZINA et al, 1989), intestinal hypoxia (BOYD et al, 1989), kidneys preserved for transplantation (SHOLOKHOV et al, 1989), ionizing radiation (LABORIT et al., 1965), alloxic diabetes (PIERREFICHE et al, 1991). ).

4-hydroxybutyric acid is an agent that maintains tissue structures and functions despite adverse environmental conditions; it will be seen that this effect is exerted on the condition that certain other indispensable metabolic agents are available, in particular nicotinamide (precursor of NAD,
NADP).

The properties of 4-hydroxybutyric acid can be related to its metabolic activities: activation of the pentose phosphate pathway (VPP), activation (by coupling) of the glucuronic acid pathway (VAG) (KAUFMAN et al, 1983 ), activation of the endogenous opioid system (naloxone inhibition of the hypothermic effect, increase of striatum dopamine, increase of GH secretion, increase of cGMP in the hippocampus and brain tissue). In certain tissues, it acts by interaction with GABA B receptors (BERNASCONI et al, 1992).

Due to its properties, 4-hydroxybutyric acid is a repolarizing membrane agent that replenishes cellular K + ions.

In addition, it tends to decrease blood cholesterol (ROSENGARTEN et al, 1963) and to increase the secretion of glucocorticoids, especially when it is lowered (LABORIT et al, 1966).

Activation of the glucuronic pathway is a favorable element for connective tissue metabolism.

Nicotinamide (nicotinamide) or vitamin PP is the active moiety of two coenzymes, NAD and NADP, which, in combination with specific apo-enzymes, are involved in oxidation-reduction reactions, at different stages of degradation or degradation. synthesis of carbohydrates, fatty acids, amino acids and many other substances of cellular metabolism. Nicotinamide also intervenes in ADP ribosylation reactions for example, stopping translation by inactivation of the translocase in protein synthesis.

Nicotinamide has been shown to be able to decrease the diabetogenic effect of streptozotocin (LAZAROW et al., 1950) or alloxan (LAZARUS and SHAPIRO, 1973) and to reduce diabetes in the NOD mouse (YAMADA et al. 1982) or children with type I diabetes (CHASE et al., 1990).

The activity of nicotinamide is explained by an activating effect on the synthesis of pyridine dinucleotides (NAD, NADP) which decrease significantly in the pancreas during experimental diabetes induced by streptozotocin (HO and HASHIM, 1972).

The activity of nicotinamide is also explained by its inhibitory effect of poly (ADP-ribose) synthetase (YAMAMOTO and OKAMOTO, 1980) which is activated in pancreatic B cells under the action of agents such as streptozotocin, alloxane, ionizing radiation or inflammation.

According to OKAMOTO (1985), these agents induce the formation of oxidizing free radicals which cause alterations of the DNA at the mitochondrial level (WELSH et al., 1991) and at the nuclear level; these trigger the activation of poly (ADP-ribose) synthetase, resulting in the decrease of NAD and NADP and the decrease of NAD- and NADP-dependent cellular activities. This sequence of effects (OKAMOTO mechanisms) leads to the reduction of activity and death of pancreatic B cells. Thus, in general, cumulative alterations, especially at the level of mitochondrial DNA, could be an important factor promoting tissue aging and degenerative diseases (TROUNCE et al, 1989 - WELSH and roll, 1991). LINNANE et al., 1989).

- The action of 4-hydroxybutyric acid is NAD- and NADP-dependent
(pentose phosphate route, glucuronic acid route). A
sufficient availability in NAD and NADP is therefore necessary which,
in the present invention is provided by the supply of nicotinamide
and favored by 4-hydroxybutyric acid (availability in
ribose-5-P). In a situation of metabolic crisis, the interest of the acid
4-hydroxybutyric acid is to activate metabolic circuits of
which represent an energetic
several advantages
VPP and VAG lead to the production of trioses phosphates
(3-PGA, DHAP) which can form glycerol-3-phosphate; this one,
with DHAP, is one of the mitochondrial shuttles that
feed the respiratory chain (energy production in form
ATP) and provide regeneration of NAD from NADH
cytoplasmic, thus allowing the continued operation of
NAD-dependent pathways (eg glycolysis, VAG)
VPP generates NADPH that is used in GAW; this one, by a
series of reactions, provides some sort of transhydrogenation
of NADPH on NAD with NADH production. This feeds
mitochondrial shuttles and thus participates in the production
of energy (ATP).

