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Revision as of 08:01, 20 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').← Previous edit Latest revision as of 19:19, 15 November 2024 edit undo2a00:23c8:513:3800:b413:e226:7dca:780a (talk) Reworded because mannitol is not a drug. 
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{{Short description|Chemical compound}}
{{Drugbox
{{Use dmy dates|date=December 2019}}
| Watchedfields = changed
{{cs1 config|name-list-style=vanc|display-authors=6}}
| verifiedrevid = 340535424
{{Infobox drug
| IUPAC_name = (2''R'',3''R'',4''R'',5''R'')-Hexane-1,2,3,4,5,6-hexol
| verifiedrevid = 456482551
| image = Mannitol structure.png
| image2 = D-Mannitol 3d space fill.png | image = D-Mannitol structure.svg
| alt =
| drug_name = <small>D</small>-Mannitol
| image2 = Mannitol-3D-balls.png
| alt2 =


<!--Clinical data--> <!-- Clinical data -->
| tradename = | tradename = Osmitrol, Bronchitol, others
| Drugs.com = {{drugs.com|monograph|mannitol}} | Drugs.com = {{drugs.com|monograph|mannitol}}
| DailyMedID = Mannitol
| pregnancy_category = C: (])
| pregnancy_AU = B2
| routes_of_administration = ]<br>]
| routes_of_administration = ], ], ]
| ATC_prefix = A06
| ATC_suffix = AD16
| ATC_supplemental = {{ATC|B05|BC01}} {{ATC|B05|CX04}} {{ATC|R05|CB16}} {{ATC|V04|CX04}}


| legal_CA = Rx-only
<!--Pharmacokinetic data-->
| legal_CA_comment = <ref>{{Cite web |date=23 October 2014 |title=Regulatory Decision Summary - Aridol |url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00599 |access-date=7 June 2022 |website=Health Canada}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="DailyMed-2018">{{cite web | title=Osmitrol- mannitol injection, solution | website=DailyMed | date=15 November 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0d914965-7001-45cb-ba51-d7c5964b05bc | access-date=28 October 2020}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Bronchitol EPAR">{{cite web | title=Bronchitol EPAR | date=17 September 2018 | publisher=] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/bronchitol | access-date=28 October 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

<!-- Pharmacokinetic data -->
| bioavailability = ~7% | bioavailability = ~7%
| metabolism = ], negligible. | metabolism = ], negligible
| elimination_half-life = 100 minutes | elimination_half-life = 100 minutes
| excretion = ]: 90% | excretion = ]: 90%


<!--Identifiers--> <!-- Identifiers -->
| CASNo_Ref = {{cascite}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 69-65-8 | CAS_number = 69-65-8
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ATC_prefix = A06
| ATC_suffix = AD16
| ATC_supplemental = {{ATC|B05|BC01}} {{ATC|B05|CX04}} {{ATC|R05|CB16}}
| ChEBI = 16899 | ChEBI = 16899
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C6H14O6/c7-1-3(9)5(11)6(12)4(10)2-8/h3-12H,1-2H2/t3-,4-,5-,6-/m1/s1 | StdInChI = 1S/C6H14O6/c7-1-3(9)5(11)6(12)4(10)2-8/h3-12H,1-2H2/t3-,4-,5-,6-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FBPFZTCFMRRESA-KVTDHHQDSA-N | StdInChIKey = FBPFZTCFMRRESA-KVTDHHQDSA-N
| PubChem = 6251 | PubChem = 6251
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00742 | DrugBank = DB00742
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 6015 | ChemSpiderID = 6015
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3OWL53L36A | UNII = 3OWL53L36A
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00062 | KEGG = D00062
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 689 | ChEMBL = 689
| synonyms = {{sm|d}}-Mannitol, mannite, manna sugar


<!--Chemical data--> <!-- Chemical data -->
| IUPAC_name = <small>D</small>-Mannitol<br>(2''R'',3''R'',4''R'',5''R'')-Hexane-1,2,3,4,5,6-hexol
| C=6 | H=14 | O=6
| C=6 | H=14 | O=6
| molecular_weight = 182.172
| smiles = O((O)CO)(O)(O)CO | smiles = O((O)CO)(O)(O)CO
| InChI = 1/C6H14O6/c7-1-3(9)5(11)6(12)4(10)2-8/h3-12H,1-2H2/t3-,4-,5-,6-/m1/s1
| InChIKey = FBPFZTCFMRRESA-KVTDHHQDBH
}} }}


