Neuropharmacological effects of 1,4-butanediol and related congeners compared with those of gamma-hydroxybutyrate and gamma-butyrolactone

Sprince, Herbert; Josephs, Joseph A.; Wilpizeski, Chester R.

doi:10.1016/0024-3205(66)90245-1

Cited by 51 publications

(17 citation statements)

References 9 publications

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“…11 Alternatively, the generalized central ner vous system anticonvulsant 23,24 and depressant effects of alcohols could contribute to the protective effect by a direct reduction of brain oxygen demand and func tion. 25 This mechanism was explored in preliminary studies which indicate that the effect of 1,3-butanediol on brain tissue metabolites is not similar to that seen with other central nervous system depressants like bar biturates 26,27 or ethanol. 28 Another potentially significant similarity in the bio logical effects of ethanol and its dimer 1,3-butanediol" is that both compounds have been reported to produce a systemic ketosis.…”

Section: Dose Response Of Ethanolmentioning

confidence: 99%

The role of ethanol in diluents of drugs that protect mice from hypoxia.

Moursi¹,

Luyckx²,

DʼAlecy³

1983

Stroke

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SUMMARY This study evaluates the hypothesis that ethanol alone, or in diluents for drugs used to protect hypoxic mice, is responsible in part for an increased tolerance to hypoxia (4-5% oxygen). The change in hypoxic tolerance following i.v. or i.p. administration of ethanol, diazepam, nimodipine and various diluent components was measured. Diazepam (50 mg/kg i.v.) increased hypoxic tolerance to 700 ± 47% (n = 11) of saline control, its diluent increased hypoxic tolerance to 468 ± 60% (n = 10) of saline control but the ethanol component of the diluent accounted for almost half of this diluent effect. Nimodipine (2 mg/kg i.p.), a calcium antagonist, increased tolerance to 180 ±18% of control (n = 19) and nimodipine diluent showed an even greater increase to 226 ±25% of control (n = 15). In this case essentially all of the protective effect of nimodipine diluent (81.3%) is accounted for by ethanol. Dose response curves indicate the maximum ethanol induced increase in hypoxic tolerance was approximately 335% of control at a dose of 2.4 g/kg. Buffers, etc. in the diluents evidently add to the protective effect of ethanol. Our data clearly indicate ethanol is the important component of some treatments which protect mice from hypoxia. The pharmacological activity of ethanol, even when used in a diluent, should not be ignored in evaluating therapeutic intervention for protection from hypoxia. Stroke Vol 14, No 5, 1983THE INCREASED SURVIVAL TIME in mice sub jected to hypoxia has been investigated in several labo ratories to identify procedures which may be of thera peutic value in cerebral hypoxia. The importance of these experiments stems from the high morbidity and mortality associated with cerebral hypoxia. The brain appears to be particularly sensitive to hypoxia presum ably because of its high metabolic rate, relatively small stores of high energy phosphates and glucose as well as a relatively low capillary density.1 Although the cause of death or sequence of events leading to death in the hypoxic mouse model have not been established there is evidence to suggest that during hypoxia the cessation of spontaneous ventilation results from reduced brain activity. Recent work in our laboratory using a Levine rat preparation, which includes on-line monitoring of blood pressure, heart rate, respiratory rate, central ve nous pressure and electroencephalogram, indicates that loss of cerebral electrical activity invariably pre cedes loss of spontaneous respiration and ultimate loss of cardiac activity 2 when an animal is exposed to hy poxia. In contrast it has been shown that cardiac func tion is maintained during hypoxia because coronary blood flow is increased by local mechanisms in order to maintain a relatively constant myocardial oxygen tension. 3Clinically, hypoxia may be encountered at high altitudes, 4 during childbirth, deep-sea diving, as a complication during surgery, with a sedative over dose, or because of carbon monoxide poisoning. Fur thermore, hypoxia has been identified as an avoidable extracranial factor as...

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Section: Dose Response Of Ethanolmentioning

confidence: 99%

The role of ethanol in diluents of drugs that protect mice from hypoxia.

Moursi¹,

Luyckx²,

DʼAlecy³

1983

Stroke

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“…1,4-Butanediol has a pronounced pharmacologic effect on the central nervous system (Sprince et al, 1966). Administration of 496 mg kg −1 of 1,4-butanediol to male Sprague-Dawley or Holtzman rats caused central nervous system depression and induced a state of sleep or anesthesia characterized by loss of righting reflex, struggle response, and voluntary motor activity, but retaining the ability to respond to pain and tactile stimuli.…”

Section: Pharmacologymentioning

confidence: 99%

“…After administration of gammabutyrolactone sleep induction time was similar to that observed with γ-hydroxybutyric acid but sleeping time was nearly as long as observed with 1,4-butanediol. Since previous work (Giarman and Roth, 1964;Roth et al, 1966;Roth and Giarman, 1966) had indicated that the CNS depressant effects of γ-butyrolactone were due to its conversion to γ-hydroxybutyric acid, it was suggested that the CNS depressant activity of 1,4-butanediol was the result of metabolic conversion to γ-hydroxybutyric acid (Sprince et al, 1966).…”