- The combined intake of 4-hydroxybutyric acid and nicotinamide
also presents a synergy in terms of maintenance
cyto-tissue (repair, protection, regeneration). activation
of the pentose phosphate pathway regenerates reduced NADP, which is
used for biosynthetic reactions and that is essential for
cell protection against oxidative free radicals
(glutathione reductase). Activation of the pentose pathway
phosphates and the glucuronic route also leads to the formation of
pentose phosphates and triose phosphates. Ribose-5-phosphate is
used for the formation of coenzymes of nucleotide structure
(NAD, NADP, FAD, ATP, GTP, UTP, CTP, Coenzyme A,
Adenosyl-methionine, adenosyl-cobalamin) and for the synthesis of
nucleotides precursors of DNA and RNA.The activation of the
formation of triosephosphates (3-PGA, DHAP) leads, via
glycerol-3-phosphate, increased formation of precursor glycerides
phospholipids as well as diacylglycerols (DGs) which are
activators of protein kinase C. It also drives via the
3-phospho-glycerate, to the increased formation of other precursors of
phospholipids (glycine, serine) as well as glutathione (glycine,
cysteine) and keratins.

By the activities mentioned above, together with the effect of inhibiting nicotinamide on poly (ADP-ribose) synthetase, the combined supply of 4-hydroxybutyric acid and nicotinamide not only avoids the decrease in availability of adenosyl structures ( adenosine and nucleotide derivatives), but may increase it. The decrease of cholesterol and the increase of glucocorticoid secretion under the action of 4-hydroxybutyric acid alone could be explained by adenosine-dependent mechanisms. These may contribute to the effect of 4-hydroxybutyric acid and nicotinamide on streptozotocin-induced diabetes by decreasing triglyceride and free fatty acid levels (HOFFMAN et al, 1986).

The overall metabolic properties of 4-hydroxybutyric acid and nicotinamide can be amplified by growth hormone (GH) whose secretion is stimulated by 4-hydroxybutyric acid (TAKAHARA et al, 1977).

The properties of 4-hydroxybutyric acid and nicotinamide explain that the combinations of these products exhibit a synergy of protection and regeneration action, tissue. This can be checked on experimental diabetes induced in mice by streptozotocin (STZ) chosen as a model of degenerative pathology.

Repeated injection of streptozotocin (in 25 mM citrate buffer, pH 4.5) in the mouse at a dose of 40 mg / kg / day, ip, for 5 consecutive days makes it possible to obtain a progressive degradation of glucoregulation, which clearly appears 12 days after the start of treatment with streptozotocin (KOLB-BACHOFEN et al, 1988).

The administration of 4-hydroxybutyric acid (sodium salt), nicotinamide or combinations of 4-hydroxybutyric acid + nicotinamide, ip of J1 to Jll, decreases the increase in blood glucose and glucosuria. at day 12 (Tables 1 and 2), measured after 6 hours of fasting (from day 1 to day 5, the products are administered 1 hour before the injection of streptozotocin).