<!-- Definition and uses -->
'''Mannitol''' is a white, crystalline<ref name="Lawson, P pp 219-225">Lawson, P. In In Mannitol; Blackwell Publishing Ltd: 2007; pp 219-225.</ref> ] with the formula (C<sub>6</sub>H<sub>8</sub>(OH)<sub>6</sub>). This ] is used as an ] agent and a weak ] ]. It was originally isolated from the secretions of the ], called ] after their resemblance to the Biblical food, and is also referred to as '''mannite''' and '''manna sugar'''.<ref>Cooley's Cyclopaedia of Practical Receipts, 6th ed. (1880)</ref>
'''Mannitol''' is a type of ] used as a ] and medication.<ref name="Varzakas-2012">{{cite book | vauthors = Varzakas T, Labropoulos A, Anestis S |title=Sweeteners: Nutritional Aspects, Applications, and Production Technology|date=2012|publisher=CRC Press|isbn=9781439876732|pages=59–60|url=https://books.google.com/books?id=oLDMBQAAQBAJ&pg=PA59|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910183505/https://books.google.com/books?id=oLDMBQAAQBAJ&pg=PA59|archive-date=10 September 2017}}</ref><ref name="World Health Organization-2009">{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=332 }}</ref> It is used as a low calorie sweetener as it is poorly absorbed by the ].<ref name="Varzakas-2012" /> As a medication, it is used to decrease pressure in the eyes, as in ], and to lower ].<ref name="Wakai-2013">{{cite journal | vauthors = Wakai A, McCabe A, Roberts I, Schierhout G | title = Mannitol for acute traumatic brain injury | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 8 | pages = CD001049 | date = August 2013 | pmid = 23918314 | pmc = 7050611 | doi = 10.1002/14651858.CD001049.pub5 }}</ref><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=332 }}</ref><ref name="World Health Organization-2009" /> Medically, it is given by injection or inhalation.<ref name=AHFS2016>{{cite web|title=Mannitol|url=https://www.drugs.com/monograph/mannitol.html|publisher=The American Society of Health-System Pharmacists|access-date=8 January 2015|url-status=live|archive-url=https://web.archive.org/web/20150526105959/http://www.drugs.com/monograph/mannitol.html|archive-date=26 May 2015}}</ref><ref>{{Cite web |title=BRONCHITOL® (mannitol) inhalation powder Patient Site |url=https://bronchitol.com/ |website=bronchitol.com}}</ref> Effects typically begin within 15 minutes and last up to 8 hours.<ref name="AHFS2016" />
In plants, it is used to induce ].


<!-- Side effects and mechanism -->
==Chemistry==
Common side effects from medical use include ] and ].<ref name="AHFS2016" /> Other serious side effects may include worsening ] and ].<ref name="AHFS2016" /><ref name="World Health Organization-2009" /> It is unclear if use is safe in ].<ref name="AHFS2016" /> Mannitol is in the ] family of medications and works by pulling fluid from the brain and eyes.<ref name="AHFS2016" />
Mannitol is a ]; that is, it is derived from a sugar by reduction, with a ] of 182.17 g/mol,<ref name="ReferenceA">Lawson, P. In In Mannitol; Blackwell Publishing Ltd: 2007; pp 219-225</ref> and a ] of 1.52 g/mL.<ref name="toxnet.nlm.nih.gov">Anonymous. D-Mannitol. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~hwwDKg:1 (accessed November 11, 2010).</ref> Other sugar alcohols include ] and ]. Mannitol and sorbitol are isomers, the only difference being the orientation of the hydroxyl group on carbon 2.<ref name="Kearsley, M. W. pp 249-249">Kearsley, M. W.; Deis, R. C. Sorbitol and Mannitol. In Sweeteners and Sugar Alternatives in Food Technology; Ames: Oxford, 2006; pp 249-249-261.</ref> Aqueous solutions of mannitol are mildly ]ic and sometimes such solutions are treated to lower the ]. Chemical Abstracts Registry Numbers for mannitol are 123897-58-5, 69-65-8 (D-Mannitol), 75398-80-0, 85085-15-0, and 87-78-5 (mannitol with unspecified stereochemistry).
D-Mannitol (CAS# 69-65-8) has a solubility of 22g mannitol/ 100mL water (25°C), and a relative sweetness of 50 (]=100).<ref name="ReferenceA"/> It melts between 165°-169°C (7.6 ]), and boils at 295°C at 3.5 torr, indicating a greater boiling point at ] conditions.<ref name="toxnet.nlm.nih.gov"/>
===Similarity to sorbitol===
Mannitol and sorbitol are ]. Both are (C<sub>6</sub>H<sub>8</sub>(OH)<sub>6</sub>). The difference is the second carbon atom in the chain is ] like, leading to physically different molecules.


