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| Trade names | Osmitrol, Bronchitol, others |
| Other names | d-Mannitol, mannite, manna sugar |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intravenous,By mouth,inhalation |
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| Pharmacokinetic data | |
| Bioavailability | ~7% |
| Metabolism | Liver, negligible |
| Eliminationhalf-life | 100 minutes |
| Excretion | Kidney: 90% |
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| E number | E421(thickeners, ...) |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.647 |
| Chemical and physical data | |
| Formula | C6H14O6 |
| Molar mass | 182.172 g·mol−1 |
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Mannitol is a type ofsugar alcohol used as asweetener and medication.[5][6] It is used as a low calorie sweetener as it is poorly absorbed by theintestines.[5] As a medication, it is used to decrease pressure in the eyes, as inglaucoma, and to lowerincreased intracranial pressure.[7][8][6] Medically, it is given by injection or inhalation.[9][10] Effects typically begin within 15 minutes and last up to 8 hours.[9]
Common side effects from medical use includeelectrolyte problems anddehydration.[9] Other serious side effects may include worseningheart failure andkidney problems.[9][6] It is unclear if use is safe inpregnancy.[9] Mannitol is in theosmotic diuretic family of medications and works by pulling fluid from the brain and eyes.[9]
The discovery of mannitol is attributed toJoseph Louis Proust in 1806.[11] It is on theWorld Health Organization's List of Essential Medicines.[12] It was originally made from theflowering ash and calledmanna due to its supposed resemblance to the Biblical food.[13][14] Mannitol is on theWorld Anti-Doping Agency's banned substances list due to concerns that it may mask prohibited drugs.[15]
In the United States, injected mannitol isindicated for the reduction of intracranial pressure and treatment of cerebral edema and elevated intraocular pressure.[3]
Mannitol is used intravenously to reduce acutely raised intracranial pressure until more definitive treatment can be applied,[16] e.g., afterhead trauma. 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.[17]
It may also be used for certain cases ofkidney failure with low urine output, decreasingpressure in the eye, to increase the elimination of certain toxins, and to treatfluid build up.[9]
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]
Mannitol is commonly used in the circuit prime of aheart lung machine duringcardiopulmonary 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 ofendothelial 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 anartificial pacemaker) while it passes through the venous system. Because the mannitol dissolves readily in blood, the sharp point becomes exposed at its destination.
Intra-arterial infusions of mannitol can transiently open theblood–brain barrier by disruptingtight junctions.[18][19]
Mannitol is also the first drug of choice to treat acuteglaucoma (high eye pressure) in veterinary medicine. It is administered as a 20% solution intravenously. It dehydrates thevitreous humor and, therefore, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.[20]
In the European Union, inhaled mannitol is indicated for the treatment ofcystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.[4]
The use of mannitol, when inhaled, as a bronchial irritant as an alternative method of diagnosis ofexercise-induced asthma has been proposed. A 2013 systematic review concluded evidence to support its use for this purpose at this time is insufficient.[21]
Mannitol acts as an osmoticlaxative[3][22] in oral doses larger than 20 g,[23] and is sometimes sold as a laxative for children.[citation needed]
Mannitol increases blood glucose to a lesser extent thansucrose (thus having a relatively lowglycemic index[24]) so is used as asweetener for people withdiabetes, and inchewing gums. Although mannitol has a higherheat 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.[25] Also, it has a very lowhygroscopicity – 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.[26] The pleasant taste and mouthfeel of mannitol also makes it a popularexcipient for chewable tablets.[27]
Mannitol forms stable complexes withboric acid. This considerably enhances the acidity of boric acid, allowing for greater precision in the volumetric titration of this acid.[28] 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 pKa from 9 to below 4 for a sufficient concentration of mannitol. The resulting solution is referred to as mannitoboric acid.
Mannitol is the primary ingredient ofmannitol salt agar, a bacterial growth medium, and is used in others.
Mannitol is used as acutting agent[29][30] in various drugs that are used intranasally (snorted), such asheroin andcocaine. A mixture of mannitol andfentanyl (orfentanyl analogs) in ratio 1:10 is labeled and sold as "China white", a popular heroin substitute.[citation needed]
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."[31]
Mannitol is contraindicated in people withanuria, severehypovolemia, pre-existing severe pulmonary vascular congestion or pulmonary edema, irritable bowel syndrome (IBS), and active intracranial bleeding except during craniotomy.[3]
Adverse effects includehyponatremia and volume depletion leading tometabolic acidosis.[11]
Mannitol is anisomer ofsorbitol, another sugar alcohol; the two differ only in the orientation of thehydroxyl group on carbon 2.[25] While similar, the two sugar alcohols have very different sources in nature,melting points, and uses.
Mannitol is classified as asugar alcohol; that is, it can be derived from a sugar (mannose) by reduction. Other sugar alcohols includexylitol andsorbitol.
Mannitol is commonly produced via thehydrogenation of fructose, which is formed from eitherstarch orsucrose (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 aninvert 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 nickelcatalyst into a mixture of isomerssorbitol and mannitol. Yield is typically 50%:50%, although slightlyalkaline reaction conditions can slightly increase mannitol yields.[25]
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.[32]Fermentation by microorganisms is an alternative to the traditional industrial synthesis. A fructose to mannitolmetabolic 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.[33] A class oflactic 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 oflactic acid,acetic acid, andcarbon 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 asyeast[32] andE. 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.[33]
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 fromseaweed is the most common form of mannitol production.[26] Mannitol concentrations of plantexudates can range from 20% in seaweeds to 90% in theplane tree. It is a constituent of saw palmetto (Serenoa).[34]
Traditionally, mannitol is extracted by theSoxhlet extraction, usingethanol, water, andmethanol to steam and then hydrolysis of the crude material. The mannitol is thenrecrystallized from the extract, generally resulting in yields of about 18% of the original natural product. Another method of extraction is usingsupercritical andsubcritical fluids. These fluids are at such a stage that no difference exists between the liquid and gas stages, so are morediffusive 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.
Supercriticalcarbon 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 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.[33]
In the early 1880s,Julije Domac elucidated the structure ofhexene and mannitol obtained fromCaspian 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.[35][36][37][38]
The three studies[39][40][41] 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.[42] 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 theCochrane review excludes all studies by Julio Cruz, leaving only four studies.[7] Due to differences in selection of control groups, a conclusion about the clinical use of mannitol has not been reached.
Media related toMannitol at Wikimedia Commons