Section: Pharmacologymentioning

confidence: 99%

“…However, after parenteral administration the pharmacologic action of γ-butyrolactone is essentially identical to that of 1,4-butanediol and γ-hydroxybutyric acid (Giarman and Roth, 1964;Sprince et al, 1966;Snead, 1992) due to its conversion to γ-hydroxybutyric acid in liver. The cyclic lactone is less polar than the acid and therefore absorbed much more rapidly after oral administration, however, conversion to the acid is so rapid after absorption that γ-hydroxybutyric acid bioavailability is actually greater after administration of γ-butyrolactone than after administration of an equivalent dose of Na-γ-hydroxybutyric acid (Vree et al, 1978;Lettieri and Fung, 1978).…”

Section: Pharmacologymentioning

confidence: 99%

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A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Irwin

2005

J. Appl. Toxicol.

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1,4-Butanediol is an industrial chemical used primarily as an intermediate in the manufacture of other organic chemicals. It has recently been associated with deaths, addiction and withdrawal related to its promotion and use as a dietary supplement. The rapid absorption and conversion of 1,4-butanediol to gamma-hydroxybutyric acid (GHB, or date rape drug) in animals and humans is well documented and is the basis for its abuse potential. A disposition and metabolism study conducted in F344 rats by the National Toxicology Program (NTP) confirmed the rapid conversion of 1-(14)C-1,4-butanediol to (14)CO2. Because of this, the toxicological profile of 1,4-butanediol resembles that of gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid occurs naturally in the brain and peripheral tissues and is converted to succinate and metabolized through the TCA cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is not known, the presence of specific high affinity receptors for gamma-hydroxybutyric acid suggests that it functions as a neuromodulator in the brain and neuronal tissue. Gamma-hydroxybutyric acid readily crosses the blood-brain barrier and elicits characteristic neuropharmacologic responses after oral, i.p., or i.v. administration. The same responses are observed after administration of 1,4-butanediol. The cyclic lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver in animals and humans, and produces pharmacological effects identical to those produced by 1,4-butanediol and gamma-hydroxybutyric acid. Gamma-butyrolactone was previously evaluated by the NTP in 14-day and 13-week prechronic toxicology studies and in 2-year chronic toxicology and carcinogenesis studies in F344 rats and B6C3F1 mice. No organ specific toxicity occurred. In the carcinogenesis studies there was an equivocal response in male mice based on a marginal increase in the incidence of pheochromocytomas of the adrenal medulla. Because the absence of chronic toxicity and significant carcinogenicity of gamma-hydroxybutyric acid were established in NTP prechronic and chronic studies with gamma-butyrolactone, it is concluded that similar results would be obtained in a 2-year study with 1,4-butanediol, and that 1,4-butanediol is not a carcinogen.

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“…Gamma-hydroxybutyric acid (GHB), a normal constituent of mammalian brain (Bessrnan and Fishbein, 1963;Roth and Giarrnan, 1970) produces CNS depression and a "sleep-like" state both in experimental animals and humans (Sprince, 1966;Roth and Giarrnan, 1968;Laborit et al, 1960;Blurnenfeld et ~l., 1962). Current interest in this substance stemmed from reports which showed that GHB administered in large doses produces considerable increase in the brain dopamine (DA) levels of rats (Gessa et aI., 1968;Agha~anian and Rot/o, 1970;Hutchins et aI., 1972).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological evidence for a selective antidopaminergic action of gamma-hydroxybutyric acid

Menon

Bieger

Hornykiewicz

1976

J. Neural Transmission

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D-Amphetamine (Amph) and p-chloroamphetamine (PCA) induced dose-dependent increases in oropharyngeal myocloniform twitch activity (MTA) in rats anesthetized with urethane. In doses of 80-120 mg/kg, gamma-hydroxybutyric acid (GHB) blocked Amph-induced MTA. The blockade was readily surmountable. Pretreatment with reserpine markedly enhanced the myoclonigenic effect of Amph and rendered it insensitive blockade by GHB, 160 mg/kg. PCA and tryptamine also effectively stimulated MTA, but unlike Amph were antagonized by low doses of the serotonin (5-HT) antagonist methysergide. In doses which blocked Amph, GHB failed to antagonize the myoclonigenic effect of PCA. It is concluded that: (a) the actions of Amph and PCA on MTA is less sensitive to GHB blockade than DA-mediated MTA; and (c) the GHB-Amph antagonism may be of a functional nature, i.e. result from a depression of the firing activity of DA neurons produced by GHB. Since reserpinization abolished the GHB effect on Amph-induced MTA, the functional integrity of granular DA binding and releasing mechanisms appears to be a pre-requisite for the antagonism between GHB and Amph.

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Neuropharmacological effects of 1,4-butanediol and related congeners compared with those of gamma-hydroxybutyrate and gamma-butyrolactone

Cited by 51 publications

References 9 publications

The role of ethanol in diluents of drugs that protect mice from hypoxia.

The role of ethanol in diluents of drugs that protect mice from hypoxia.

A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Pharmacological evidence for a selective antidopaminergic action of gamma-hydroxybutyric acid

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