Mannitol

{{Short description|Chemical compound}} {{Use dmy dates|date=December 2019}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | verifiedrevid = 456482551 | image = D-Mannitol structure.svg | image_class = skin-invert-image | alt = | image2 = Mannitol-3D-balls.png | image_class2 = bg-transparent | alt2 =  | tradename = Osmitrol, Bronchitol, others | Drugs.com = {{drugs.com|monograph|mannitol}} | DailyMedID = Mannitol | pregnancy_AU = B2 | routes_of_administration = Intravenous, by mouth, inhalation | ATC_prefix = A06 | ATC_suffix = AD16 | ATC_supplemental = {{ATC|B05|BC01}} {{ATC|B05|CX04}} {{ATC|R05|CB16}} {{ATC|V04|CX04}} | legal_CA = Rx-only | 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=European Medicines Agency (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>

| bioavailability = ~7% | metabolism = Liver, negligible | elimination_half-life = 100 minutes | excretion = Kidney: 90%

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 69-65-8 | ChEBI_Ref = {{ebicite|correct|EBI}} | 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = FBPFZTCFMRRESA-KVTDHHQDSA-N | PubChem = 6251 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00742 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 6015 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 3OWL53L36A | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00062 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 689 | synonyms = {{sm|d}}-Mannitol, mannite, manna sugar

| IUPAC_name = D-Mannitol (2''R'',3''R'',4''R'',5''R'')-Hexane-1,2,3,4,5,6-hexol | C = 6 | H = 14 | O = 6 | smiles = O[C@H]([C@H](O)CO)[C@H](O)[C@H](O)CO }}

'''Mannitol''' is a type of sugar alcohol used as a sweetener 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=978-1-4398-7673-2|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 = 978-92-4-154765-9 | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | 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 intestines.<ref name="Varzakas-2012" /> As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to lower increased intracranial pressure.<ref name="World Health Organization-2009" /><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 | article-number = 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 = 978-92-4-154765-9 | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | publisher = World Health Organization | hdl-access=free | page=332 }}</ref> 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" />

Common side effects from medical use include electrolyte problems and dehydration.<ref name="AHFS2016" /> Other serious side effects may include worsening heart failure and kidney problems.<ref name="World Health Organization-2009" /><ref name="AHFS2016" /> It is unclear if use is safe in pregnancy.<ref name="AHFS2016" /> Mannitol is in the osmotic diuretic family of medications and works by pulling fluid from the brain and eyes.<ref name="AHFS2016" />

The discovery of mannitol is attributed to Joseph Louis Proust 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=978-0-931292-17-0|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 World Health Organization's List of Essential Medicines.<ref>{{Cite book |title=World Health Organization model list of essential medicines: 21st list 2019 |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 flowering ash and called manna 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=978-0-323-46112-2 |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=978-1-4377-3578-9 |page=411 |language=en}}</ref> Mannitol is on the World Anti-Doping Agency'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>

Mannitol is a natural constituent of most microorganisms and plants, having an essential role in maintaining cell and tissue water balance, and responding to environmental stresses, such as drought or low temperature.<ref name="Edmond_2025">{{cite journal | vauthors = Edmond VD, Hong Z, Nelson AS | title = Sugar alcohols in plants: implications for enhancing tree seedlings drought tolerance and production strategies | journal = BMC Plant Biology | volume = 25 | issue = 1 | page = 891 | date = July 2025 | pmid = 40634904 | pmc = 12239448 | doi = 10.1186/s12870-025-06860-9 | doi-access = free }}</ref>

==Uses== thumb|Mannitol 15% solution for intravenous use

===Medical uses===

==== Injected ==== In the United States, injected mannitol is indicated for the reduction of intracranial pressure and treatment of cerebral edema and elevated intraocular pressure.<ref name="DailyMed-2018" />

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 head trauma. While mannitol injection is the mainstay for treating high pressure in the skull after a serious 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>

It may also be used for certain cases of kidney failure with low urine output, to decrease pressure in the eye, to increase the elimination of certain toxins, and to treat fluid build up.<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 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 resultant cell damage.{{Citation needed|date=January 2026}}

Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial pacemaker) while it passes through the venous system. Because the mannitol dissolves readily in blood, the sharp point becomes exposed at its destination.{{Citation needed|date=January 2026}}

Intra-arterial infusions of mannitol can transiently open the blood–brain barrier by disrupting tight junctions.<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 | pmc = 11537517 }}</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 is also the first drug of choice to treat acute glaucoma (high eye pressure) in veterinary medicine. It is administered as a 20% solution intravenously. It dehydrates the vitreous humor 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>