<!-- History, society and culture -->
==Obtaining mannitol==
The discovery of mannitol is attributed to ] in 1806.<ref name="Kremers-1986">{{cite book | vauthors = Kremers E, Sonnedecker G |title=Kremers and Urdang's History of Pharmacy|date=1986|publisher=Amer. Inst. History of Pharmacy|isbn=9780931292170|page=360|url=https://books.google.com/books?id=r__FmMNS7qIC&pg=PA360|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910183505/https://books.google.com/books?id=r__FmMNS7qIC&pg=PA360|archive-date=10 September 2017}}</ref> It is on the ].<ref>{{Cite book |author-link=World Health Organization |title=World Health Organization model list of essential medicines: 21st list 2019 |vauthors=((World Health Organization)) |publisher=World Health Organization |year=2019 |location=Geneva |hdl=10665/325771 |id=WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO |hdl-access=free}}</ref> It was originally made from the ] and called ] due to its supposed resemblance to the Biblical food.<ref>{{Cite book |url=https://books.google.com/books?id=xVboDAAAQBAJ&pg=PT175 |title=Cottrell and Patel's Neuroanesthesia |vauthors=Cottrell JE, Patel P |date=2016 |publisher=Elsevier Health Sciences |isbn=9780323461122 |page=160 |language=en}}</ref><ref>{{Cite book |url=https://books.google.com/books?id=CZZ6YpzVA0UC&pg=PA411 |title=Applied Pharmacology |vauthors=Bardal S, Waechter J, Martin D |date=2010 |publisher=Elsevier Health Sciences |isbn=978-1437735789 |page=411 |language=en}}</ref> Mannitol is on the ]'s banned substances list due to concerns that it may mask prohibited drugs.<ref>{{Cite web |date=January 2017 |title=THE 2017 PROHIBITED LIST INTERNATIONAL STANDARD |url=https://www.wada-ama.org/sites/default/files/resources/files/2016-09-29_-_wada_prohibited_list_2017_eng_final.pdf |access-date=7 July 2018 |page=5}}</ref>
===Industrial synthesis===
Mannitol is commonly formed via the hydrogenation of fructose, which is formed from either ] or ]. Although starch is cheaper than sucrose, the transformation of starch is much more complicated. Eventually, it yields a syrup containing about 42% ], 52% ], and 6% ]. ] is simply hydrolyzed into an ] 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 ] reaction conditions can slightly increase mannitol yields.<ref name="Kearsley, M. W. pp 249-249"/>


==Uses==
===Biological syntheses===
]
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.<ref name="Song, S. H. 2009">Song, S. H.; Vieille, C. Recent advances in the biological production of mannitol. Appl. Microbiol. Biotechnol. 2009, 84, 55-62.</ref> ] by microorganisms is a possible alternative to traditional industrial synthesis, producing much higher yields of mannitol, with minimal to no side products. A fructose to mannitol ], 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.<ref name="Ghoreishi, S. M. 2009">Ghoreishi, S. M.; Shahrestani, R. G. Innovative strategies for engineering mannitol production. Trends Food Sci. Technol. 2009, 20, 263-270.</ref> A class of ] ],labeled heterofermentive because of their multiple fermentation pathways, convert either 3 fructose molecules or 2 fructose and 1 glucose molecule into 2 mannitol molecules, and one molecule each of ], ], and ]. ] syrups containing medium to large concentrations of fructose (for example, ], containing 55% fructose: 45% ]) can produce yields 200g mannitol/ liter feedstock. Further research is being conducted, studying ways to engineer even more efficient mannitol pathways in lactic acid bacteria, and also studying the use of other microorganism, such as ]<ref name="Song, S. H. 2009"/> and ] bacteria in mannitol productions. 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.<ref name="Ghoreishi, S. M. 2009"/>