TABLE I
Effect of treatment with GHB, NCA and GHB + NCA
J.1 to J.ll on diabetes induced in the mouse by the STZ
(5x40 tg / kg / d, ip)

<tb><SEP> Controls <SEP> Controls <SEP> + NCA <SEP> 1.64 <SEP> + GHB <SEP> 1.64 <SEP> + GHB <SEP> 1.64
<tb><SEP> normal <SEP> STZ <SEP> (mM / kg) <SEP> (mM / kg) <SEP> + NCA <SEP> 1.64
<tb><SEP> (mM / kg)
<tb><SEP> n <SEP> = <SEP> 8 <SEP> n <SEP> = <SEP> 38 <SEP> n <SEP> = <SEP> 8 <SEP> n <SEP> = <SEP> 8 <SEP> = <SEP> 38
<tb> Blood glucose
<tb> mmol / l <SEP> 8.3 <SEP> 1.6 <SEP> 14.4 <SEP> 4.6 <SEP> 11.9 <SEP><SEP> 2.4 <SEP> 9, 2 <SEP><SEP> 2.4 <SEP> 9.5 <SEP><SEP> 2.1
<tb> to <SEP> J.12
<tb> Glycosuria
<tb> g / l <SEP> 0 <SEP> 23 <SEP> 2.5 <SEP> 0.5 <SEP> 0
<tb> to <SEP> J.12
<Tb>
TABLE 1 Bis
Effect of treatment with different doses of GHB + NCA
and by gamma-butyrolactone (GBL) + NCA
J.1 to J.11 on diabetes induced in the mouse by STZ (5x40 sg / kg / day, ip)

<tb><SEP> + GBL <SEP> 1.64 <SEP> GBH <SEP> 1.64 <SEP> GBH <SEP> 1.64 <SEP> GBH <SEP> 0.82 <SEP> GBH <SEP > 0.41
<tb><SEP> + NCA <SEP> 1.64 <SEP> NCA <SEP> 0.82 <SEP> NCA <SEP> 0.41 <SEP> NCA <SEP> 1.64 <SEP> NCA <SEP > 1.64
<tb><SEP> (mM / kg) <SEP> (mM / kg) <SEP> (mM / kg) <SEP> (mM / kg) <SEP> (mM / kg)
<tb><SEP> n = 8 <SEP> n = 8 <SEP> n = 8 <SEP> n = 8 <SEP> n = 8
<tb> Blood glucose
<tb> mmol / l <SEP> 8.3 <SEP> i <SEP> 0.8 <SEP> 8.0 <SEP> + <SEP> 1.7 <SEP> 10.2 <SEP> i <SEP > 3.1 <SEP> 11.0 <SEP> i <SEP> 2.3 <SEP> 12.7 <SEP> t <SEP> 4.2
<tb> to <SEP> J.12
<tb> Glycosuria
<tb> g / l <SEP> O <SEP> 1 <SEP> 1 <SEP> 0.5 <SEP> 7
<tb> to <SEP> J.12
<Tb>
Table II
Effect of treatment with GHB, NCA, GBB + NCA or GBL + NCA
from J.1 to J.25
on diabetes induced in the mouse by the STZ
(5 x 40 mg / kg / day, ip)

<tb><SEP> Controls <SEP> + <SEP> GBH <SEP>1;; 64 <SEP> + NCA <SEP> 1.64 <SEP> + GBH <SEP> 1.64 <SEP> + GBL <SEP> 1.64
<tb><SEP> STZ <SEP> + NCA <SEP> 1.64 <SEP> + NCA <SEP> 1.64
<tb><SEP> (mM / kg) <SEP> (mM / kg) <SEP> (mM / kg) <SEP> (mM / kg)
<tb><SEP> n = 8 <SEP> n = 8 <SEP> n = 8 <SEP> n = 8 <SEP> n = 8
<tb> Blood glucose
<tb> mmol / l <SEP> (D12) <SEP> 15.1 <SEP> 4.7 <SEP> 9.0 <SEP> 2.6 <SEP> 11.0 <SEP> 2.5 <SEP > 9.0 <SEP> 1.7 <SEP> 8.3 <SEP> 0.8 <SEP>
<tb><SEP> (D18) <SEP> 26.3 <SEP> 8.0 <SEP> 17.8 <SEP> 7.6 <SEP> 17.1 <SEP> 8.5 <SEP> 8, 9 <SEP> 3.1 <SEP> 7.9 <SEP> 2.6
<tb> Glycosuria
<tb> g / l <SEP> (512) <SEP> 20 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb><SEP> (J18) <SEP> 70 <SEP> 5 <SEP> 10 <SEP> 0 <SEP> 0
<tb><SEP> (J26) <SEP> 70 <SEP> 12 <SEP> 48 <SEP> 0 <SEP> 0
<tb><SEP> (J32) <SEP> 70 <SEP> 45 <SEP> 55 <SEP> 15 <SEP> 12
<Tb>
The activity of 4-hydroxybutyric acid is dose-dependent and is significantly higher than that of nicotinamide. J12 is not significantly potentiated between 4-hydroxybutyric acid and nicotinamide, probably because the availability of nicotinamide and NADP with 4-hydroxybutyric acid is still sufficient during the first days; indeed, by its action, 4-hydroxybutyric acid alone can slow down the onset of NAD deficiency and
NADP. Without 4-hydroxybutyric acid, the deficit would match, allowing the nicotinamide activity to manifest on D12.

