|Systematic (IUPAC) name|
|Biological half-life||100 minutes|
|ATC code||A06AD16 (WHO) B05BC01 (WHO) B05CX04 (WHO) R05CB16 (WHO)|
Mannitol, also known as mannite or manna sugar, is a white, crystalline solid that looks and tastes sweet like sucrose. Medically it is used to treat increased intracranial pressure. It also has several industrial uses. In plants its purpose is to alleviate osmotic stress.
Serious side effects may include worsening heart failure, electrolyte abnormalities, or low blood volume. It is unclear if it is safe in pregnancy. Mannitol is classified as a sugar alcohol; that is, it is derived from a sugar (mannose) by reduction. Other sugar alcohols include xylitol and sorbitol. Mannitol and sorbitol are isomers, the only difference being the orientation of the hydroxyl group on carbon 2.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. It was originally isolated from the flowering ash and called manna after its supposed resemblance to the Biblical food.
The use of mannitol, when inhaled, as a bronchial irritant as an alternative method of diagnosis of exercise induced asthma has been proposed. A 2013 systematic review concluded there is insufficient evidence to support its use for this purpose at this time.
Mannitol is commonly used in the circuit prime of a heart lung machine during cardiopulmonary bypass. The presence of mannitol preserves renal function during the times of low blood flow and pressure, while the patient is on bypass. The solution prevents the swelling of endothelial cells in the kidney, which may have otherwise reduced blood flow to this area and resulted in cell damage.
Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial pacemaker) while it is passed through the venous system. Because the mannitol dissolves readily in blood, the sharp point will become exposed at its destination.
Mannitol is the primary ingredient of Mannitol Salt Agar, a bacterial growth medium, and is used in others.
Mannitol is also the first drug of choice for the treatment of acute glaucoma in veterinary medicine. It is administered as a 20% solution IV. It dehydrates the vitreous humor and, therefore, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.
Mannitol increases blood glucose to a lesser extent than sucrose (thus having a relatively low glycemic index) and is therefore used as a sweetener for people with diabetes, and in chewing gums. Although mannitol has a higher heat of solution than most sugar alcohols, its comparatively low solubility reduces the cooling effect usually found in mint candies and gums. However, when mannitol is completely dissolved in a product, it induces a strong cooling effect. Also, it has a very low hygroscopicity – it does not pick up water from the air until the humidity level is 98%. This makes mannitol very useful as a coating for hard candies, dried fruits, and chewing gums, and it is often included as an ingredient in candies and chewing gum. The pleasant taste and mouthfeel of mannitol also makes it a popular excipient for chewable tablets.
Mannitol is commonly produced via the hydrogenation of fructose, which is formed from either starch or sucrose (common table sugar). Although starch is a cheaper source than sucrose, the transformation of starch is much more complicated. Eventually, it yields a syrup containing about 42% fructose, 52% glucose, and 6% maltose. Sucrose is simply hydrolyzed into an invert sugar syrup, which contains about 50% fructose. In both cases, the syrups are chromatographically purified to contain 90–95% fructose. The fructose is then hydrogenated over a nickel catalyst into a mixture of isomers sorbitol and mannitol. Yield is typically 50%:50%, although slightly alkaline reaction conditions can slightly increase mannitol yields.
Mannitol is one of the most abundant energy and carbon storage molecules in nature, produced by a plethora of organisms, including bacteria, yeasts, fungi, algae, lichens, and many plants. Fermentation by microorganisms is an alternative to the traditional industrial synthesis. A fructose to mannitol metabolic pathway, known as the mannitol cycle in fungi, has been discovered in a type of red algae (Caloglossa leprieurii), and it is highly possible that other microorganisms employ similar such pathways. A class of lactic acid bacteria, labeled heterofermentive because of their multiple fermentation pathways, convert either three fructose molecules or two fructose and one glucose molecule into two mannitol molecules, and one molecule each of lactic acid, acetic acid, and carbon dioxide. Feedstock syrups containing medium to large concentrations of fructose (for example, cashew apple juice, containing 55% fructose: 45% glucose) can produce yields 200 g (7.1 oz) mannitol per liter of feedstock. Further research is being conducted, studying ways to engineer even more efficient mannitol pathways in lactic acid bacteria, as well as the use of other microorganisms such as yeast and E. coli in mannitol production. When food grade strains of any of the aforementioned microorganisms are used, the mannitol and the organism itself are directly applicable to food products, avoiding the need for careful separation of microorganism and mannitol crystals. Although this is a promising method, steps are needed to scale it up to industrially needed quantities.