==={{anchor|Medical uses}}Medical uses===
===Natural product extraction===
In the United States, mannitol is ] for the reduction of intracranial pressure and treatment of cerebral edema and elevated intraocular pressure.<ref name="DailyMed-2018" />
As stated above, mannitol is found in a wide variety of natural products, including almost all plants. This allows for direct extraction from natural products, rather than chemical or biological syntheses. In fact, in China, isolation from seaweeds is the most common form of mannitol production.<ref name="Lawson, P pp 219-225"/> Mannitol concentrations of plant ]s can range from 20% in seaweeds to 90% in the ]. Traditionally, mannitol is extracted by the ] extraction, utilizing ethanol, water, and methanol to steam and then hydrolyze the crude material. The mannitol is then ] 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 ] and ] fluids. These fluids are at such a stage that there is no difference between the liquid and gas stages, and are therefore more ] 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 ] extraction of olive leaves has been shown to require less solvent per grams of leaf than a traditional extraction (141.7 g CO2 vs. 194.4 g ethanol/ 1 g 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 water/ 1 g 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 high required operating temperatures and pressures are cause for hesitancy in the industrial use of this technique.<ref name="Ghoreishi, S. M. 2009"/>


In the European Union, mannitol is indicated for the treatment of ] (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.<ref name="Bronchitol EPAR" />
==Uses==
===Medical applications===
Mannitol is used clinically in ] to reduce acutely raised ] until more definitive treatment can be applied, e.g., after ]. It is also used to treat patients with ] ]. It is administered ]ly, and is filtered by the ] of the ], but is incapable of being resorbed from the ], resulting in decreased water and ]<sup>+</sup> reabsorption via its ] effect. Consequently, mannitol increases water and Na<sup>+</sup> excretion, thereby decreasing extracellular fluid volume.


Mannitol is used intravenously to reduce acutely raised intracranial pressure until more definitive treatment can be applied,<ref>{{Cite web |title=Mannitol (Intravenous Route) |url=https://www.mayoclinic.org/drugs-supplements/mannitol-intravenous-route/description/drg-20452323 |publisher=Mayo Clinic}}</ref> e.g., after ]. While mannitol injection is the mainstay for treating high pressure in the skull after a bad brain injury, it is no better than hypertonic saline as a first-line treatment. In treatment-resistant cases, hypertonic saline works better.<ref>{{cite journal | vauthors = Gu J, Huang H, Huang Y, Sun H, Xu H | title = Hypertonic saline or mannitol for treating elevated intracranial pressure in traumatic brain injury: a meta-analysis of randomized controlled trials | journal = Neurosurgical Review | volume = 42 | issue = 2 | pages = 499–509 | date = June 2019 | pmid = 29905883 | doi = 10.1007/s10143-018-0991-8 }}</ref> Intra-arterial infusions of mannitol can transiently open the ] by disrupting ].<ref>{{cite journal | vauthors = Rapoport SI | title = Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications | journal = Cellular and Molecular Neurobiology | volume = 20 | issue = 2 | pages = 217–230 | date = April 2000 | pmid = 10696511 | doi = 10.1023/a:1007049806660 | s2cid = 20258642 }}</ref><ref>{{cite journal | vauthors = Linville RM, DeStefano JG, Sklar MB, Chu C, Walczak P, Searson PC | title = Modeling hyperosmotic blood-brain barrier opening within human tissue-engineered in vitro brain microvessels | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 40 | issue = 7 | pages = 1517–1532 | date = July 2020 | pmid = 31394959 | pmc = 7308510 | doi = 10.1177/0271678X19867980 | s2cid = 199507024 }}</ref>
Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals directly into the brain. The arteries of the ] are much more selective than normal arteries. Normally, molecules can diffuse into tissues through gaps between the ]s 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 ]s, and simple diffusion through them is impossible. Rather, ] 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.<ref>Best, B. . Perfusion & Diffusion in Cryonics Protocol. http://www.benbest.com/cryonics/protocol.html (accessed November 10, 2010).</ref> 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.<ref>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.</ref> 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.<ref>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.</ref> This makes mannitol indispensable for delivering various drugs directly to the ] (e.g., in the treatment of ], or in chemotherapy for brain tumors.<ref>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</ref>

It may also be used for certain cases of ], decreasing ], to increase the elimination of certain toxins, and to treat ].<ref name="AHFS2016" />

Intraoperative mannitol prior to vessel clamp release during renal transplant has been shown to reduce post-transplant kidney injury, but has not been shown to reduce graft rejection.{{medical citation needed|date=January 2020}}

Mannitol acts as an osmotic ]<ref name="DailyMed-2018" /><ref>{{Cite web |date=April 2013 |title=Select Committee on GRAS Substances (SCOGS) Opinion: Mannitol |url=https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm260072.htm |url-status=dead |archive-url=https://web.archive.org/web/20141022095810/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm260072.htm |archive-date=22 October 2014 |publisher=FDA.gov}}</ref> in oral doses larger than 20 g,<ref>{{Cite journal |vauthors=Ellis FW, Krantz JC |year=1941 |title=Sugar alcohols: XXII. Metabolism and toxicity studies with mannitol and sorbitol in man and animals |url=http://www.jbc.org/content/141/1/147.citation |url-status=live |journal=J. Biol. Chem. |volume=141 |pages=147–154 |doi=10.1016/S0021-9258(18)72829-9 |archive-url=https://web.archive.org/web/20170910183505/http://www.jbc.org/content/141/1/147.citation |archive-date=10 September 2017 |doi-access=free}}</ref> and is sometimes sold as a laxative for children.{{Citation needed|date=December 2008}}

