sodium-oxybate and Respiratory-Insufficiency

Topics: Adolescent; Adult; Alcohol Drinking; Autopsy; Cause of Death; Female; Heart Arrest; Humans; Male; Postmortem Changes; Respiratory Insufficiency; Sodium Oxybate; Substance-Related Disorders

N-methyl-2-pyrrolidone (NMP) and γ-hydroxybutyrate acid (GHB) are synthetic solvents detected in the recreational drug market. GHB has sedative/hypnotic properties and is used for criminal purposes to compromise reaction ability and commit drug-facilitated sexual assaults and other crimes. NMP is a strong solubilizing solvent that has been used alone or mixed with GHB in case of abuse and robberies. The aim of this experimental study is to compare the acute pharmaco-toxicological effects of NMP and GHB on neurological signs (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, and motor activity (bar, drag, and accelerod test) in CD-1 male mice. Moreover, since cardiorespiratory depression is one of the main adverse effects related to GHB intake, we investigated the effect of NMP and GHB on cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in mice. The present study demonstrates that NMP inhibited sensorimotor and motor responses and induced cardiorespiratory depression, with a lower potency and efficacy compared to GHB. These results suggest that NMP can hardly be used alone as a substance to perpetrate sexual assault or robberies.

Topics: Adjuvants, Anesthesia; Animals; Dose-Response Relationship, Drug; Hypnotics and Sedatives; Illicit Drugs; Locomotion; Male; Mice; Mice, Inbred ICR; Models, Animal; Psychomotor Performance; Pyrrolidinones; Rape; Reflex, Startle; Respiratory Insufficiency; Sodium Oxybate

Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton-dependent and sodium-coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC

Topics: Anesthetics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Transport, Active; Brain; Cells, Cultured; Diclofenac; Dose-Response Relationship, Drug; Drug Interactions; Endothelial Cells; Hydroxybutyrates; Monocarboxylic Acid Transporters; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Sodium Oxybate; Symporters

γ-hydroxybutyrate (GHB) has a high potential for illicit use; overdose of this compound results in sedation, respiratory depression and death. Tolerance to the hypnotic/sedative and electroencephalogram effects of GHB occurs with chronic GHB administration; however, tolerance to respiratory depression has not been evaluated. GHB toxicodynamic effects are mediated predominantly by GABA. To determine effects of chronic GHB dosing on GHB toxicokinetics, GHB-induced respiratory depression, and MCT expression.. Rats were administered GHB 600 mg/kg intravenously daily for 5 days. Plasma, urine and tissue samples and respiratory measurements were obtained on days 1 and 5. Plasma and urine were analyzed for GHB by LC/MS/MS and tissue samples for expression of MCT1, 2 and 4 and their accessory proteins by QRT-PCR.. No differences in GHB pharmacokinetics or respiratory depression were observed between days 1 and 5. Opposing changes in MCT1 and MCT4 mRNA expression were observed in kidney samples on day 5 compared to GHB-naïve animals, and MCT4 expression was increased in the intestine.. The lack of tolerance observed with GHB-induced respiratory depression, in contrast to the tolerance reported for the sedative/hypnotic and electroencephalogram effects, suggests that different GABA

Topics: Animals; Cells, Cultured; Hypnotics and Sedatives; Male; Monocarboxylic Acid Transporters; Rats; Respiratory Insufficiency; Sodium Oxybate; Time Factors; Toxicokinetics

Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).. Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 h. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.. AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).. The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.

Topics: Administration, Intravenous; Administration, Oral; Animals; Antidotes; Brain; Cell Line; Drug Overdose; Kidney; Male; Metabolic Clearance Rate; Monocarboxylic Acid Transporters; Rats, Sprague-Dawley; Renal Reabsorption; Respiratory Insufficiency; Respiratory Rate; Sodium Oxybate; Thiophenes; Tissue Distribution; Uracil

γ-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1-0.2% and 0.3-0.4% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABAA receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABAB receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1-0.2% (4 of 10) and 0.3-0.4% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, l-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1-0.2% (0 of 10) and 0.3-0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3-0.4% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABAB receptor inhibition represent potentially effective treatments in GHB-ethanol intoxication.

Topics: Animals; Central Nervous System Depressants; Conscious Sedation; Drug Overdose; Ethanol; GABA-B Receptor Antagonists; Hypnotics and Sedatives; Lactic Acid; Male; Monocarboxylic Acid Transporters; Plethysmography; Poisoning; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Respiratory Mechanics; Sodium Oxybate

Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of γ-hydroxybutyrate (GHB) and its precursor γ-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL were administered in doses of 1.92, 5.77, and 14.4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL. The competitive MCT inhibitor l-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration. Oral administration of l-lactate and the MCT inhibitor luteolin was also evaluated. Respiratory depression was measured using plethysmography. Intravenous l-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances. At the low dose of GHB and GBL, i.v. l-lactate increased GHB renal clearance. Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance. At the highest GHB dose, oral clearance was increased without a significant change in renal clearance. The lack of effect of i.v. l-lactate on renal clearance after a high oral GHB dose suggests possible effects of i.v. l-lactate on MCT-mediated absorption. The resulting increases in oral clearance improved respiratory depression. Intravenous l-lactate also reduced mortality with the high GBL dose. These data indicate i.v. l-lactate represents a potential treatment strategy in oral overdose of GHB and GBL.