Beyond J12, when the treatment with 4-hydroxybutyric acid or 4-hydroxybutyric acid + nicotinamide is continued until D25 (Table 2), there is observed, from J18, a depletion of the effect protection with 4-hydroxybutyric acid and nicotinamide alone, while the 4-hydroxybutyric acid + nicotinamide combination continues to provide complete protection. After stopping the treatment on D25, the 4-hydroxybutyric acid + nicotinamide combination maintains a significantly higher protective effect at D32. These results highlight the effect of potentiation that is obtained with the combination of 4-hydroxybutyric acid and nicotinamide.

Identical results are obtained when the 4-hydroxybutyric acid in the form of sodium salt is replaced by γ-butyrolactone (GBL) (Table 1a and 2), at equimolar dose (GBL is the lactone of 4-hydroxybutyric acid ).

The 4-hydroxybutyric acid + nicotinamide combination also exerts a protective effect on islets of Langerhans in vitro treated with streptozotocin (0.5 mmol / l) and stimulated with glucose (3 g / l). The results are expressed in pU of secreted insulin / ilot / min: normal controls = 3.81 + 1.66 normal controls treated with 4-hydroxybutyric acid (1 mmol) + nicotinamide (1 mmol) = 3.44 + 1.73; streptozotocin controls = 0.57 + 0.67, streptozotocin treated with 4-hydroxybutyric acid (1 mmol) + nicotinamide (1 mmol) = 3.32 + 0.99.

All of the literature data and results above show - that nicotinamide protects against streptozotocin-induced diabetes. It works by compensating for NAD and NADP deficiency, inhibiting the activation of poly (ADP-ribose) synthetase and increasing the synthesis of pyridine nucleotides.

- that 4-hydroxybutyric acid acts on diabetes induced by streptozotocin (or by alloxan), provided that the cellular levels of NAD and NADP are sufficient, because its effect of protection and tissue regeneration puts NAD and NADP-dependent metabolic pathways - that 4-hydroxybutyric acid and nicotinamide mutually enhance their activity. The potentiating effect is all the more marked as the deficiency of NAD and NADP and the activation of poly (ADP-ribose) synthetase are high. 4-hydroxybutyric acid and nicotinamide allow a cyto-tissue function that is compatible with energy requirements and with those of maintenance, especially when the environmental conditions are unfavorable. This mode of operation is of the same type as that involved in the hibernation process which is favored by 4-hydroxybutyric acid (MARGULES, 1979 - OELTGEN et al, 1982). The general nature of the mechanism of action of combinations of 4-hydroxybutyric acid and nicotinamide in experimental diabetes with streptozotocin makes it possible to predict their therapeutic interest in the prevention and the treatment of other degenerative pathologies.

In addition to their tissue protection and regeneration action, it is interesting to note that 4-hydroxybutyric acid and nicotinamide exhibit synergistic action at the level of the central nervous system.