The use of mannitol, when inhaled, as a bronchial irritant as an alternative method of diagnosis of ] has been proposed. A 2013 systematic review concluded evidence to support its use for this purpose at this time is insufficient.<ref>{{cite journal | vauthors = Stickland MK, Rowe BH, Spooner CH, Vandermeer B, Dryden DM | title = Accuracy of eucapnic hyperpnea or mannitol to diagnose exercise-induced bronchoconstriction: a systematic review | journal = Annals of Allergy, Asthma & Immunology | volume = 107 | issue = 3 | pages = 229–34.e8 | date = September 2011 | pmid = 21875541 | doi = 10.1016/j.anai.2011.06.013 }}</ref>


Mannitol is commonly used in the circuit prime of a ] during ]. 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 ]s in the kidney, which may have otherwise reduced blood flow to this area and resulted in cell damage. Mannitol is commonly used in the circuit prime of a ] during ]. 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 ]s 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 ]) while it passes through the venous system. Because the mannitol dissolves readily in blood, the sharp point becomes exposed at its destination.
Mannitol is also being developed by an Australian pharmaceutical company as a treatment for ] and ] and as a diagnostic test for airway hyperresponsiveness. 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 ].


Mannitol is also the first drug of choice for the treatment of acute ] in veterinary medicine. It is administered as a 20% solution IV. It dehydrates the ] and, thus, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.<ref>Veterinary Class Notes, Ophthalmology, The Ohio State University, provided by David Wilkie, DVM, DACVO</ref> Mannitol is also the first drug of choice to treat acute ] in veterinary medicine. It is administered as a 20% solution intravenously. It dehydrates the ] and, therefore, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.<ref>{{Citation |title=Veterinary Class Notes, Ophthalmology, The Ohio State University, provided by David Wilkie, DVM, DACVO}}</ref>


===Food===
Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an ]) 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 increases blood glucose to a lesser extent than ] (thus having a relatively low ]<ref>{{Cite book |title=Advances in Sweeteners |vauthors=Grenby TH |date=2011 |publisher=Springer |isbn=978-1461285229 |pages=66}}</ref>) so is used as a ] for people with ], and in ]s. Although mannitol has a higher ] 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.<ref name="Kearsley-2006">{{cite book | vauthors = Kearsley MW, Deis RC | date = 2006 | chapter = Sorbitol and Mannitol | pages = 249–261 | title = Sweeteners and Sugar Alternatives in Food Technology | publisher = Wiley-Blackwell | isbn = 0470659688 }}</ref> Also, it has a very low ] – 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.<ref name="Lawson-2007">{{cite book | vauthors = Lawson P | date = 2007 | title = Mannitol | publisher = Blackwell Publishing Ltd. | pages = 219–225 }}</ref> The pleasant taste and mouthfeel of mannitol also makes it a popular ] for chewable tablets.<ref>{{Cite book |url=https://archive.org/details/excipienttoxicit103wein/page/370 |title=Excipient Toxicity and Safety |vauthors=Weiner ML, Kotkoskie LA |publisher=Taylor & Francis |year=1999 |isbn=9780824782108 |pages= |url-access=registration}}</ref>


===Analytical chemistry===
Mannitol may be administered in cases of severe ] poisoning. Severe ], or "tropical fish poisoning" can produce stroke-like symptoms.
Mannitol can be used to form a complex with ]. This increases the acid strength of the boric acid, permitting better precision in volumetric analysis of this acid.<ref>{{Cite book |title=Quantitative Inorganic Analysis |vauthors=Belcher R, Nutten AJ |date=1960 |publisher=Butterworths |edition=2nd |location=London, UK |pages=194}}</ref>


===Other===
Mannitol is the primary ingredient of ], a bacterial growth medium, and is used in others.
Mannitol is the primary ingredient of ], a bacterial growth medium, and is used in others.


