|Systematic (IUPAC) name|
|Pregnancy cat.||C: (USA)|
|ATC code||A06 B05 B05 R05|
|(what is this?)|
Mannitol (also referred to as mannite or manna sugar) is a white, crystalline solid with the chemical formula C6H8(OH)6. It was originally isolated from the secretions of the flowering ash and called manna after its resemblance to the Biblical food. In plants, it is used to induce osmotic stress. It has several industrial uses, but is mainly used to produce tablets of medicine. Its fetal safety is "C" in Briggs' Reference Guide to Fetal and Neonatal Risk. 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.
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% dextrose, 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 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.
Natural product extraction
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. Traditionally, mannitol is extracted by the Soxhlet extraction, utilizing ethanol, water, and methanol to steam and then hydrolyze 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.
Mannitol is used clinically in osmotherapy to reduce acutely raised intracranial pressure until more definitive treatment can be applied, e.g., after head trauma. It is also used to treat patients with oliguric renal failure. It is administered intravenously, and is filtered by the glomeruli of the kidney, but is incapable of being reabsorbed from the renal tubule, resulting in decreased water and Na+ reabsorption via its osmotic effect. Consequently, mannitol increases water and Na+ excretion, thereby decreasing extracellular fluid volume.
Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals directly into the brain. The arteries of the blood–brain barrier are much more selective than normal arteries. Normally, molecules can diffuse into tissues through gaps between the endothelial cells of the blood vessels. However, what enters the brain must be much more rigorously controlled. The endothelial cells of the blood–brain barrier are connected by tight junctions, and simple diffusion through them is impossible. Rather, active transport is necessary, requiring energy, and only transporting molecules that the arterial endothelial cells have receptor signals for. Mannitol is capable of opening this barrier by temporarily shrinking the endothelial cells, simultaneously stretching the tight junctions between them. An intracarotid injection of high molarity mannitol (1.4–1.6M), causes the contents of the artery to be hyperosmotic to the cell. Water leaves the cell and enters the artery in order to recreate an osmotic equilibrium. This loss of water causes the cells to shrivel and shrink, stretching the tight junctions between the cells. The newly formed gap reaches its peak width five minutes after mannitol injection, and stays widely open for thirty minutes. During this timespan, drugs injected into the artery can easily diffuse though the gaps between cells directly into the brain. This makes mannitol indispensable for delivering various drugs directly to the brain (e.g., in the treatment of Alzheimer's disease, or in chemotherapy for brain tumors.)
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 is also the basis of Bronchitol which was developed by the Australian pharmaceutical company Pharmaxis as a treatment for cystic fibrosis and bronchiectasis. The mannitol is orally inhaled as a dry powder through what is known as an osmohaler and osmotically draws water into the lungs to thin the thick, sticky mucus characteristic of cystic fibrosis. This is intended to make it easier for the sufferer to cough the mucus up during physiotherapy. The critical characteristic of the mannitol is its particle size distribution. Pharmaxis has also developed Aridol – a diagnostic test for airway hyperresponsiveness based on mannitol.
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, thus, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.
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.
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 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.
In analytical chemistry
Mannitol can be used to form a complex with boric acid. This increases the acid strength of the boric acid permitting better precision in volumetric analysis of this acid.
In illicit drugs
Mannitol is sometimes used as an adulterant or cutting agent for heroin, methamphetamines, cocaine, or other illicit drugs. In popular culture, when it is used in this manner, it is often referred to as baby laxative.
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. Currently, therefore, the Cochrane review recommending high-dose mannitol has been withdrawn pending re-evaluation, as there is some evidence that mannitol may worsen cerebral edema.
- Parkinson disease:
Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson's disease (PD) using a common sweetener, mannitol. This research has been presented at the Genetics Society of America's 54th Annual Drosophila Research Conference in Washington D.C., April 3–7, 2013.
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 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.
Notes and references
- Cooley's Cyclopaedia of Practical Receipts, 6th ed. (1880)
- Lawson, P. In In Mannitol; Blackwell Publishing Ltd: 2007; pp 219–225.
- Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8th edition. 2008. Published by: Lippincott Williams & Wilkins.