Since mannitol is found in a wide variety of natural products, including almost all plants, it can be directly extracted from natural products, rather than chemical or biological syntheses. In fact, in China, isolation from seaweed is the most common form of mannitol production. Mannitol concentrations of plant exudates can range from 20% in seaweeds to 90% in the plane tree. It is a constituent of saw palmetto (Serenoa). Traditionally, mannitol is extracted by the Soxhlet extraction, utilizing ethanol, water, and methanol to steam and then hydrolysis of the crude material. The mannitol is then recrystallized from the extract, generally resulting in yields of about 18% of the original natural product. Another up and coming method of extraction is by using supercritical and subcritical fluids. These fluids are at such a stage that there is no difference between the liquid and gas stages, and are therefore more diffusive than normal fluids. This is considered to make them much more effective mass transfer agents than normal liquids. The super-/sub-critical fluid is pumped through the natural product, and the mostly mannitol product is easily separated from the solvent and minute amount of byproduct. Supercritical carbon dioxide extraction of olive leaves has been shown to require less solvent per measure of leaf than a traditional extraction — 141.7 g (5.00 oz) CO2 versus 194.4 g (6.86 oz) ethanol per 1 g (0.035 oz) olive leaf. Heated, pressurized, subcritical water is even cheaper, and is shown to have dramatically greater results than traditional extraction. It requires only 4.01 g (0.141 oz) water per 1 g (0.035 oz) of olive leaf, and gives a yield of 76.75% mannitol. Both super- and sub-critical extractions are cheaper, faster, purer, and more environmentally friendly than the traditional extraction. However, the required high operating temperatures and pressures are causes for hesitancy in the industrial use of this technique.
The three studies that initially found that high-dose mannitol was effective in cases of severe head injury have been the subject of a recent investigation. Although several authors are listed with Dr. Julio Cruz, it is unclear whether the authors had knowledge of how the patients were recruited. Further, the Federal University of São Paulo, which Dr. Cruz gave as his affiliation, has never employed him. As a result of doubt surrounding Cruz's work, an updated version of the Cochrane review excludes all studies by Julio Cruz, leaving only 4 studies. Due to differences in selection of control groups, a conclusion about the clinical use of mannitol could not be reached.
These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of California, San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.
- Cooley's Cyclopaedia of Practical Receipts, 6th ed. (1880)
- Lawson, P. (2007) Mannitol. Blackwell Publishing Ltd. pp 219–225.
- Wakai, A; McCabe, A; Roberts, I; Schierhout, G (5 August 2013). "Mannitol for acute traumatic brain injury.". The Cochrane database of systematic reviews. 8: CD001049. doi:10.1002/14651858.CD001049.pub5. PMID 23918314.
- "Mannitol". The American Society of Health-System Pharmacists. Retrieved Jan 8, 2015.
- Kearsley, M. W.; Deis, R. C. (2006) "Sorbitol and Mannitol", pp. 249–261 in Sweeteners and Sugar Alternatives in Food Technology. Wiley-Blackwell. ISBN 0470659688
- "19th WHO Model List of Essential Medicines" (PDF). World Health Organization. April 2015. Retrieved 6 January 2016.
- "Select Committee on GRAS Substances (SCOGS) Opinion: Mannitol". FDA.gov. April 2013. Retrieved October 2014. Check date values in:
- Ellis, F.W.; Krantz, J.C. Jr. (1941). "Sugar alcohols: XXII. Metabolism and toxicity studies with mannitol and sorbitol in man and animals". J. Biol. Chem. 141: 147–154.