Mannitol is used as a ]<ref>{{Cite web |date=December 2005 |title=Cut the Shit |url=https://www.vice.com/en_ca/read/cut-v12n4 |url-status=live |archive-url=https://web.archive.org/web/20160927173938/http://www.vice.com/en_ca/read/cut-v12n4 |archive-date=27 September 2016 |access-date=4 September 2017}}</ref><ref>{{cite journal | vauthors = El-Haj BM, Al-Amri AM, Ali HS | title = Heroin profiling: mannitol hexaacetate as an unusual ingredient of some illicit drug seizures | journal = Forensic Science International | volume = 145 | issue = 1 | pages = 41–46 | date = October 2004 | pmid = 15374593 | doi = 10.1016/j.forsciint.2004.03.012 }}</ref> in various drugs that are used intranasally (]), such as ] and ]. A mixture of mannitol and ] (or ]) in ratio 1:10 is labeled and sold as "China white", a popular heroin substitute.{{citation needed|date=August 2018}}
In oral doses larger than 20 g, mannitol acts as an osmotic ], and is sometimes sold as a laxative for children{{Citation needed|date=December 2008}}.


Mannitol is a sugar alcohol with "50-70 percent of the relative sweetness of sugar, which means more must be used to equal the sweetness of sugar. Mannitol lingers in the intestines for a long time and therefore often causes bloating and diarrhea."<ref>{{Cite web |title=Eat Any Sugar Alcohol Lately? |url=https://www.ynhh.org/services/nutrition/sugar-alcohol#:~:text=Mannitol%20has%2050%2D70%20percent,naturally%20in%20fruits%20and%20vegetables. |archive-url=https://web.archive.org/web/20240704060507/https://www.ynhh.org/services/nutrition/sugar-alcohol |archive-date=2024-07-04}}</ref>
===In foods===
Mannitol does not stimulate an increase in blood glucose, and is therefore used as a ] for people with ], and in ]s. It also has a low ], making it a low carb food. Although mannitol has a higher ] 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.<ref name="Kearsley, M. W. pp 249-249"/> Also, it has a very low ]- 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.<ref>Lawson, P. In In Mannitol; (1); Blackwell Publishing Ltd: 2007; pp 219-225.</ref> The pleasant taste and mouthfeel of mannitol also makes it a popular ] for chewable tablets.<ref>
{{Cite book
| isbn = 0824782100, 9780824782108
| pages = 370
| last = Weiner
| first = Myra L.
| coauthors = Lois A. Kotkoskie
| title = Excipient Toxicity and Safety
| year = 1999
}}</ref>


== Contraindications ==
===In illicit drugs===
Mannitol is contraindicated in people with ], severe ], pre-existing severe pulmonary vascular congestion or pulmonary edema, irritable bowel syndrome (IBS), and active intracranial bleeding except during craniotomy.<ref name="DailyMed-2018" />
Mannitol is sometimes used as an ] or ] for ], ]s, ], or other ]s. In popular culture, when it is used in this manner, it is often referred to as ''baby laxative''.<ref>An interview on the History Channel show ] showed a man claiming to be the chief methamphetamine "cooker" for the ] in ], 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.</ref>


Adverse effects include ] and volume depletion leading to ].<ref name="Kremers-1986" />
==Controversy==
The three studies<ref>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</ref><ref>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</ref><ref>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</ref> that initially found that high-dose mannitol was effective in cases of severe head injury have been the subject of a recent investigation.<ref>Roberts I, Smith R, Evans S. BMJ. 2007 Feb 24;334(7590):392-4. {{DOI|10.1136/bmj.39118.480023.BE}} PMID 17322250</ref> 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 ] recommending high-dose mannitol<ref>Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001049. PMID 16235278</ref> has been withdrawn pending re-evaluation, as there is some evidence that mannitol may worsen ].<ref>Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992 Oct;77(4):584-9. PMID 1527619</ref>


== Toxicology == ==Chemistry==
Mannitol is an ] of ], another sugar alcohol; the two differ only in the orientation of the ] group on carbon 2.<ref name="Kearsley-2006" /> While similar, the two sugar alcohols have very different sources in nature, ]s, and uses.
Mannitol is contraindicated in patients with ] and ].{{Citation needed|date=January 2010}}

==Production==
Mannitol is classified as a ]; that is, it can be derived from a sugar (]) by reduction. Other sugar alcohols include ] and ].