==== Inhaled ==== In the European Union, inhaled mannitol is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.<ref name="Bronchitol EPAR" />

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 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>

==== Oral ==== Mannitol acts as an osmotic laxative<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 |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 |journal=J. Biol. Chem. |volume=141 |pages=147–154 |doi=10.1016/S0021-9258(18)72829-9 |doi-access=free}}</ref> and is sometimes sold as a laxative for children.{{Citation needed|date=December 2008}}

===Food=== Mannitol increases blood glucose to a lesser extent than sucrose (thus having a relatively low glycemic index<ref>{{Cite book |title=Advances in Sweeteners |vauthors=Grenby TH |date=2011 |publisher=Springer |isbn=978-1-4612-8522-9 |page=66}}</ref>) so is 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.<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 = 0-470-65968-8 }}</ref> 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.<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 excipient 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=978-0-8247-8210-8 |pages=[https://archive.org/details/excipienttoxicit103wein/page/370 370] |url-access=registration}}</ref>

===Analytical chemistry=== Mannitol forms stable complexes with boric acid. This considerably enhances the acidity of boric acid, allowing for greater precision in the volumetric titration of this acid.<ref>{{Cite book |title=Quantitative Inorganic Analysis |vauthors=Belcher R, Nutten AJ |date=1960 |publisher=Butterworths |edition=2nd |location=London, UK |page=194}}</ref> The stability of the mannitoborate ester anions shifts the acid dissociation equilibrium to the right, thereby increasing the solution's acidity by five orders of magnitude compared to that of pure boric acid. This lowers the p''K''a from 9 to below 4 for a sufficient concentration of mannitol. The resulting solution is referred to as mannitoboric acid.{{Citation needed|date=January 2026}}

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

Mannitol is used as a cutting agent<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 (snorted), such as heroin and cocaine. A mixture of mannitol and fentanyl (or fentanyl analogs) in ratio 1:10 is labeled and sold as "China white", a popular heroin substitute.{{citation needed|date=August 2018}}

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>

== Contraindications == Mannitol is contraindicated in people with anuria, severe hypovolemia, pre-existing severe pulmonary vascular congestion or pulmonary edema, irritable bowel syndrome (IBS), and active intracranial bleeding except during craniotomy.<ref name="DailyMed-2018" />

Adverse effects include hyponatremia and volume depletion leading to metabolic acidosis.<ref name="Kremers-1986" />

==Chemistry== Mannitol is an isomer of sorbitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2.<ref name="Kearsley-2006" /> While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.{{Citation needed|date=January 2026}}

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

===Industrial synthesis=== 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.<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> It is a natural constituent of most microorganisms and plants, having roles in maintaining cellular water balance, and responding to drought or low temperature.<ref name="Edmond_2025"/>

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.<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 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 {{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 yeast<ref name="Song-2009" /> 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.<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 seaweed is the most common form of mannitol production.<ref name="Lawson-2007" /> 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'').<ref>{{cite journal | vauthors = Wagner H, Flachsbarth H, Vogel G | title = [A New Antiphlogistic Principle from Sabal serrulata, II] | 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  from the crude material in a Soxhlet apparatus using a mixture of ethanol, water, and methanol. The mannitol is then recrystallized from the extract, generally resulting in yields of about 18% of the original natural product. Another method of extraction is using supercritical and subcritical fluids. These fluids are at such a stage that no difference exists between the liquid and gas stages, so are more diffusive 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 carbon dioxide 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}} CO2 versus {{convert|abbr=on|194.4|g|oz}} ethanol per {{convert|abbr=on|1|g|oz}} olive leaf. Heated, pressurized, subcritical water 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, Julije Domac elucidated the structure of hexene and mannitol obtained from Caspian manna. 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=Justus Liebig's Annalen der Chemie |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. The results of that investigation, published in 2007 after the death of the original studies' lead author Dr Julio Cruz, questioned whether his 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> Cruz's co-authors 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 this doubt surrounding Cruz's work, an updated version of the Cochrane review 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 == * British Pharmacopoeia<ref>{{Cite web |last=British Pharmacopoeia Commission Secretariat |year=2009 |title=Index, BP 2009 |url=http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf |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> * Japanese Pharmacopoeia<ref>{{Cite web |year=2006 |title=Japanese Pharmacopoeia | edition = Fifteenth |url=http://jpdb.nihs.go.jp/jp15e/JP15.pdf |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> * United States Pharmacopeia<ref>{{Cite web | work = USP 32 |year=2008 |title=Mannitol Injection |url=http://www.usp.org/pdf/EN/USPNF/mannitolInjectionMonograph.pdf |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>

== References == {{reflist}}

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