- Stickland, MK; Rowe, BH; Spooner, CH; Vandermeer, B; Dryden, DM (September 2011). "Accuracy of eucapnic hyperpnea or mannitol to diagnose exercise-induced bronchoconstriction: a systematic review.". Annals of Allergy, Asthma & Immunology. 107 (3): 229–34.e8. doi:10.1016/j.anai.2011.06.013. PMID 21875541.
- Veterinary Class Notes, Ophthalmology, The Ohio State University, provided by David Wilkie, DVM, DACVO
- Grenby, T.H (2011) Advances in Sweeteners. Springer. ISBN 1461285224. p. 66
- Weiner, Myra L.; Lois A. Kotkoskie (1999). Excipient Toxicity and Safety. p. 370. ISBN 9780824782108.
- Belcher, R.; Nutten, A. J. (1960). Quantitative Inorganic Analysis (2nd ed.). London, UK: Butterworths. p. 194.
- Song, S. H.; Vieille, C. (2009). "Recent advances in the biological production of mannitol". Applied Microbiology and Biotechnology. 84 (1): 55–62. doi:10.1007/s00253-009-2086-5. PMID 19578847.
- Ghoreishi, S. M.; Shahrestani, R. G. (2009). "Innovative strategies for engineering mannitol production". Trends in Food Science & Technology. 20 (6–7): 263–270. doi:10.1016/j.tifs.2009.03.006.
- Wagner, H; Flachsbarth, H; Vogel, G (Mar 1981). "[A New Antiphlogistic Principle from Sabal serrulata, II].". Planta Medica. 41 (3): 252–8. doi:10.1055/s-2007-971711. PMID 17401849.
- Cruz, J.; Minoja, G.; Okuchi, K. (2001). "Improving Clinical Outcomes from Acute Subdural Hematomas with the Emergency Preoperative Administration of High Doses of Mannitol: A Randomized Trial". Neurosurgery. 49 (4): 864–71. doi:10.1097/00006123-200110000-00016. PMID 11564247.
- Cruz, J.; Minoja, G.; Okuchi, K. (2002). "Major Clinical and Physiological Benefits of Early High Doses of Mannitol for Intraparenchymal Temporal Lobe Hemorrhages with Abnormal Pupillary Widening: A Randomized Trial". Neurosurgery. 51 (3): 628–638. doi:10.1097/00006123-200209000-00006. PMID 12188940.
- Cruz, J.; Minoja, G.; Okuchi, K.; Facco, E. (2004). "Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scale scores of 3 and bilateral abnormal pupillary widening: A randomized trial". Journal of Neurosurgery. 100 (3): 376–83. doi:10.3171/jns.2004.100.3.0376. PMID 15035271.
- Roberts, I.; Smith, R.; Evans, S. (2007). "Doubts over head injury studies". BMJ. 334 (7590): 392–4. doi:10.1136/bmj.39118.480023.BE. PMC . PMID 17322250. PMID 17322250
- "Flies model a potential sweet treatment for Parkinson's disease", Genetics Society of America's 54th Annual Drosophila Research Conference, Washington D.C., April 3–7, 2013.
- Artificial sweetener a potential treatment for Parkinson's disease. Science Daily. June 17, 2013
- Shaltiel-Karyo, R.; Frenkel-Pinter, M.; Rockenstein, E.; Patrick, C.; Levy-Sakin, M.; Schiller, A.; Egoz-Matia, N.; Masliah, E.; Segal, D.; Gazit, E. (2013). "A BBB Disrupter is also a Potent α-Synuclein (α-syn) Aggregation Inhibitor: A Novel Dual Mechanism of Mannitol for the Treatment of Parkinson's Disease (PD)". Journal of Biological Chemistry. 288 (24): 17579–88. doi:10.1074/jbc.M112.434787. PMC . PMID 23637226.
- British Pharmacopoeia Commission Secretariat (2009). "Index, BP 2009" (PDF). Retrieved 31 January 2010.
- "Japanese Pharmacopoeia, Fifteenth Edition" (PDF). 2006. Retrieved 31 January 2010.
- USP 32 (2008). "Mannitol Injection" (PDF). Retrieved 31 January 2010.