GB2023421A - gamma -Butyrolactone for therapy of insomnia and anxiety - Google Patents

Abstract

gamma -Butyrolactone in a dosage of usually 0.5 to 5 g preferably administered orally induces physiological sleep and is useful in the therapy of anxiety and insomnia without toxic side effects. The gamma -butyrolactone may be in the form of sterile injectable solutions, syrups, tablets, capsules or powders.

Description

SPECIFICATION The use of y-butyrolactone for therapy of insomnia and anxiety This invention relates to therapy of insomnia and anxiety, and provides a new drug, namely y-butyrolactone, which can be administered either i.v. (intravenously) or i.p. (intraperitoneally), and, more pa rticu larly, per os.

In 1960 Langlais and Coll. [Agressiologie 1, 431-433 (1960)] reported the sedative effectiveness of y-hydroxybutyric acid (I): HOCH2-CH2-CH2-COOH (I) in the therapy of psychomotor agitation states and gave cases of patients refractory to neuroleptics solved by e-hydroxybutyric acid. According to these Authors, in all cases of psychomotor excitement and anxious agitation, y-hydroxybutyric acid provides a sedation similar to physiological somonolence. With y-hydroxybutyric acid a sleep is achieved which has an aspect quite different from that provided by neuroleptics for sleeping therapy. y-hydroxybutyric acid does not provide any of the extrapyramidal symptoms which form part of the pattern produced by neoroleptics.

The action of y-hydroxybutyric acid is also differentfrom that of barbiturates, since, on introduction of sleep, no reduction of oxygen consumption occurs, so that the sleep is really physiological, without side effects and collateral toxic actions.

The reason for this lack of toxic and collateral effects is that -hydroxybutyric acid converts, in the organism, into natural metabolites which partake in the cycles of normal physiological functions.

y-Hydroxybutyric acid is however active only by i.v. administration.

Again on the same biochemical bases, Benda and Perles, C.R.Acad.Sci. 251, 1312-1313 (1960), describe the therapeutic action of y-hydroxybutyric acid and of the corresponding lactone, again by i.v.

administration, in the case of confusion access and Danon-Boileau and Coll. Presse Medicale 70, 2205-2207 (1962) recommend using y-hydroxybutyric acid in neurotic situations to control, in particular, the anxiety crisis on which neuroleptics and anti-depressants have no effect. Du Couedic and Voisse - Ag ressuikig ue 5,73-85(1964) describe y-hydroxybutyric acid as a drug particularly interesting for combatting acute anxiety of any origin. With y-hydroxybutyric acid both sleep and a relaxation state is achieved, with an undoubted discharge of anxiety.

As, however, the specified induction of physiological sleep and treatment of nervous diseases requires, with y-hydroxybutyric acid, i.v. administration, this acid, while having almost ideal pharmacotoxicologycal properties, is not suitable, or at least very inconvenient, for therapeutic use.

This invention provides a drug useful for the therapy of insomnia states, which is capable of inducing physiological sleep, suitablefortherapy of anxiety and insomnia states, free from undesired toxic or side effects (as it is capable of partaking in the metabolic balance normal for the organism), and administerable i.v., i.p., or preferablyperos.

It has now been found that y-butyrolactone behaves, on i.v. administration, in a similar way, from the pharmacological viewpoint, to y-hydroxybutyric acid, as described by Sprince and Coll. in Life Sci 5, 2041-2052(1966). The possible interrelations are summarised in the reaction scheme below. Furthermore, it has been ascertained that y-butyrolactone administered per os, unlike y-hydroxybutyric acid, keeps its therapeutic properties unaltered. y-Butyrolactone when administered from outside, is capable of affecting the metabolic balance, by correcting the same in cases of alteration.

COCH C H2-CH2-C H-NH2 OW cH2-cH2-CH2-HH2 L-glutamic acid COUCH CocH O CH2-CH2-CHO CH2H2-a-CoOH succinic ;ketoglutaric acid semialdehyde COON COOH OH CH2-CH2-COOH CH2-C H2-CH2 succinic acid 7-hydroxybutyrie acid Krebs cycle C H2- CH2 CH2 O y-butyrolactone The invention provides pharmaceutical compositions containing y-butyrolactone as active substance, in admixture with a compatible pharmaceutically acceptable carrier for example a solution (which may be sterile and injectable), a syrup, a tablet, a capsule or a powder, with or without additives, support material, pharmaceutical stabilisers, suitably brought into an adequate dosage form, i.e. a dosage producing the desired effect. Suitably, the unit dosage is from about 0.5 g and about 5 g, preferably from 2.59 to 5g, but either higher or lower unit dosages can be applied, which may optionally be divided or multiplied before administration. The dosage per day is generally from 2 and 5 g of active substance.

The drug administeredperos at dosages up to 2 g/kg of body weight, has shown neither toxic effects nor undesired side effects and has not revealed signs of teratogenic activity.

The same therapeutics effects which are noticed on administering y-butyrolactoneperos, also occur when said compound is administered intravenously or intraperitoneally.

The following Examples illustrate the present invention.

EXAMPLE 1 2 g of y-butyrolactone, rectified and subjected to analytical control so that the presence of any impurity can be excluded, are added to 2 ml of bidistilled and deionized water and to 1 g of 70% sorbitol solution. The mixture is, if desired, flavoured, stirred well, and sterilised in small bottles which are then stored, hermetically sealed by a plug which does not leak. The small bottles may either be of neutral glass or an inert plastics material. The pH of the solution must be rigorously neutral. The so-prepared small bottles each contain a daily dose and are storable indefinitely. Obviously, instead of single small bottles, solutions of greater volume can be prepared, provided the relative concentrations of the components are maintained.

EXAMPLE2 Since, on pharmacokinetic studies, the haematic level ofbutyrnIactone, administered both i.v. and per os, have been shown to be identical, also with time, one can use in therapy phials containing 1 g of the drug in 10 ml of water, the solution being prepared according to the usual manufacturing standards for solutions for i.v. use.

EXAMPLE3 With the solutions prepared according to Examples 1 and 2, the results shown in the accompanying drawing, upon i.v. or i.p. administration, have been achieved. The drawing shows representative EEG plots (1 -15 cps) of4 rats injected intraperitoneally with y-hydroxybutyrate (GHB) (sodium salt), y-butyrolactone (GBL), 1.4 bidistilled water (BD) and 1.3 BD, respectively. Dose: 5.5 x 10-3 moles/kg for GHB GBL and 1.4 BD; 77.6 x 10-3 moles/kg for 1.3 BD.

The diagrams refer to time zero (immediately before injection) and to 30 minutes, 2 hours and 4 hours after injection. Diagram of normal sleep of a fifth rat is included.

Claims (5)

1. The use of y-butyrolactone for therapy of insomnia and anxiety.

2. The use of y-butyrolactone for oral therapy of insomnia and anxiety.

3. A pharmaceutical composition comprising y-butyrolactone in admixture with a compatible pharmaceutically acceptable carrier.

4. A composition according to Claim 3 in the form of a sterile injectable solution, syrup, tablet, capsule, or powder.

5. A composition according to Claim 3 substan tially as described in Example 1 or 2.