Forensic toxicology findings in deaths involving gamma-hydroxybutyrate

Kugelberg, Fredrik C.; Holmgren, Anita; Eklund, Arne; Jones, Alan Wayne

doi:10.1007/s00414-008-0299-2

Cited by 46 publications

(31 citation statements)

References 45 publications

(46 reference statements)

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“…The current studies show that, similar to humans, renal elimination of GHB is negligible in rats at low plasma concentrations but significantly contributes to total GHB clearance in rats at high oral doses. Case reports of GHB intoxication have reported very high urine concentrations, also suggesting significant renal elimination of GHB in clinical overdose (Kintz et al, 2005;Mazarr-Proo and Kerrigan, 2005;Kugelberg et al, 2010). Our data are also consistent with previous studies in rats demonstrating much higher plasma concentrations of GHB after GBL administration compared with administration of equimolar doses of GHB itself (Lettieri and Fung, 1978).…”

Section: Discussionsupporting

confidence: 92%

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Morse

Morris

2013

J Pharmacol Exp Ther

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Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of g-hydroxybutyrate (GHB) and its precursor g-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.

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Section: Discussionsupporting

confidence: 92%

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Morse

Morris

2013

J Pharmacol Exp Ther

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“…Measurement of ethyl glucuronide is a helpful tool to determine in vivo ingestion of ethanol. If ethyl glucuronide is not detectable along with ethanol, ethanol formation might have occurred postmortem; however, alcohol synthesis can not be excluded with certainty if both ethanol and its glucuronide conjugate are present, and ethyl glucuronide may also disappear from blood due to marked putrefaction [6,16,17].…”

Section: Postmortem Changes Of Bloodmentioning

confidence: 97%

“…Many drugs interact with ethanol, commonly present in postmortem specimens, thereby altering the mechanism or effect of the alcohol and the drug involved. Ethanol is a central nervous system depressant and a similar effect is found with other hypnotic or narcotic drugs [3,6]. Interaction may also occur through the induction of CYP2E1-a member of the cytochrome P450 family with high catalytic activity towards ethanol.…”

Section: Antemortem Factorsmentioning

confidence: 99%

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Postmortem toxicology

Skopp

2010

Forensic Sci Med Pathol

147

101

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Results from toxicological analyses in death investigations are used to determine whether foreign substances were a cause of death, whether they contributed to death, or whether they caused impairment. Drug concentrations are likely to change during pre-terminal stages due to altered pharmacokinetics, to treatment during resuscitation or in the intensive care unit, to concomitant illness or to the presence of drug tolerance. The potential for postmortem changes must be considered in all but a few drugs. Formation of new entities as well as degradation of drugs may occur, especially in putrefied corpses; in addition, body fluids and tissues may be severely affected by autolysis and putrefaction. Specimens should be selected based on individual case history and on their availability. Analytical procedures should be performed in accordance with a proper quality assurance program for toxicological investigations. Problems are most likely to occur during the isolation and identification of a drug. Interpretation of analytical results is often limited by the inadequate information provided in a particular case.

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“…In one series of 49 GHB-related deaths, the mean femoral blood GHB concentration was 292 mg/L and in a series of 18 GHB intoxications in which toxicological screening was undertaken, all three patients with a GHB concentration of greater than 220 mg/L had a GCS of 3/15. 11,12 GBL is rapidly metabolized to gammahydroxybutyrate (GHB) in vivo and ingestion of both of these agents, and the other GHB precursor 1,4-BD, cause similar clinical features and complications. 1,2,13 In a recent large UK series (n=158) of acute GHB/GBL toxicity, 47.4% of patients had a GCS % 8/15 on presentation to A&E.…”

Section: Discussionmentioning

confidence: 99%