Macrogol, also known as polyethylene glycol (PEG), is used as a medication to treat constipation in children and adults.[1] It is taken by mouth.[1] Benefits usually occur within three days.[2] Generally it is only recommended for up to two weeks.[3] It is also used as an excipient.[4] It is also used to clear the bowels (known as "bowel prep") before a colonoscopy,[1] when the onset of the laxative effect is more rapid, typically within an hour.[5]
Macrogol came into use as a bowel prep in 1980 and was approved for medical use in the United States in 1999.[8][9][10] It is available as a generic medication and over the counter.[1][11] In 2020, it was the 226th most commonly prescribed medication in the United States, with more than 2million prescriptions.[12][13] Typically it is formulated together with electrolytes.[14]
Macrogol 3350, often in combination with electrolytes, is used for short-term relief of constipation as well as for long-term use in constipation of various causes, including in multiple sclerosis and Parkinson's disease patients (an often-overlooked non-motor symptom) as well as constipation caused by pharmaceutical drugs such as opioids and anticholinergics. Whole bowel irrigation with macrogol is part of the bowel preparation before surgery or colonoscopy. Limited data also support its use for the treatment of fecal impaction.[15]
In those with chronic constipation it works better than lactulose.[16]
A 2007 comparison showed that people with constipation had a better response to macrogol than to tegaserod.[17] Popular types include: macrogol 3350,[18] macrogol 4000, and macrogol 6000.[19] The number represents the average molecular mass.[citation needed] Combining different molecular masses provides some control over the consistency.[20]
Excipient
Macrogol is used as an excipient in pharmaceutical products.[4] Lower-molecular-weight variants are used as solvents in oral liquids and soft capsules, whereas solid variants are used as ointment bases, tablet binders, film coatings, and lubricants.[20]
Macrogols are also attached to biopharmaceutical drugs to slow down their degradation in the human body and increase their duration of action, as well as to reduce immunogenicity. This process is called PEGylation.[23][24]
The doses of macrogol as an excipient are too low to have relevant contraindications.[25]
Allergy to macrogol is rare, and usually appears as an allergy to an increasing number of seemingly unrelated products, including cosmetics, drugs that use it as an excipient, and peri-procedural substances such as ultrasound gel.[26]
Adverse effects
Oral macrogol is generally well tolerated. Possible side effects include headache, bloating, nausea, allergies, and electrolyte imbalance, mainly hypokalaemia (low blood potassium levels) and hyperkalaemia (high blood potassium levels). Hyperkalaemia is not an effect of macrogol itself but of potassium salts which are usually part of macrogol formulations.[15] With excessive use, it can cause diarrhea.
Interactions
The interaction potential is low. Absorption of other pharmaceutical drugs can be reduced because oral macrogol accelerates intestinal passage, but this is seldom clinically relevant. For antiepileptic drugs, such a mechanism has been described in rare cases.[15]
Pharmacology
Mechanism of action as a laxative
Macrogol is an osmotically acting laxative; that is, an inert substance that passes through the gut without being absorbed into the body. It relieves constipation because it causes water to be retained in the bowel instead of being absorbed into the body. This increases the water content and volume of the stools in the bowel, making them softer and easier to pass, as well as improving gut motility.[15][27][28]
When sold for gut cleansing (and as a laxative), it is usually in combination with salts such as sodium bicarbonate, sodium chloride and potassium chloride[29] to help mitigate the possibility of electrolyte imbalance and dehydration. Brand names include CosmoCol, Cololyt, Glycoprep, Laxido, MiraLax, Molaxole, Movicol, and Osmolax.
Polyethylene glycol-electrolyte solution is a fixed-dose combination medication sold under various brand names in the US, including Colyte,[30] Gavilyte, Golytely,[31] Nulytely,[32] Moviprep,[33] and Trilyte.[34][35] Brand names available in the UK include CosmoCol, Klean-Prep, Laxido, Molaxole, Movicol, Plenvu, TransiSoft, and VistaPrep.[36] As of June 2023[update], polyethylene glycol 3350 is available in the US as a combination with sodium sulfate, potassium chloride, magnesium sulfate, and sodium chloride and sold under the brand name Suflave.[37] It is indicated for cleansing of the colon in preparation for colonoscopy in adults.[37]
Research
PEGylation
The protein uricase can be PEGylated to form pegloticase, which improves its solubility at physiological pH, increases serum half-life and reduces immunogenicity without compromising activity. Upper images show the whole tetramer, lower images show one of the lysines that is PEGylated. (PDB: 1uox PEG-uricase model from reference[38])
When attached to various biopharmaceutical medications (which are proteins), macrogol results in a slowed clearance of the carried protein from the blood. This makes for a longer-acting medicinal effect and reduces toxicity, and it allows for longer dosing intervals. It also reduces the proteins' immunogenicity. Examples for PEGylated proteins include peginterferon alfa-2a and -2b, which are used to treat hepatitis C, pegfilgrastim, which is used to treat neutropenia, and pegloticase for the treatment of gout.[15]
Nerves and spinal cords
There is evidence demonstrating PEG-induced repair of specific nerve cells in animal models:
It has been shown that macrogol can improve healing of spinal injuries in dogs.[39]
One of the earlier findings is that macrogol can aid in nerve repair in earthworms.[40]
The subcutaneous injection of macrogol 2000 in guinea pigs after spinal cord injury leads to rapid recovery through molecular repair of nerve membranes.[41] The effectiveness of this treatment to prevent paraplegia in humans after an accident is not known yet.
