Vol 3 | Issue 2 | 2012 | 104-113. e - ISSN – 2249-7552 Print ISSN – 2229 7502 HISTORY OF SODIUM OXYBATE – A REVIEW I. Govardhan Kumar*, B. Kumar, NS. Midhuna Sagari *Department of Pharmacology, Krishna Teja Pharmacy College, Chadalawada Nagar, Tirupati, Andhra Pradesh – 517 501, India. ABSTRACT Gamma Hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid and sodium oxybate is a naturally occurring substance found in the human central nervous system as well as in wine, beef, small citrus fruits, and almost all animals in small amounts. It is also categorized as an illegal drug in many Article countries. It is currently regulated in Australia and New Zealand, Canada, most of Europe and in the US. Key Words: Gamma Hydroxybutyric acid (GHB), 4-hydroxybutanoic acid, Sodium oxybate, History. view INTRODUCTION for the treatment of cataplexy in adult patients Re GHB as the sodium salt, known as with narcolepsy. It is considered to act in a sodium oxybate, is sold by Jazz Pharmaceuticals different way to the only other the licensed under the name Xyrem to treat cataplexy and medication, clomipramine, for this indication. excessive daytime sleepiness in patients with Cataplexy is an abrupt, reversible decrease in narcolepsy. GHB has been used in a medical muscle tone caused by emotion and is reported in setting as a general anesthetic, to treat conditions approximately 75% of patients with narcolepsy. such as insomnia, clinical depression, Sodium oxybate is the sodium salt of narcolepsy, and alcoholism, and to improve gamma hydroxybutyrate (GHB) and is a schedule athletic performance. It is also used as an 4 (part 1 CD Benz) controlled drug in the UK. intoxicant (illegally in many jurisdictions) or as a Sodium oxybate is associated with dose-related date rape drug.GHB is naturally produced in the improvements in the symptoms of narcolepsy and human body's cells and is structurally related to reductions in the number of attacks of cataplexy. the ketone body beta-hydroxybutyrate. As a The most significant improvements/reductions supplement/drug, it is used most commonly in were seen in patients taking 9g/day. These effects the form of a salt, for example sodium gamma- have been demonstrated for treatment periods of hydroxybutyrate (Na.GHB, sodium oxybate, or 12 months or longer. The most commonly under the brand name Xyrem.) or potassium reported adverse effects of sodium oxybate gamma-hydroxybutyrate (K.GHB, potassium included headache, nausea and dizziness. No oxybate). GHB is also produced as a result of withdrawal effects were seen in trials. Abrupt fermentation, and so is found in small quantities withdrawal leads to a gradual increase in the in some beers and wines. number of cataplexy attack. Succinic semialdehyde dehydrogenase Oxybate (GHB) is a metabolite of γ- deficiency is a disease that causes GHB to aminobutyric acid (GABA) which is synthesised accumulate in the blood. Sodium oxybate and accumulated by neurons in the brain. It is (Xyrem) is the sodium salt of gamma present at μM concentrations in all brain regions hydroxybutyrate (GHB). Xyrem 500mg/ml investigated as well as in several peripheral solutions licensed for the treatment of cataplexy organs, particularly in the gastro-intestinal system. in adult patients with narcolepsy. Cataplexy is an Neuronal depolarization releases GHB into the abrupt, reversible decrease in muscle tone caused extracellular space in a Ca2+-dependent manner. by emotion, reported by approximately 75%of A family of GHB receptors in rat brain have been patients with narcolepsy. The term narcolepsy is identified and cloned and most probably belong to used to describe a syndrome comprising of the G-protein-coupled receptors. High-affinity symptoms: cataplexy, hypnologic hallucinations receptors for GHB are present only in neurones, and sleep paralysis Sodium oxybate is indicated with a restricted specific distribution in the Corresponding Author: I. Govardhan Kumar Email: [email protected] International Journal of Preclinical and Pharmaceutical Research Page 104 Vol 3 | Issue 2 | 2012 | 104-113. hippocampus, cortex and dopaminergic structure so frat and overnight poly somno grams(PSG) were recorded, brain. suggests that GHB modifies sleep architecture, specifically In general, stimulation of these receptors with low a dose-related increase in Stage 3 & 4 slow wave sleep (physiological) amounts of GHB induce hyperpolarisation (SWS, deltasleep). The cause of human narcolepsy and in dopaminergic structures with a reduction of dopamine cataplexy is, as yet, unknown. Recent evidence points to the release. However, in the hippocampus and frontal cortex, loss of hypocretin-containing neurones, possibly due to GHB seems to induced polarization with an accumulation autoimmune attack, as