Mannitol

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Mannitol is a naturally occurring polyol (sugar alcohol) found in fruits and vegetables and has multiple uses in the food industry and pharmacology. Historically herbal preparations from say plant sap were used as a mild purgative. Since about 1940 it has been available in industrial qualities cheaply. It is used currently therapeutically as an osmotic diuretic (also since the 1940's when it became cheap) and to treat intracranial hypertension[1]. Mannitol is a common excipient in pharmacological manufacture and although often considered a potential placebo in randomised controlled trials it has a number of potential active functions which may be important (see pharmacology below). As it is freely filtered by the glomerulus and poorly reabsorbed from the renal tubule, it can be used to estimate renal function[2]. It has recently been demonstrated to be a superior alternative to lactulose in initial treatment of hepatic encephalopathy[3].

Contents

Clinical Use

Indications

  • Diuresis in the oliguric phase of acute renal failure
  • Reduction of intracranial pressure and cerebral oedema, when blood-barrier is intact
    • Note -mannitol might increase blood brain barrier permeability in chronic use - see pharmacology below.
  • Reduction of elevated intraocular pressure
  • Promotion of elimination of renally excreted toxic substances in poisoning

Administration

  • Oral
  • IV - as 10% or 20% solutions.

Clinical Issues

Contra-indications

  • Heart failure
  • Anuria

Cautions and Interactions

Side effects

  • Diarrhoea (adult dose would typically need to be more than 10g/day)
  • Aggravate symptoms in those with irritable bowel syndrome
  • Hyponatraemia
  • Dehydration

Special advice

Widely used to reduce sugar intake in diabetic diet, as anti-caking agent, low-calorie sweetener, bulking agent. Intake under 16mg/kg body weight (say 10g in 70kg adult) is definitely harmless[5] and might be beneficial as part of a balanced diet. Some might start to have bowel symptoms with intakes approaching 32mg/kg and risk benefit for individual health conditions may be in its favour. LD50 in rats is 1700 mg/kg which is approximately 200g intake a day in adult humans[6].

Pharmacology

Mannitol is an isomer of sorbitol widely found in plants and fungi. It forms white crystals at room temperature. As it is stable at elevated temperatures and has a low hygroscopicity it is used in the food industry for applications such as a coating for hard candies and chocolates and a dusting powder for chewing gum, dried fruits, and chewing gum. Commercial production is by catalytic hydrogenation of a glucose/fructose mixture (formed from starch or sucrose) with a second fermentation step by lactic acid bacteria. It is about 50% as sweet as sugar and has a relatively low calorific value at 1.6 kcal/g (sugar is 4 kcal/g). It was first characterised in 1806 by Joseph Louis Proust who started out as a pharmacist. Another pharmacist, Julije Domac, determined its full structure in 1881[7][8] Oral mannitol has unpredictable absortion from the gut. There is evidence that those individuals who absorb it well are more likely to have irritable bowel symptoms[9]. Gut asorbtion is known to be negatively modulated in the presence of other sugars or polyols (ie more if pure mannitol load). Mannitol is freely filtered by the glomerulus and poorly reabsorbed from the renal tubule, thereby causing an increase in osmolarity of the glomerular filtrate. This increase in osmolarity limits tubular reabsorption of water and inhibits the renal tubular reabsorption of sodium, chloride, and other solutes, thereby promoting diuresis. In addition, mannitol elevates blood plasma osmolarity, resulting in enhanced flow of water from tissues into interstitial fluid and plasma. Intestinal permeability is often determined by a lactulose/mannitol test as the former is a much larger molecule. In animal models duodenal motility can be stimulated by hyperosmolar solutions of mannitol. It is likely to alter the gut microbiome but specific studies isolated to its effect alone are rare.

Postulated effects

There are multiple potential postulated effects from its known properties from in vitro experiments. Such suggested effects need in vivo proof and are very difficult to control for. This applies to even in vitro experiments where like glucose it might be used in solvents for its other properties. But in vitro experiments can also be challenging when the substance is commonly used, as as a placebo but known to alter for example trace metal toxicity in living systems[10]. In animal models it is a disruptor of α-synuclein aggregation[11]. Accordingly it is a potential treatment in the synucleinopathies. In animal models it enhances the permeability of the brain to drugs such as methotrexate[12]. Accordingly it is being studied in cerebral tumours as an enhancer for chemotherpeutic agents. With other drugs such as gentamicin BBB permeability does not change but blood endolymph concentration could be so enhanced causing ototoxicity[13]. Like other hyperosmolar treatments (hyperosmolar saline or sorbitol) it would affect in vivo neutrophil extracellular trap formation and apoptosis but net benefit would depend upon the disease scenario[14]. Mannitol's free radical scavenging properties are well known. However while this might be beneficial in say diseases where there is inappropriate activation of such activity, as the bodies immune system uses its free radical generating capacity to deal with bacterial infection, high extracelluar concentrations of mannitol might be a bad idea where we are say dealing with a bacterial biofilm infection on say a urinary catheter or pacemaker[15].

