γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.

Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons.

BACKGROUND: Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse ("Liquid Ecstasy") associated with a withdrawal syndrome with anxiety features. Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states. METHODS: Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats. RESULTS: A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats. CONCLUSIONS: Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers.

[Disorder of the serum albumin transport function in chronic oxygen starvation and its pharmacological correction]. / Narushenie transportnoi funktsii syvorotochnogo al'bumina pri khronicheskom kislorodnom golodanii i ee farmakologicheskaia korrektsiia.

Grade II chronic intermittent hypoxic hypoxia under normal barometric pressure, which was reproduced in pregnant rats 2.0-2.5 weeks before expected delivery and in the offsprings in the first 2 days of neonatality caused a decrease in serum albumin functional activity associated with bilirubin transport, as evidenced in vitro, as well as accumulation of serum albumin-bound nonesterified higher fatty acids and acetaldehyde along with uncompensated acidosis, an increase in brain levels of bilirubin in adult and newborn rats, and enhancement of its hemoxygenase activity. Administration of alpha-tocopherol acetate, nicotinamide, sodium oxybutyrate, and trisamine to animals exposed to hypoxia normalized the above biochemical parameters, except for hemoxygenase activity and promoted a greater binding of endogenous bilirubin to albumin in adult and newborn rats in vivo.

Intrathalamic injections of gamma-hydroxybutyric acid increase genetic absence seizures in rats.

The effects of intrathalamic injections of gamma-hydroxybutyric acid (GHB) and of NCS 382 85, a specific antagonist of GHB receptors, were evaluated in rats with spontaneous generalized absence epilepsy. Bilateral injections of GHB (25 and 50 micrograms/side) into the mediolateral thalamus increased spontaneous spike and wave discharges (SWD) in a dose-dependent fashion. This effect was suppressed by administration of NCS 382 85 (50 micrograms/side). Bilateral injection of NCS 382 85 alone (50 and 100 micrograms/side) into the same sites had no effect on SWD duration. Injection of GHB or NCS 382 85 into the midline thalamus and the area of reticular nuclei did not modify the SWD. These data suggest that GHB receptors in the mediolateral thalamus may be involved in the control of spontaneous SWD in this rat model of petit mal epilepsy.

[Experience with the use of sodium oxybutyrate electrophoresis by sinusoidal modulated currents in the combined treatment of patients with stable stenocardia]. / Opyt primeneniia élektroforeza oksibutirata natriia sinusoidal'nymi modulirovannymi tokami v kompleksnom lechenii bol'nykh stabil'noi stenokardiei.

Stable angina pectoris (functional class I, II, III) was treated by SHE with sinusoidal modulated current plus sodium chloride baths against placebo plus balneotherapy. Macro- and microcirculatory analysis of cardiovascular function and clinical evidence indicated that the addition of the electrophoresis raises the efficacy of the treatment 2-3-fold. The use of the combination proposed is advocated in prevention and treatment of stable angina pectoris.