===Industrial synthesis===
Mannitol is commonly produced via the ] of fructose, which is formed from either ] or ] (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% ], 52% ], and 6% ]. Sucrose is simply hydrolyzed into an ], 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 ] into a mixture of isomers ] and mannitol. Yield is typically 50%:50%, although slightly ] reaction conditions can slightly increase mannitol yields.<ref name="Kearsley-2006" />

===Biosyntheses===
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.<ref name="Song-2009">{{cite journal | vauthors = Song SH, Vieille C | title = Recent advances in the biological production of mannitol | journal = Applied Microbiology and Biotechnology | volume = 84 | issue = 1 | pages = 55–62 | date = August 2009 | pmid = 19578847 | doi = 10.1007/s00253-009-2086-5 | s2cid = 42103028 }}</ref> ] by microorganisms is an alternative to the traditional industrial synthesis. A fructose to mannitol ], 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.<ref name="Ghoreishi-2009">{{Cite journal | doi = 10.1016/j.tifs.2009.03.006| title = Innovative strategies for engineering mannitol production| journal = Trends in Food Science & Technology| volume = 20| issue = 6–7| pages = 263–270| year = 2009| vauthors = Ghoreishi SM, Shahrestani RG }}</ref> A class of ], 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 ], ], and ]. ] syrups containing medium to large concentrations of fructose (for example, ], containing 55% fructose: 45% ]) can produce yields {{convert|abbr=on|200|g|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 ]<ref name="Song-2009" /> and '']'' 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.<ref name="Ghoreishi-2009" />

===Natural 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 ] is the most common form of mannitol production.<ref name="Lawson-2007" /> Mannitol concentrations of plant ]s can range from 20% in seaweeds to 90% in the ]. It is a constituent of saw palmetto ('']'').<ref>{{cite journal | vauthors = Wagner H, Flachsbarth H, Vogel G | title = | journal = Planta Medica | volume = 41 | issue = 3 | pages = 252–258 | date = March 1981 | pmid = 17401849 | doi = 10.1055/s-2007-971711 | s2cid = 260249165 }}</ref>

Traditionally, mannitol is extracted by the ] extraction, using ], water, and ] to steam and then hydrolysis of the crude material. The mannitol is then ] from the extract, generally resulting in yields of about 18% of the original natural product. Another method of extraction is using ] and ] fluids. These fluids are at such a stage that no difference exists between the liquid and gas stages, so are more ] than normal fluids. This is considered to make them much more effective mass transfer agents than normal liquids. The super- or subcritical fluid is pumped through the natural product, and the mostly mannitol product is easily separated from the solvent and minute amount of byproduct.

Supercritical ] extraction of olive leaves has been shown to require less solvent per measure of leaf than a traditional extraction – {{convert|abbr=on|141.7|g|oz}} CO<sub>2</sub> versus {{convert|abbr=on|194.4|g|oz}} ethanol per {{convert|abbr=on|1|g|oz}} olive leaf. Heated, pressurized, ] is even cheaper, and is shown to have dramatically greater results than traditional extraction. It requires only {{convert|abbr=on|4.01|g|oz}} water per {{convert|abbr=on|1|g|oz}} of olive leaf, and gives a yield of 76.75% mannitol. Both super- and subcritical 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.<ref name="Ghoreishi-2009" />

==History==
In the early 1880s, ] elucidated the structure of ] and mannitol obtained from ]. He determined the place of the double bond in hexene obtained from mannitol and proved that it is a derivative of a normal hexene. This also solved the structure of mannitol, which was unknown until then.<ref>{{cite journal | vauthors = Inić S, Kujundzić N | title = The first independent pharmacognosy institute in the world and its founder Julije Domac (1853-1928) | language = de | journal = Die Pharmazie | volume = 66 | issue = 9 | pages = 720–726 | date = September 2011 | pmid = 22026131 }}</ref><ref>{{Cite journal |vauthors=Domac J |year=1881 |title=Über das Hexylen aus Mannit |journal=Sitzungsberichte der Kaiserlichen Akademie der Wissenschaften, Mathematisch-Naturwissenschaftliche Classe |language=de |volume=23 |pages=1038–1051}}</ref><ref>{{Cite journal |vauthors=Domac J |year=1881 |title=Über das Hexylen aus Mannit |url=https://zenodo.org/record/1623981 |journal=Monatshefte für Chemie |language=de |volume=2 |pages=309–322 |doi=10.1007/BF01516516 |s2cid=94940823}}</ref><ref>{{Cite journal |vauthors=Domac J |year=1882 |title=II. Ueber die Einwirkung der Unterchlorsäure auf Hexylen |url=https://zenodo.org/record/2020631 |journal=] |language=de |volume=213 |pages=124–132 |doi=10.1002/jlac.18822130107}}</ref>