Metabolism

Its metabolism in plants, fungi, yeast and algae is well understood but is species dependent. The predominant pathway is the conversion from fructose in fungi but in higher plants it can be produced by a different pathway from mannitol-1-phosphate (which in turn is produced from fructose-6-phosphate). In celery, mannitol is an osmoprotectant and in addition an interchange carbon and energy source. In various fungi its production is associated with enhanced pathogenicity to host plant species, which have evolved metabolic counters. In healthy man about 18% of an oral dose is metabolised presumably by the gut microbiome or conversion into hepatic glycogen and subsequent human metabolic pathways to be found in expired carbon dioxide, but only 2.5% of an intravenous dose is so metabolised[16] . Nitrophenide, a known anticoccidial drug used in poultry farming works by inhibiting a key enzyme used by Eimeria tenella to store mannitol in its ovocysts[17]. Human cyclosporiasis due to Cyclospora cayetanensis is so very closely related it presumably also uses mannitol in its ovocysts.

Food content

As mannitol might modulate some health conditions the following table may be useful. Sorbitol although its isomer, can have quite different properties.

Sorbitol and mannitol in common foods/products[18].[19]
Food/Product Sorbitol g/100g Mannitol g/100g
Celery 0 1.5
Cauliflower 0 2.6
Mushrooms 0.1 2.6
Snow Peas 0 1.2
Broccoli 0.4 0
Sweet corn 0.5 0
Capsican, green 0.4 0
Plum 2.4 0
Apricot 1.2 0
Apple 1.2 0
Blackberries 4.1 0
Pear 2.3 0
Prunes 12 0
Chewing gum (sugarless) 41.9 0
Horseradish sauce 11.1 0.3
Articoke 0 0
Celeriac 0 0.1
Leek 0 0
Lettuce, rocket 0 0
Sugar snap peas 0 0
Butternut 0 0.4
Parsnip 0 0
Sundried tomatoes 0 0
Radish 0 0
Seaweed, american 0 trace
Water chestnut 0 0
Asparagus 0 0.1
Bok choy 0.2 0
Brussel spouts 0.2 0
Cabbage 0.2 0
Cucumber 0 0
Sweet potato 0 0.3
Nicorette 4 mg Gum 70 0
Beans, continental 0 0
Beans, lima 0 0.1
Boysenberries 0 0
Cherries 0.7 0
Grapes 0 0
Nectarine 0.6 0
Peach 0.9 0.5
Figs 0 0
Pomegranate 0.05 0.3
Rhubarb 0 0
Strawberries 0 0
Tamarillo (Tree tomato) 0 0
Dried apple 1.9 0
Dried apricot 6.0 0
Black olives in brine 0 0.1
Dried apricot 6.0 0
Coconut - dessicated 0.6 0
Dried pear 8.1 0
Bread 0 0
Apple juice 0.5 0
Coconut milk 0.1 0
Beer 0 0
Coconut milk 0.1 0