4-hydroxybutyric acid is a hypnotic agent that binds to specific receptors in the brain (LABORIT, 1990) and may interfere with the GABA-benzodiazepine (BDZ) complex (SNEAD and NICHOLS, 1987). It has affinity for GABA-B receptors (BERNASCONI et al, 1992); 4-hydroxybutyric acid (TAKAHARA et al., 1982) as baclofen-GABA-B agonist (PASSARIELLO et al., 1982) stimulates the secretion of GH. On the other hand, nicotinamide has benzodiazepine-type activities (MOHLER et al, 1979).

It has been observed that the administration of 4-hydroxybutyric acid and nicotinamide in mice at the respective dose of 1.64 mM,
Kg-1 (ip) - causes a decrease in locomotor activity (no sleep)
markedly more marked than with 4-hydroxybutyric acid alone (with
this dose, nicotinamide does not affect locomotor activity); - significantly increases the sleep time induced by a
barbiturate; - reduces the response variability observed with a barbiturate
(hexobarbital, pentobarbital) in the presence of 4-hydroxybutyric acid
only.

At the dose of 3.28 mM.Kg-1 (ip), the sleep time induced by 4-hydroxybutyric acid and nicotinamide is significantly increased (+ 45%) compared to that induced by the same dose of 4-hydroxybutyric acid alone (at this dose, nicotinamide does not induce sleep and only slightly changes locomotor activity).

The combination of 4-hydroxybutyric acid and nicotinamide thus has a potential anxiolytic, tranquillizing and sleep-assisting activity.

On the other hand, it should be noted, on the one hand, that 4-hydroxybutyric acid is oxidized to succinic semi-aldehyde (SAS) under the action of an aldehyde reductase (ALR 1), NADP-dependent, in a coupled reaction the reduction of glucuronate to gulonate (VAG) (KAUFMAN et al, 1983) and, on the other hand, that 4-hydroxybutyric acid can be regenerated by two other aldehyde reductases (ALR2 and SSA reductase)
NADPH-dependent, NADPH itself being regenerated by the pentose phosphate (VPP).

The 4-hydroxybutyric acid can therefore undergo recycling, in parallel with the activation of VPP and VAG that it entails.

Therefore, it can be understood that 4-hydroxybutyric acid can act at low doses in the animal (from O, Smg / kg-1) (KAUFMAN et al, 1990) as well in its signaling actions at receptor-specific level only as substrate catalyzing, by coupling, the metabolic pathways of substitution (VPP, VAG). The action at low doses is also true in humans in various tissue dysfunctions (examples: pancreatitis, diabetic angiopathy, hair loss).

In practice, after an attack treatment intended to ensure, if necessary, a sufficient charge of 4-hydroxybutyric acid (500 to 2000 mg / day or 4 to 20 mmol / day), the maintenance treatment can use lower doses (10 to 600 mg / day or 0.1 to 6 mmol / d).

Finally, given the mechanisms involved with 4-hydroxybutyric acid and nicotinamide, it is important that certain essential metabolic elements are available. This is the case, for example, with folate and methionine (methylations and transfers of monocarbon radicals in the synthesis of nucleotides, phospholipids), magnesium and potassium (intracellular cations related to membrane repolarization and the operation of many enzymatic systems), zinc (cofactors of many enzymes, including alkaline phosphatase involved in the metabolism of phospholipids), aspartic acid (precursor of purine and pyrimidine bases, mitochondrial shuttle, nitrogen scavenger, neurostimulator) ) as well as other mineral salts, vitamins or trace elements.

Preparations containing 4-hydroxybutyric acid and nicotinamide may therefore contain one or more of these elements.

The pharmaceutical compositions according to the invention can find applications in various therapeutic areas for which they can be used either alone or in addition to specific treatments whose effectiveness they can potentiate and improve tolerance.