Macrogol is being used in the repair of motor neurons damaged in crush or laceration incidents in vivo and in vitro in rats. When coupled with melatonin, 75% of damaged sciatic nerves were rendered viable.[42]
The Chemoprevention Database shows macrogol is the most effective known agent for the suppression of chemical carcinogenesis in rats. Cancer prevention applications in humans, however, have not yet been tested in clinical trials.[44]
^Mahmoud NN, Bleier JI, Aarons CB, Paulson EC, Shangmugan S, Fry RD (2016). "Colon and Rectum". In Townsend CM, Beauchamp RD, Evers BM, Mattox KL (eds.). Sabiston Textbook of Surgery E-Book: The Biological Basis of Modern Surgical Practice. Elsevier Health Sciences. p. 1325. ISBN9780323401630.
^Aronson JK (2015). "Glycols". Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. Elsevier. p. 567. ISBN9780444537164.
^ abcdefHaberfeld, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
^Lee-Robichaud H, Thomas K, Morgan J, Nelson RL (July 2010). "Lactulose versus Polyethylene Glycol for Chronic Constipation". The Cochrane Database of Systematic Reviews (7): CD007570. doi:10.1002/14651858.CD007570.pub2. PMID20614462.
^Di Palma JA, Cleveland MV, McGowan J, Herrera JL (September 2007). "A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation". The American Journal of Gastroenterology. 102 (9): 1964–1971. doi:10.1111/j.1572-0241.2007.01365.x. PMID17573794. S2CID32055676.
^Hardikar W, Cranswick N, Heine RG (2007). "Macrogol 3350 plus electrolytes for chronic constipation in children: a single-centre, open-label study". Journal of Paediatrics and Child Health. 43 (7–8): 527–531. doi:10.1111/j.1440-1754.2007.01116.x. PMID17635680. S2CID42699177.
^Veronese FM, Harris JM (June 2002). "Introduction and overview of peptide and protein pegylation". Advanced Drug Delivery Reviews. 54 (4): 453–456. doi:10.1016/S0169-409X(02)00020-0. PMID12052707.
^Wenande E, Garvey LH (July 2016). "Immediate-type hypersensitivity to polyethylene glycols: a review". Clinical and Experimental Allergy. 46 (7): 907–922. doi:10.1111/cea.12760. PMID27196817. S2CID1247758.
^Mutschler E (2013). Arzneimittelwirkungen (in German) (10 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 608. ISBN978-3-8047-2898-1.
^Chaussade S (November 1999). "Mechanisms of action of low doses of polyethylene glycol in the treatment of functional constipation". Italian Journal of Gastroenterology and Hepatology. 31 (Suppl 3): S242–S244. PMID10726227.
^Sherman MR, Saifer MG, Perez-Ruiz F (January 2008). "PEG-uricase in the management of treatment-resistant gout and hyperuricemia". Advanced Drug Delivery Reviews. 60 (1): 59–68. doi:10.1016/j.addr.2007.06.011. PMID17826865.
^Borgens RB, Bohnert D (December 2001). "Rapid recovery from spinal cord injury after subcutaneously administered polyethylene glycol". Journal of Neuroscience Research. 66 (6): 1179–1186. doi:10.1002/jnr.1254. PMID11746451. S2CID11902183.
^Stavisky RC, Britt JM, Zuzek A, Truong E, Bittner GD (March 2005). "Melatonin enhances the in vitro and in vivo repair of severed rat sciatic axons". Neuroscience Letters. 376 (2): 98–101. doi:10.1016/j.neulet.2004.11.033. PMID15698928. S2CID24634247.
^Corpet DE, Parnaud G, Delverdier M, Peiffer G, Taché S (June 2000). "Consistent and fast inhibition of colon carcinogenesis by polyethylene glycol in mice and rats given various carcinogens". Cancer Research. 60 (12): 3160–3164. PMID10866305.
Clinical trial number NCT04446299 for "Study 301: BLI4900 Versus an FDA-approved Comparator in Adult Subjects Prior to Colonoscopy" at ClinicalTrials.gov
Clinical trial number NCT04446312 for "Study 302: BLI4900 Versus an FDA-approved Comparator in Adult Subjects Prior to Colonoscopy" at ClinicalTrials.gov
Drugs for constipation (laxatives and cathartics) (A06)
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