Glycols

Diethylene glycol

Diethylene glycol is important in the history of adverse drug reactions.

The first major drug catastrophe in the 20th-century history of the public control of drugs occurred in 1937 in the USA and involved diethylene glycol. A pharmacist introduced a drug, Elixir Sulfanilamide, that consisted of sulfanilamide dissolved in diethylene glycol. It had been tested for flavor, appearance, and fragrance, but not for safety. After taking the drug, over 100 patients died in severe pain; many were children, who were given Elixir Sulfanilamide for sore throats and coughs. Public outrage created support for proposed legislation to reinforce the public control of drugs that was pending in the US Congress [ ]. And so, the US 1938 Food, Drug, and Cosmetic Act came into being, and is still the country’s legal foundation for the public control of drugs and devices intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals. It has been a model for similar legislation in many other countries.

The 1938 US Food, Drug, and Cosmetic Act prohibited traffic in new drugs, unless they were safe for use under the conditions of use prescribed on their labels. The Act also explicitly required the labelling of drug products with adequate directions for use.

The burden of proof of harm of new drugs was laid on the Federal Food and Drug Agency (FDA). Companies that wanted to manufacture and sell new drugs in interstate commerce had to investigate their safety and report to the FDA. Unless the FDA, within a specified period of time, found that the safety of a drug had not been established, the company could proceed with its marketing. The FDA was also authorized to remove from the market any drug it could prove to be unsafe [ ].

The US Supreme Court also established in 1941, in a legal case over drug adulteration, that responsible individuals in a company can be held personally accountable for the quality of the products manufactured by the company, and that distributors of pharmaceuticals are responsible for the quality of their products, even if they are manufactured elsewhere [ ].

After World War II, the pharmaceuticals market changed radically, as many companies started industrial production of drugs that had previously been manufactured in pharmacies. Announcements of new industrially produced drugs were hailed as part of technological advancement, as significant a sign of progress as the launching of satellites and putting a man on the moon. However, public safeguards against the risks of drugs remained unchanged in most countries. Thus, control of the effects of drugs largely lay in the hands of the manufacturers, even though the responsibility for taking precautions rested with pharmacists and doctors.

Ethylene glycol, ethylene glycol monoethyl ether, and ethylene monomethyl ether

Ethylene glycol is a colorless, sweet-tasting liquid that is used as an anti-freeze, in the manufacture of polyester fibers and films, as a heat-transfer fluid, in aircraft and runway de-icing mixtures, to provide freeze-thaw stabilization to latex coatings, to improve the flexibility and drying time of paints, as a dehydrating agent in natural gas, in motor oil additives, as an additive in inks, pesticides, wood stains, and adhesives, and as a solvent and suspending medium for ammonium perborate, the conductor in most electrolytic capacitors. The monoethyl ether of ethylene glycol, 2-ethoxyethanol or ethyl glycol, has been used as an excipient in some drug formulations, in the semiconductor industry, in duplicating fluids, epoxy resins, lacquers, paints, printing inks, varnish removers, and wood stains. The monomethyl ether of ethylene glycol, 2-methoxyethanol or methyl glycol, is used as a jet fuel de-icer and as a solvent for cellulose acetate, dyes, enamels, nail polishes, resins, varnishes, and wood stains.

In one study, occupational exposure to ethylene glycol was not associated with adverse reactions [ ]. However, other adverse effects of occupational exposure have been noted, including anemia, subfertility, and renal stones.

Ethylene glycol is sometimes used in suicide attempts. It is not itself toxic, but is converted to toxic metabolites. Conversion to glycoaldehyde by alcohol dehydrogenase is the rate-limiting step, and further metabolism yields glycolate, glyoxylate, and oxalate.

Polyethylene glycol

Polyethylene glycol is a high molecular weight inert molecule that is commonly combined with electrolytes (potassium chloride, sodium bicarbonate, sodium chloride, and sodium sulfate) in colonic lavage systems. Owing to the osmotic properties of these solutions, there is little absorption or secretion of electrolytes or water, although small amounts of polyethylene glycol and sulfates have been detected in the urine of healthy patients and higher concentrations in the urine of patients with inflammatory bowel disease [ ]. Common adverse reactions to the use of solutions containing polyethylene glycol and electrolytes include nausea, abdominal fullness, and bloating in up to 50% of patients. These solutions are contraindicated in patients with gastric outlet obstruction or gastroparesis, gastrointestinal obstruction or perforation, ileus, or toxic colitis [ ].

Polyethylene glycol (PEG) is also used to convert certain compounds of relatively high molecular weights to more soluble products, known as pegylated derivatives. Such compounds include pegylated interferons and interleukins. The safety and activity of outpatient-based continuous intravenous interleukin-2 (IL-2) or a modified-release pegylated IL-2 have been studied in 115 HIV-positive patients with CD4 cell counts of 200–500 × 106/l randomized to antiretroviral therapy plus cyclical continuous intravenous IL-2 (n = 27), subcutaneous pegylated IL-2 (n = 58), or no IL-2 (n = 30) [ ]. The termination rates due to adverse events were 4% with continuous intravenous IL-2 and 7% with pegylated IL-2. The frequency and severity of grade 3 and 4 adverse events were similar in both IL-2 groups, with the exception of local erythema and induration associated with subcutaneous injections of pegylated IL-2. Fever, fatigue, stomatitis, erythema, gastrointestinal symptoms, and mood alterations constituted the majority of clinically significant toxic reactions. Most of the adverse events resolved by 8–15 days of each cycle. There were several unusual adverse reactions to IL-2 that were apparently not dose-related, including worsening of pre-existing diarrhea, cardiomyopathy in a patient with a history of heroin abuse, and attempted suicide in a patient with a psychiatric history; these were probably not drug-related.

In 68 patients randomly assigned to receive either sulfate-free polyethylene glycol electrolyte lavage or sodium picosulfate plus magnesium sulfate, the day before colonoscopy, bowel cleansing was significantly better with picosulfate plus magnesium sulfate [ ]. Adverse reactions were more common with polyethylene glycol electrolyte lavage, especially nausea, vomiting, and palpitation, and four patients did not complete treatment owing to adverse reactions.

Propylene glycol

Propylene glycol is widely used as a solvent in topical glucocorticoids, other medicines (including diazepam, etomidate, and lorazepam), foodstuffs, cosmetics, household detergents, paints, and brake fluids.