Topics: 4-Butyrolactone; Absorption; Administration, Oral; Animals; Dose-Response Relationship, Drug; Drug Overdose; Humans; Injections, Intravenous; Kidney; Lactic Acid; Male; Metabolic Clearance Rate; Monocarboxylic Acid Transporters; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Sodium Oxybate

Overdose of γ-hydroxybutyrate (GHB) frequently causes respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABA(B) receptor antagonist, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABA(A) receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABA(B) receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor l-lactate increased GHB renal and total clearance, also improving respiratory rate. Administration of 5 mg/kg SCH50911 plus l-lactate further improved respiratory rate compared with the same dose of either agent alone, indicating that GABA(B) and MCT inhibitors, alone and in combination, represent potential treatment options for GHB-induced respiratory depression.

Topics: Animals; Bicuculline; Dose-Response Relationship, Drug; Drug Overdose; Male; Morpholines; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Respiratory Insufficiency; Sodium Oxybate; Treatment Outcome

Gamma-hydroxybutyrate and its metabolic precursors gamma butyrolactone and 1,4-butanediol are widely used recreational drugs known to cause short periods of deep sedation with rapid recovery. We present a case of survival with good neurological outcome following massive ingestion in which the patient remained sedated for 14 h.

Topics: Adult; Butylene Glycols; Female; Humans; Illicit Drugs; Respiratory Insufficiency; Seizures; Sodium Oxybate

Topics: Female; Humans; Obstetric Labor Complications; Pregnancy; Respiratory Insufficiency; Sodium Oxybate; Substance-Related Disorders

In this case report we describe the first recorded case of alveolar gas exchange impairment caused by "liquid ecstasy" ingestion, and perhaps inhalation, by a 4 year old child. The pulmonary gas diffusion disturbance was sufficiently prolonged to raise the suspicion of a direct toxic effect on the alveolar-capillary membrane.

Topics: 4-Butyrolactone; Child, Preschool; Coma; Humans; Male; Paint; Pulmonary Edema; Respiratory Insufficiency; Sodium Oxybate; Solvents

Gamma hydroxybutyrate (GHB) is a product of the metabolism of both gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD). Gamma hydroxybutyrate (GHB) is an illegal agent that causes central nervous system depression. Chemical precursors of GHB, such as GBL and 1,4-BD, have been available for purchase from many health food stores and Internet websites for mood-enhancement, sleep-induction, and stimulation of growth hormone release. We report three cases of ingestion of products containing GHB and chemical precursors of GHB. All three patients had severe presentations followed by full recoveries. Some products containing GBL were withdrawn from the market after the FDA issued a warning regarding these products. Products containing 1,4-butanediol remain on the market today.

Topics: Adult; Central Nervous System Depressants; Coma; Humans; Male; Middle Aged; Respiratory Insufficiency; Sodium Oxybate; Substance-Related Disorders

Gamma hydroxy butyrate (GHB) is a central nervous system depressant approved as an anaesthetic in some countries; however, with the exception of investigational research, it is not approved for any use in the United States. Primary groups using GHB include party and nightclub attendees and bodybuilders. In addition, GHB is one of several agents characterized as a "date rape" drug. During August 1995-September 1996, poison control centers in New York and Texas received reports of 69 acute poisonings and one death attributed to ingestion of GHB. This report describes two cases and summarizes the investigations of GHB use in Texas and New York. The findings of these investigations underscore the health hazards associated with use of GHB.

Topics: Adolescent; Adult; Central Nervous System Depressants; Coma; Fatal Outcome; Female; Heart Arrest; Humans; Male; New York; Respiratory Insufficiency; Seizures; Sodium Oxybate; Substance-Related Disorders; Texas

Topics: Adolescent; Adult; Central Nervous System Depressants; Coma; Fatal Outcome; Female; Heart Arrest; Humans; Male; New York; Respiratory Insufficiency; Seizures; Sodium Oxybate; Substance-Related Disorders; Texas

Topics: Adult; Alcohol Drinking; Humans; Male; Nonprescription Drugs; Respiratory Insufficiency; Sodium Oxybate

The investigation of gas exchange, central hemodynamics and real oxygen transport has shown expediency of using ether and fluothane as main anesthetic drugs in operations on the lungs in patients with a compensated form of chronic pulmonary respiratory insufficiency. Neuroleptoanalgesia decreased the operative risk as compared with ether and fluothane. A combined anesthesia with sodium hydroxybutyrate in association with drugs for NLA and tranquilizers is thought to be the method of choice in patients with a pronounced respiratory insufficiency.

Topics: Anesthesia, General; Chronic Disease; Ether; Fentanyl; Halothane; Hemodynamics; Humans; Lung Diseases; Neuroleptanalgesia; Nitrous Oxide; Pulmonary Circulation; Pulmonary Gas Exchange; Respiratory Insufficiency; Sodium Oxybate