- Kearsley, M. W.; Deis, R. C. Sorbitol and Mannitol. In Sweeteners and Sugar Alternatives in Food Technology; Ames: Oxford, 2006; pp 249-249-261.
- Song, S. H.; Vieille, C. Recent advances in the biological production of mannitol. Appl. Microbiol. Biotechnol. 2009, 84, 55–62.
- Ghoreishi, S. M.; Shahrestani, R. G. Innovative strategies for engineering mannitol production. Trends Food Sci. Technol. 2009, 20, 263–270.
- Best, B. . Perfusion & Diffusion in Cryonics Protocol. http://www.benbest.com/cryonics/protocol.html (accessed November 10, 2010).
- Ikeda, M.; Bhattacharjee, A. K.; Kondoh, T.; Nagashima, T.; Tamaki, N. Synergistic Effect of Cold Mannitol and Na+/Ca2+ Exchange Blocker on Blood-Brain Barrier Opening. Biochem. Biophys. Res. Commun. 2002, 291, 669–674.
- Wang, M.; Etu, J.; Joshi, S. Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits. J. Neurosurg. Anesthesiol. 2007, 19, 249–256.
- Ikeda, M.; Bhattacharjee, A. K.; Kondoh, T.; Nagashima, T.; Tamaki, N. Synergistic Effect of Cold Mannitol and Na+/Ca2+ Exchange Blocker on Blood-Brain Barrier Opening. Biochem. Biophys. Res. Commun. 2002, 291, 669–674
- Veterinary Class Notes, Ophthalmology, The Ohio State University, provided by David Wilkie, DVM, DACVO
- 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 : official publication of the American College of Allergy, Asthma, & Immunology 107 (3): 229–34.e8. doi:10.1016/j.anai.2011.06.013. PMID 21875541.
- Grenby, T.H Advances in Sweetners pp 66"
- Kearsley, M. W. pp 249-249"
- Lawson, P. In In Mannitol; (1); Blackwell Publishing Ltd: 2007; pp 219–225.
- Weiner, Myra L.; Lois A. Kotkoskie (1999). Excipient Toxicity and Safety. p. 370. ISBN 9780824782108.
- An interview on the History Channel show Gangland showed a man claiming to be the chief methamphetamine "cooker" for the Pagans MC in Philadelphia, who stated that he used mannitol, a "baby laxative", as a "cut" for methamphetamine. He stated that in his hands the drug began as a purple color, and became first dark pink, then light pink, finally white as successive adulterations were done with mannitol. In the interview he stated that people snorting a line of the powder would need to go to the bathroom as a result of using it. He said that they incorrectly believed that this was the result of the potency of the drug, but it was actually caused by the added mannitol.
- Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery. 2001 Oct;49(4):864–71. doi:10.1097/00006123-200110000-00016 PMID 11564247
- Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial. Neurosurgery. 2002 Sep;51(3):628–37; discussion 637–8. doi:10.1097/00006123-200209000-00006 PMID 12188940
- Cruz J, Minoja G, Okuchi K, Facco E. 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. J Neurosurg. 2004 Mar;100(3):376–83. doi:10.3171/jns.2004.100.3.0376 PMID 15035271
- Roberts I, Smith R, Evans S. Doubts over head injury studies. BMJ. 2007 Feb 24;334(7590):392–4. doi:10.1136/bmj.39118.480023.BE PMID 17322250
- Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001049. PMID 16235278
- Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992 Oct;77(4):584–9. PMID 1527619
- [ Flies model a potential sweet treatment for Parkinson's disease]
- [ Flies Model a Potential Sweet Treatment for Parkinson's Disease]
- [ Artificial sweetener a potential treatment for Parkinson's disease]
- [ Mannitol - a BBB disrupter is also a potent -synuclein aggregation inhibitor for treating Parkinson's disease]
- British Pharmacopoeia Commission Secretariat (2009). "Index, BP 2009". Retrieved 31 January 2010.
- "Japanese Pharmacopoeia, Fifteenth Edition". 2006. Retrieved 31 January 2010.
- USP 32 (2008). "Mannitol Injection". Retrieved 31 January 2010.