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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The introduction of sulphonamides for the treatment of infection in 1935 was a major advance in medical care. However, sulphonamides are relatively insoluble in water and, consequently, there was a problem in preparing a paediatric formulation. In 1937 the use of diethylene glycol as a solvent to prepare elixir of sulphanilamide - done without appreciation that the vehicle was a potent toxin - was responsible for the deaths of at least 76 American children and adults [16]. Unfortunately, this historical tragedy has been repeated numerous times. Diethylene glycol has been used as a solvent for paracetamol, resulting in the death of 47 children in Nigeria in 1992, 51 children in Bangladesh in 1995 and 85 children in Haiti in 1998 [2]. It is important to remember that medicines contain not only the desired active compound but also numerous other chemicals which are added to make the drug more palatable, soluble, stable or for a variety of other reasons (e.g., to add colouring, to enhance drug suspension). Thus, it is important to consider every component of a drug formulation as a substance with the potential of producing an ADR in the paediatric patient.
Endotoxin: Historical Perspectives
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Ernst T. Rietschel, Otto Westphal
Using a similar approach, Walter T. J. Morgan (48–50) in London and Walther F. Goebel (1899–1994) in New York developed further extraction procedures using mixtures of organic solvents and water. Their purified substances, similar to Boivin and Mesrobeanu’s products, were composed of polysaccharide, lipid, and protein. Morgan’s diethylene glycol extracts from Salmonella and Shigella appeared as physicochemically homogeneous and uniform substances. In systematic studies, Morgan then described methods for the dissociation of the complex into structural subunits like undegraded polysaccharide or degraded polysaccharide, conjugated or simple protein, and loosely bound kephalin-like lipid.
Ethylene Glycol
Published in David J. George, Poisons, 2017
Ethylene glycol is a member of a chemical family of compounds that are collectively classified as glycols. Two other glycols that are often confused with ethylene glycol are diethylene glycol and propylene glycol. In practicality, ethylene glycol and diethylene glycol can be considered identical in terms of their toxic potential. Propylene glycol does not share this toxic potential and is generally considered safe when used in a specified manner in food products and pharmaceuticals. Due to the similarity in names, products containing propylene glycol are often mistaken as objects of major consumer concern and can mislead investigators.
Variable sensitivity to diethylene glycol poisoning is related to differences in the uptake transporter for the toxic metabolite diglycolic acid
Published in Clinical Toxicology, 2023
Julie D. Tobin, Courtney N. Jamison, Corie N. Robinson, Kenneth E. McMartin
Diethylene glycol (DEG) is a colorless organic solvent that is found in industrial lubricants and chafing fuel. It has also been mistakenly used in pharmaceutical formulations as a cheaper alternative to glycerin or has been an adulterant in the procured glycerin [1]. Ingestion of these adulterated pharmaceutical preparations has resulted in several epidemic poisonings, with multiple fatalities. The hallmark sign of DEG poisoning is renal failure or acute kidney injury (AKI), while other clinical manifestations include metabolic acidosis, mild to moderate hepatotoxicity, and a delayed peripheral neuropathy [2–4]. The kidney injury observed in many patients is characterized by remarkable necrosis of the proximal tubular epithelium [5]. Diethylene glycol undergoes metabolism first by alcohol dehydrogenase, eventually yielding two primary metabolites, diglycolic acid (DGA) and 2-hydroxyethoxyacetic acid (2-HEAA). A study by Besenhofer et al. [6] showed that DEG toxicity is blocked when metabolism by alcohol dehydrogenase is inhibited in rats, suggesting that it is a metabolite of DEG that is responsible for the toxicity and not the parent compound. Moreover, several studies have shown that direct DGA administration both in vitro and in vivo mimic the toxicity found in DEG studies, suggesting that DGA is the metabolite responsible for the toxicity [7–9]. Furthermore, DGA accumulation of up to 100-fold is found in kidney tissue after DEG administration, compared to concentrations in the blood [10].
Toxicological assessment of electronic cigarette vaping: an emerging threat to force health, readiness and resilience in the U.S. Army
Published in Drug and Chemical Toxicology, 2022
Marc A. Williams, Gunda Reddy, Michael J. Quinn, Amy Millikan Bell
Humectants commonly found in e-cigs include combinations of glycerol, propylene glycol, trimethylene glycol and, to a lesser extent, ethylene glycol – exposures to which, exceeded the minimal risk level thought to be protective of human health as defined by the DHHS-ATSDR (DHHS 2010), and compounds that are not currently listed on the FDA’s list of chemicals that are recognized as GRAS (see Table 1; Hahn et al.2014). Others have attempted to determine the toxicity of diethylene glycol (DEG) in 18 brands of e-cig cartridges (e.g., the Smoking Everywhere 555 High brand), but its quantities were not provided, thus limiting an evaluation of its potential toxicity (FDA 2009). As others have indicated (Orr 2014), it is noteworthy that the U.S. Code of Federal Regulations (CFR) (2011) permits up to 0.2% of DEG in polyethylene glycol when polyethylene glycol is used as a food additive (see 21CFR172.820, 2013). However, this regulation applies to oral, and not inhalational exposure.
Diethylene glycol produces nephrotoxic and neurotoxic effects in female rats
Published in Clinical Toxicology, 2022
Courtney N. Jamison, Robert D. Dayton, Brian Latimer, Mary P. McKinney, Hannah G. Mitchell, Kenneth E. McMartin
Diethylene glycol (DEG) has been implicated in mass poisonings throughout the world due to accidental ingestion of contaminated drugs or liquids [1–4]. DEG is also a constituent of common consumer products such as brake fluid and fog machine fluid, ingestion of which can lead to individual poisonings [5]. The typical clinical indicators of human DEG poisoning are acute kidney injury (AKI) [3] and a peripheral neuropathy characterized by decreased reflexes and coordination of movement, weakness in the arms, legs, and face. The neurological damage usually manifests about 2–7 days after ingestion. Forty out of 46 patients included in a case study of the Panama DEG epidemic reported neurotoxic symptoms [3], with over 60% experiencing limb weakness and decreased or absent reflexes. Thirteen of 14 cases that showed an increase in protein concentration in the cerebrospinal fluid (CSF) later developed neurological signs, suggesting that CSF protein elevations were an early indication of neurotoxicity. Case studies in South Africa [6] and Colorado [7] also noted elevated CSF protein concentrations.