Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1992-12-29
1995-01-10
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C07C 5901, A61K 31205, A61K 3119
Patent
active
053809378
DESCRIPTION:
BRIEF SUMMARY
The invention relates to water soluble derivatives of 4-hydroxybutyric acid, processes for their production and their pharmacological use.
4-hydroxybutyric acid or also gamma-hydroxybutyric acid (GHB) has for many years been in general use clinically as a narcotic. This substance is available as a pharmaceutical exclusively as the sodium salt and is approved, for example in Germany, under the trade name SOMSANIT. All experimental and clinical investigations have without exception been performed with the sodium salt of GHB, the acid itself or the corresponding lactone.
In 1950, ROBERTS and FRANKEL detected gamma-aminobutyric acid (GABA) in the mammalian brain. Two years later, FLOREY discovered the inhibitory effect of GABA on the central nervous system which leads to the symptoms of physiological sleep. In 1958, ROBERTS and his collaborators and ALBERS and SALVADOR reported that gamma-aminobutyric acid is reduced in the brain by a specific transaminase into the succinic acid semi-aldehyde which is reduced by a dehydrogenase to GHB.
Parenterally administered gamma-aminobutyric acid cannot cross the blood-brain barrier. LABORIT and collaborators, BESSMAN and FISHBEIN sought derivatives which reach the central nervous system by haematogenous routes. Within the context of these investigations LABORIT, JOUANY, GERARD and FABIAN first reported the narcotic effect of 4-hydroxybutyric acid in 1960.
Quantitative studies by BESSMAN and FISHBEIN into the distribution of GHB and the corresponding gamma-butyrolactone in the organism confirm that GHB is a physiological metabolite of the human brain, where this probably sole metabolite with anaesthetic effects reaches concentrations of up to 0.3 mmol/g.
PHARMACOLOGICAL PROPERTIES
At a dose of 35 to approximately 90 mg/kg body weight, GHB has a hypnotic effect and at dosages in excess of 100 mg/kg body weight a narcotic effect. Since SOMSANIT has no analgesic effects below 90 mg/kg body weight, it must be combined with analgesics, neuroleptics or with a subliminal barbiturate dose in order to achieve sufficient anaesthesia in surgical interventions. For internal indications on the other hand (e.g. sleep therapy, terminal carcinomatous state), GHB may also be used as a `sole narcotic`.
A E USPENSKIJ's investigations showed that sodium 4-hydroxybutyrate inhibits the polysynaptic reflexes, while the monosynaptic reflexes remain unchanged, even at dosages of up to 2 g/kg in cats.
Several particular properties which distinguish GHB from other anaesthetics deserve mention: the eyelid reflex disappears, the eyelids slacken, but the eyes often remain half open. The corneal reflex is generally retained. Induction is slow, awakening is relatively rapid. Depending on the dose, the period of activity is 1-2 hours. According to investigations by FISHBEIN and BESSMAN, the narcosis achieved with GHB broadly resembles physiological sleep. In general, respiration becomes deeper with increased amplitude and decreased frequency. The sensitivity of the respiratory centre to carbon dioxide stimulus is retained. GHB does not therefore itself act as a respiratory depressant, but it may possibly potentiate the respiratory depressive effect of other anaesthetics.
In exceptional cases, a typical intermittent respiration occurs for a short period, particularly during the awakening phase. Disturbances of the acid-base balance could not, however, be identified during these phases, normalisation occurred after a short period without therapeutic measures.
An increase in blood pressure is more frequently observed after administration of GHB. In investigations performed to date, it has not been possible to identify any direct depressive effect on the myocardium even when high doses are used. Investigations performed on rats allow a statement to be made concerning the break-down of GHB in the organism, 97% of the marked carbon (C.sup.14) could be detected within 2 hours as CO.sub.2 in the expiratory air.
A final point to be mentioned is that the electrolyte balance is not significantly changed during G
REFERENCES:
patent: 4143159 (1979-03-01), Moller et al.
patent: 4549010 (1985-10-01), Sparer et al.
patent: 4771074 (1988-09-01), Lammerant et al.
The Merck Index, 11, (1989), Abstract 8603.
Koehler Anita
Koehler Gernot
Dees Jos,e G.
Frazier B.
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