Paediatric clinical pharmacology
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
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.
Errors in Toxicology
David Woolley, Adam Woolley in Practical Toxicology, 2017
Most dictionaries define contamination along the lines of making something impure, unclean, soiled, corrupt, etc. Sometimes, contaminations are accidental, occurring as a result of a mistake or a misunderstanding, such as oil spills, contamination of rivers, or the unintended introduction of toxic substances into food or drugs. However, sometimes, mismanagement (and greed) plays a large role. One of the most recent and perhaps most shocking examples of contamination was that of the Chinese baby milk powder, which was deliberately contaminated with melamine to increase the nitrogen content, leading to widespread effects on the children’s kidneys and even death. Diethylene glycol is another candidate for contamination that has been implicated in multiple health scares and tragedies. In a similar vein, as more and more people turn to alternative medicines, the likelihood of someone misusing or misunderstanding how the herbal product is to be used increases–excessive green tea use, fake materials (such as fake ginkgo root), and incorrect use of particular herbs such as those containing aristocholic acid.
The US regulation of off-label uses of medicines
Andrea Parziale in The Law of Off-label Uses of Medicines, 2023
However, it was the tragic Sulfanilamide scandal of 1937 that eventually made the inadequacy of the 1906 regulatory framework fully apparent to policymakers.16 Before the scandal broke out, Sulfanilamide had been safely used in tablet and powder form to treat streptococcal infections. In 1937, the manufacturing company had started distributing the drug in liquid form as well, by dissolving Sulfanilamide in diethylene glycol, a substance normally used as an antifreeze. The new formulation, however, had not been tested for toxicity (which was not required by the Pure Food and Drug Act of 1906). Thus, the manufacturers did not note that diethylene glycol is lethal. This could have been easily demonstrated with simple tests on animals and even a review of the scientific literature, which showed that diethylene glycol was toxic and could cause kidney failure. Writing to President Franklin D. Roosevelt, a mother movingly portrayed the agony of her daughter after the administration of Sulfanilamide: The first time I ever had occasion to call in a doctor for [Joan] and she was given Elixir of Sulfanilamide. All that is left to us is the caring for her little grave. Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane… . It is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind and such a bleak outlook on the future as I have tonight.17
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].
Experimental measurement – correlation of solubility and dissolution thermodynamics study of itraconazole in pure monosolvents at various temperatures
Published in Drug Development and Industrial Pharmacy, 2021
Sachin K. Jagdale, Rajesh B. Nawale
Glycerin, propylene glycol, polyethylene glycol-200, polyethylene glycol-400, and polyethylene glycol-600 are the polymerized derivatives of ethylene glycols and are physiologically acceptable. They have the adequate pharmaceutical properties like lower toxicity, low volatility, high stability, and complete miscibility with water almost at all the proportions. They are also preferred in the design and development of various pharmaceutical oral and parenteral formulations as well as used for the preclinical and clinical studies [21,22]. 1-Methyl-2-pyrrolidone (NMP) is biodegradable solvent with high solubilizing power and used in different fields of industrial applications including pharmaceutical, synthetic, and analytical industries [23]. N, N-dimethylacetamide (DMA) is an FDA approved solvent widely used in pharmaceutical industry to improve the solubility of lipophilic, high molecular weight drugs with poor water solubility [24]. Dimethyl formamide (DMF) is an extraordinary organic compound favored as solvent in pharmaceutical industry due to its favored dissolution provided by interactions with a substrate [25]. Triacetin is reported to be used as solvent in topical and cosmetic formulations and as a carrier for fragrances and flavors [26]. Diethylene glycol is used as strong solubilizer in many products including pharmaceutical, topical, transdermal, cosmetics, nutraceuticals, and is employed for various routes of administration [27]. Carbon tetrachloride, cyclohexane, and n-hexane are used in pharmaceutical industry as reaction media, in separation and purification of synthesis products [28].
Neurotoxic effects of nephrotoxic compound diethylene glycol
Published in Clinical Toxicology, 2021
Courtney N. Jamison, Robert D. Dayton, Brian Latimer, Mary P. McKinney, Hannah G. Mitchell, Kenneth E. McMartin
Diethylene glycol (DEG) is an organic compound that can be found in household products, including chafing fuels and brake fluid, but has also been a contaminant in some medicines as a counterfeit solvent [1,2]. Unfortunately, this adulteration has led to cases of accidental ingestion around the world, including China, Africa, and Panama, resulting in long term kidney damage, neurologic sequelae and death [3]. While DEG poisonings are not prevalent in the United States in comparison to more recent DEG outbreaks, an adulterated DEG poisoning was instrumental in the creation of the 1938 Federal Food, Drug, and Cosmetic Act due to the Massengill sulfanilamide disaster of 1937 [3–5] Since then, there have been numerous mass poisoning incidences involving DEG, with Brazil in late 2019 [6] being the most recent and Bangladesh from 1990 to 1992 being the deadliest [7].