1. Diabetes: the results obtained in humans (nicotinamide) and on
models of diabetes in animals (4-hydroxybutyric acid +
nicotinamide) lead to propose the use of
4-hydroxybutyric acid base + nicotinamide in diabetes
(types 1 and 2) and in the prevention of diabetes of subjects at risk
(screening). They can act on the dysglycoregulations and on
their consequences (microalbuminuria, renal angiopathies,
retinal).

2. The protective and tissue regenerative properties of
compositions according to the invention can find applications
therapeutics in areas other than dysglycoregulations.

For example: tissue protection in surgery and resuscitation
(brain, heart, intestine, kidney), protection of preserved organs
for transplantation, senescence and degeneration of the system
central nervous system (memory disorders, difficulty concentrating,
apathy, Parkinson's disease, Alzheimer's disease), sequelae
cerebral or cardiac ischemia, pancreatitis, retinitis,
cataracts, autoimmune diseases, hair loss and fragility,
disorders of healing (retardation, keloids), burns.

3. the compositions according to the invention can also find
therapeutic applications in sleep disorders
(sleepiness and quality of awakening and recovery), in the
weaning of hypnotics and benzodiazepines, in the
potentiation of the treatment of dyslipidemia, in the
corticosteroid therapy and treatment with long-term NSAIDs
(increase of efficiency-tolerance).

Claims (4)

 inert non-toxic pharmaceutically-acceptable.  in combination or in admixture with an excipient or a vehicle  active ingredients of 4-hydroxybutyric acid and nicotinamide  1 - New pharmaceutical compositions containing as a The subject of the invention is  with a mineral or organic base.  4-hydroxybutyric acid is in the form of one of its salts  2 - Compositions according to claim 10, characterized in that  the hydroxyl function with a mineral or organic acid.  4-hydroxybutyric acid is in the form of an ester of  3 - Compositions according to claim 10, characterized in that  cycloaliphatic having 1 to 12 carbon atoms.  the carboxylic function with an aliphatic alcohol or  4-hydroxybutyric acid is in the form of an ester of  4 - Compositions according to claim 10, characterized in that  4-hydroxybutyric acid is in the form of a lactone.  5 - Compositions according to claim 10, characterized in that  form of one of its salts of mineral or organic acid.  that nicotinamide is present as a base or  60- Compositions according to claims 1 to 50, characterized in that  than the relative proportions expressed in moles of acid  70- Compositions according to claims 1 to 60 characterized in that  4-hydroxybutyric and nicotinamide are between 1: 0.1  and 1:10.  and / or mineral salts and / or trace elements.  that we add other active ingredients such as vitamins  8 - Compositions according to claims 1 to 70 characterized in that  administration by digestive, parenteral or local.  the excipient or the vehicle is one of those adapted for  9 - Compositions according to one of claims 1 to 80 in which  diabetes mellitus and its prevention in the subject at risk.  view of the production of a medicament for the treatment of  100- Use of the compositions according to Claims 1 to 90 in  diabetes mellitus and its complications.  effectiveness of other preventive or curative treatments of  view of the realization of a medicament for potentiating  11 - Use of the compositions according to claims 1 to 90 in  Alzheimer's disease, keloids, burns.  sequelae of cerebral or cardiac ischemia, Parkinson's disease,  pancreatitis, retinitis, cataracts, autoimmune diseases,  degenerative pathologies of different tissues, namely  view of the production of a medicament for the treatment of  120- Use of the compositions according to Claims 1 to 90 in  aging process.  view of the production of a medicament for the treatment of  130- Use of the compositions according to claims 1 to 90 in  organs preserved for transplantation.  tissue in surgery and resuscitation and the protection of  view of making a medicine for protection  14 - Use of the compositions according to Claims 1 to 90 in  Long-term NSAIDs.  dyslipidemia, in corticosteroid therapy and treatment with  benzodiazepines, in the potentiation of the treatments of  sleep disorders, in the withdrawal of hypnotics and  view of the production of a medicament for the treatment of  15 - Use of the compositions according to Claims 1 to 90 in