References

  1. Sokhal N, Rath GP, Chaturvedi A, Singh M, Dash HH. Comparison of 20% mannitol and 3% hypertonic saline on intracranial pressure and systemic hemodynamics.J Clin Neurosci. 2017 Aug;42:148-154. doi: 10.1016/j.jocn.2017.03.016
  2. Kiss K, Molnár M, Söndergaard S, Molnár G, Ricksten SE. Mannitol clearance for the determination of glomerular filtration rate-a validation against clearance of 51 Cr-EDTA. Clin Physiol Funct Imaging. 2018 Jan;38(1):10-16. doi: 10.1111/cpf.12374
  3. Montes-Cortés DH, Novelo-Del Valle JL, Olivares-Corichi IM, Rosas-Barrientos JV, Jara LJ, Cruz-Domínguez MP. Impact of intestinal mannitol on hyperammonemia, oxidative stress and severity of hepatic encephalopathy in the ED. Am J Emerg Med. 2018 Sep;36(9):1570-1576. doi: 10.1016/j.ajem.2018.01.032
  4. Mullins ME, Hoffman RS. Is mannitol the treatment of choice for patients with ciguatera fish poisoning? Clin Toxicol (Phila). 2017 Nov;55(9):947-955. doi: 10.1080/15563650.2017.1327664
  5. Ellis FW, Krantz J. Sugar alcohols. 22. Metabolism and toxicity studies with mannitol and sorbitol in man and animals. Journal of Biological Chemistry 1941 Vol.141 pp.147-154 link to abstract
  6. Mannitol toxicology monograph FAO/WHO accessed 20 Jan 2019
  7. Domac J. Über das Hexylen aus Mannit. .itzungsberichte der Kaiserlichen Akademie der Wissenschaften, Mathematisch-Naturwissenschaftliche Classe. 23. pp. 1038–1051. 1881.
  8. [Domac J. Über das Hexylen aus Mannit (Aus dem Universitätslaboratorium des Prof. A. Lieben). Monat. Chem. (Wien). 2. p. 309. 1881]
  9. Yao CK, Tan HL, van Langenberg DR, Barrett JS, Rose R, Liels K, Gibson PR, Muir JG.Dietary sorbitol and mannitol: food content and distinct absorption patterns between healthy individuals and patients with irritable bowel syndrome. J Hum Nutr Diet. 2014 Apr;27 Suppl 2:263-75. doi: 10.1111/jhn.12144.
  10. Habiba U, Ali S, Rizwan M, Ibrahim M, Hussain A, Shahid MR, Alamri SA, Alyemeni MN, Ahmad P. Alleviative role of exogenously applied mannitol in maize cultivars differing in chromium stress tolerance. Environ Sci Pollut Res Int. 2019 Jan 3. doi: 10.1007/s11356-018-3970-2
  11. Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-Matia N, Masliah E, Segal D, Gazit E.A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD). J Biol Chem. 2013 Jun 14;288(24):17579-88. doi: 10.1074/jbc.M112.434787.
  12. Pan GY, Liu XD, Liu GQ. Intracarotid infusion of hypertonic mannitol changes permeability of blood-brain barrier to methotrexate in rats. Acta Pharmacol Sin. 2000 Jul;21(7):613-6.
  13. Le TN, Blakley BW. Mannitol and the blood-labyrinth barrier. J Otolaryngol Head Neck Surg. 2017 Dec 11;46(1):66. doi: 10.1186/s40463-017-0245-8.
  14. Nadesalingam A, Chen JHK, Farahvash A, Khan MA. Hypertonic Saline Suppresses NADPH Oxidase-Dependent Neutrophil Extracellular Trap Formation and Promotes Apoptosis. Front Immunol. 2018 Mar 8;9:359. doi: 10.3389/fimmu.2018.00359
  15. Brinkman CL, Schmidt-Malan SM, Karau MJ, Greenwood-Quaintance K, Hassett DJ, Mandrekar JN, Patel R. Exposure of Bacterial Biofilms to Electrical Current Leads to Cell Death Mediated in Part by Reactive Oxygen Species. PLoS One. 2016 Dec 19;11(12):e0168595. doi: 10.1371/journal.pone.0168595
  16. Nasrallah SM, Iber FL. Mannitol absorption and metabolism in man. Am J Med Sci. 1969 Aug;258(2):80-8 link to abstract
  17. Allocco JJ, Nare B, Myers RW, Feiglin M, Schmatz DM, Profous-Juchelka H. Nitrophenide (Megasul) blocks Eimeria tenella development by inhibiting the mannitol cycle enzyme mannitol-1-phosphate dehydrogenase. J Parasitol. 2001 Dec;87(6):1441-8.
  18. Yao CK, Tan HL, van Langenberg DR, Barrett JS, Rose R, Liels K, Gibson PR, Muir JG. Dietary sorbitol and mannitol: food content and distinct absorption patterns between healthy individuals and patients with irritable bowel syndrome. J Hum Nutr Diet. 2014 Apr;27 Suppl 2:263-75. doi: 10.1111/jhn.12144
  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213799/ Reduction of the Bitter Taste in Packaged Natural Black Manzanilla Olives by Zinc Chloride. Front Nutr. 2018 Oct 26;5:102. doi: 10.3389/fnut.2018.00102