a likely cause (Scammell 2003). of Cgmp and an increase in inositol phosphate turnover. Hypocretin is a neuro transmitter that has roles amongst However, at higher (therapeutic) exposures, GHB receptors others, in sleep-wake regulation. Alterations in hypocretin are saturated and probably desensitized and down neurotransmission have also been observed in mouse and regulated. Such GHB dopaminergic hyperactivity, strong models of narcolepsy, although no studies have been sedation with anaesthesia and EEG changes those are undertaken with GHB in these models. consistent with normal sleep. The pathogenesis of GHB reaches much higher concentrations in the narcolepsy is still unknown, but an imbalance between brain and activates GABAB receptors, which are primarily monoamines and acetylcholine is generally accepted. responsible for its sedative effects. GHB receptors are Recent research has found a marked reduction of densely expressed in many areas of the brain, including the the neuropeptide hypocretin type 1 in the cerebrospinal cortex and hippocampus, and these are the receptors that fluid of a majority of patients and a global loss of GHB displays the highest affinity for. There has been hypocretins in postmortem brain tissue of narcoleptic somewhat limited research into the GHB receptor; subjects. The hypocretins are synthesized by a small group however, there is evidence that activation of the GHB of neurons predominantly located in the lateral receptor in some brain areas results in the release of hypothalamic and perifornical regions of the hypothalamus. glutamate, the principal excitatory neurotransmitter. The hypothalamic system directly and strongly innervates Activation of both the GHB receptor and GABA (B) is and potently excites noradrenergic, dopaminergic, responsible for the addictive profile of GHB. GHB's effect serotoninergic, histaminergic and cholinergic neurones. on dopamine release is biphasic, low concentrations The effect of GHB on this system has not been stimulate dopamine release via the GHB receptor Higher investigated. However, the available data indicate that its concentrations inhibit dopamine release via GABA(B) mode of action is likely to relate to non-specific receptors as do other GABA(B) agonists such as baclofen. dopaminergic stimulation rather than the hypocretin After an initial phase of inhibition, dopamine release is then system. Formal nonclinical pharmacology studies to increased via the GHB receptor. This explains the investigate the primary pharmacodynamics have not been paradoxical mix of sedative and stimulatory properties of conducted by the applicant, rather a comprehensive review GHB, as well as the so-called "rebound" effect, experienced of the scientific literature has been conducted. The by individuals using GHB as a sleeping agent, where in publications included have been selected based on their they awake suddenly after several hours of GHB-induced relevance to the proposed indications, based on evidence of deep sleep. That is to say that, overtime, the concentration efficacy from early clinical studies. of GHB in the system decreases below the threshold for In addition, animal models of cataplexy and significant GABAB receptor activation and activates narcolepsy are continuing to be developed, but have not yet predominantly the GHB receptor, leading to wakefulness been fully validated. Little nonclinical information is [1-5]. available on its effects on narcolepsy in general, and cataplexy in particular. Available, directly relevant data, Medical use from the published literature, has been reviewed but the The only common medical applications for GHB current understanding of the role of GHB in the CNS does today are in the treatment of narcolepsy and more rarely not provide a mechanistic explanation of the positive alcoholism [6,7]. GHB is the active ingredient in a clinical effects reported in the dossier. prescription medication called Xyrem (sodium oxybate). GHB had no effect on cataplexy in dogs with Xyrem is approved by the U.S. Food and Drug hereditary narcolepsy when administered as a single dose of Administration (FDA) for the treatment of cataplexy 500mg/kg i.v. or 50mg/kg/day p.o. for 3 consecutive days. associated with narcolepsy [8] and Excessive Daytime However, although such dogs have amutation of the type 2 Sleepiness (EDS) associated with narcolepsy. hypocretin receptor, the clinical relevance of this model remains to be established. Moreover, a dose of Recreational use 75mg/kg/day for atleast 14 days is required for efficacy in GHB is a CNS depressant used as an humans. Though the precise mode of action is unknown, intoxicant.[9,10] It has many street names, including these sedative properties of GHB and its effects on sleep "Georgia