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Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation.

ABSTRACT: Propylene glycol (PG) is a frequently co-administered solvent in formulations administered to neonates, but reports on its (in)tolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv) PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.Renal (diuresis, creatinemia, sodium), metabolic (Base Excess, Anion Gap, lactate, bicarbonate) and hepatic (liver enzymes, bilirubinemia) indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol in neonates) study (intra-individual trends, ANOVA) were collected and analysed. Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-U test) were made.PG exposure (median 34.1?mg/kg/24?h) did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital-PG or 172 cases exposed to paracetamol-mannitol.Based on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.

SUBMITTER: Kulo A

PROVIDER: S-EPMC3517950 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation.

Kulo Aida A Smits Anne A Naulaers Gunnar G de Hoon Jan J Allegaert Karel K

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences 20120719 1

<h4>Background and purpose of the study</h4>Propylene glycol (PG) is a frequently co-administered solvent in formulations administered to neonates, but reports on its (in)tolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv) PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.<h4>Methods</h4>Renal (diuresis, c ...[more]

PMID: 23230503

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Project description:BackgroundEtomidate is a preferred drug for the induction of general anesthesia in cardiovascular risk patients. As with propofol and other perioperatively used anesthetics, the application of aqueous etomidate formulations causes an intensive burning pain upon injection. Such algogenic properties of etomidate have been attributed to the solubilizer propylene glycol which represents 35% of the solution administered clinically. The aim of this study was to investigate the underlying molecular mechanisms which lead to injection pain of aqueous etomidate formulations.ResultsActivation of the nociceptive transient receptor potential (TRP) ion channels TRPA1 and TRPV1 was studied in a transfected HEK293t cell line by whole-cell voltage clamp recordings of induced inward ion currents. Calcium influx in sensory neurons of wild-type and trp knockout mice was ratiometrically measured by Fura2-AM staining. Stimulated calcitonin gene-related peptide release from mouse sciatic nerves was detected by enzyme immunoassay. Painfulness of different etomidate formulations was tested in a translational human pain model. Etomidate as well as propylene glycol proved to be effective agonists of TRPA1 and TRPV1 ion channels at clinically relevant concentrations. Etomidate consistently activated TRPA1, but there was also evidence for a contribution of TRPV1 in dependence of drug concentration ranges and species specificities. Distinct N-terminal cysteine and lysine residues seemed to mediate gating of TRPA1, although the electrophile scavenger N-acetyl-L-cysteine did not prevent its activation by etomidate. Propylene glycol-induced activation of TRPA1 and TRPV1 appeared independent of the concomitant high osmolarity. Intradermal injections of etomidate as well as propylene glycol evoked severe burning pain in the human pain model that was absent with emulsification of etomidate.ConclusionsData in our study provided evidence that pain upon injection of clinical aqueous etomidate formulations is not an unspecific effect of hyperosmolarity but rather due to a specific action mediated by activated nociceptive TRPA1 and TRPV1 ion channels in sensory neurons.

Dataset Information

Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation.

Publications

Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation.

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