==Controversy==
The three studies<ref>{{cite journal | vauthors = Cruz J, Minoja G, Okuchi K | title = Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: a randomized trial | journal = Neurosurgery | volume = 49 | issue = 4 | pages = 864–871 | date = October 2001 | pmid = 11564247 | doi = 10.1097/00006123-200110000-00016 | s2cid = 43880412 }}</ref><ref>{{cite journal | vauthors = Cruz J, Minoja G, Okuchi K | title = Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial | journal = Neurosurgery | volume = 51 | issue = 3 | pages = 628–37; discussion 637–8 | date = September 2002 | pmid = 12188940 | doi = 10.1097/00006123-200209000-00006 | s2cid = 20678448 }}</ref><ref>{{cite journal | vauthors = Cruz J, Minoja G, Okuchi K, Facco E | title = 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 = Journal of Neurosurgery | volume = 100 | issue = 3 | pages = 376–383 | date = March 2004 | pmid = 15035271 | doi = 10.3171/jns.2004.100.3.0376 }}</ref> that originally found high-dose mannitol effective in treating severe head injury were the subject of an investigation. Published in 2007 after the lead author Dr Julio Cruz's death, the investigation questioned whether the studies had actually taken place.<ref>{{cite journal | vauthors = Roberts I, Smith R, Evans S | title = Doubts over head injury studies | journal = BMJ | volume = 334 | issue = 7590 | pages = 392–394 | date = February 2007 | pmid = 17322250 | pmc = 1804156 | doi = 10.1136/bmj.39118.480023.BE }}</ref> The co-authors of the paper were not able to confirm the existence of the study patients, and the Federal University of São Paulo, which Cruz gave as his affiliation, had never employed him. As a result of doubt surrounding Cruz's work, an updated version of the ] excludes all studies by Julio Cruz, leaving only four studies.<ref name="Wakai-2013" /> Due to differences in selection of control groups, a conclusion about the clinical use of mannitol has not been reached.


== Compendial status == == Compendial status ==
* ]<ref>{{Cite web |last=British Pharmacopoeia Commission Secretariat |year=2009 |title=Index, BP 2009 |url=http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf |url-status=dead |archive-url=https://web.archive.org/web/20090411071437/http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf |archive-date=11 April 2009 |access-date=31 January 2010}}</ref>
* ] <ref name=ib29>{{cite web
* ]<ref>{{Cite web |year=2006 |title=Japanese Pharmacopoeia | edition = Fifteenth |url=http://jpdb.nihs.go.jp/jp15e/JP15.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110722105441/http://jpdb.nihs.go.jp/jp15e/JP15.pdf |archive-date=22 July 2011 |access-date=31 January 2010}}</ref>
| last = British Pharmacopoeia Commission Secretariat
* ]<ref>{{Cite web | work = USP 32 |year=2008 |title=Mannitol Injection |url=http://www.usp.org/pdf/EN/USPNF/mannitolInjectionMonograph.pdf |url-status=dead |archive-url=https://web.archive.org/web/20100706114647/http://www.usp.org/pdf/EN/USPNF/mannitolInjectionMonograph.pdf |archive-date=6 July 2010 |access-date=31 January 2010}}</ref>
| first =
| authorlink =
| coauthors =
| title = Index, BP 2009
| work =
| publisher =
| year = 2009
| url = http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf
| format =
| doi =
| accessdate = 31 January 2010
}}</ref>
* ] <ref name=jp15>{{cite web
| last =
| first =
| authorlink =
| coauthors =
| title = Japanese Pharmacopoeia, Fifteenth Edition
| work =
| publisher =
| year = 2006
| url = http://jpdb.nihs.go.jp/jp15e/JP15.pdf
| format =
| doi =
| accessdate = 31 January 2010
}}</ref>
* ] <ref name=mi>{{cite web
| last = USP 32
| first =
| authorlink =
| coauthors =
| title = Mannitol Injection
| work =
| publisher =
| year = 2008
| url = http://www.usp.org/pdf/EN/USPNF/mannitolInjectionMonograph.pdf
| format =
| doi =
| accessdate = 31 January 2010
}}</ref>


== See also == == See also ==
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== References ==
==Notes and references==
{{reflist}} {{reflist}}
<References/>


==External links== == External links ==
* {{RXlist|osmitrol}} * {{Commons category-inline}}
* {{GPnotebook|1724907529}}


{{Alcohols}}
{{Antihypertensives and diuretics}}
{{Laxatives}}
{{Use dmy dates|date=November 2010}}
{{Blood substitutes and perfusion solutions}}
{{Cough and cold preparations}}
{{Portal bar|Medicine}}


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