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== Synthetic ==
== Synthetic ==
Due to high demand for pharmaceutical use, it is also made semi-synthetically by dehydrogenation of hesperidin, e.g. with iodine in pyridine.<ref>Studies in Organic Chemistry (1981), 11, 115-119</ref> Diosmin has 10 [[stereocenter]]s. It is an oral phlebotropic drug used in the treatment of venous disease, i.e., [[chronic venous insufficiency]] (CVI) including spider and varicose veins, leg swelling ([[edema]]), [[stasis dermatitis]] and [[venous ulcer]]s. It is also used as a stand-alone or surgical adjunctive therapy in [[hemorrhoid]]al disease (HD).
Due to high demand for pharmaceutical use, it is also made semi-synthetically by dehydrogenation of hesperidin, e.g. with iodine in pyridine.<ref>Studies in Organic Chemistry (1981), 11, 115-119</ref> Diosmin has 10 [[stereocenter]]s. It is an oral [[phlebotropic]] drug used in the treatment of venous disease, i.e., [[chronic venous insufficiency]] (CVI) including spider and varicose veins, leg swelling ([[edema]]), [[stasis dermatitis]] and [[venous ulcer]]s. It is also used as a stand-alone or surgical adjunctive therapy in [[hemorrhoid]]al disease (HD).


There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life.<ref>{{Cite journal|last=Jantet|first=G.|date=2002-06-01|title=Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids|journal=Angiology|volume=53|issue=3|pages=245–256|issn=0003-3197|pmid=12025911|doi=10.1177/000331970205300301}}</ref> There are no prospective studies in arterial disease.
There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life.<ref>{{Cite journal|last=Jantet|first=G.|date=2002-06-01|title=Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids|journal=Angiology|volume=53|issue=3|pages=245–256|issn=0003-3197|pmid=12025911|doi=10.1177/000331970205300301}}</ref> There are no prospective studies in arterial disease.
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Diosmin has been found to be effective in mitigating hyperglycemia in diabetic rats.<ref>Leelavinothan Pari, Subramani Srinivasan, Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats, Biomedicine & Pharmacotherapy, Volume 64, Issue 7, September 2010, Pages 477-481.</ref> It is also speculated that diosmin might have potential in the treatment of [[Neurodegeneration|neurodegenerative disease]]<nowiki/>s,<ref>{{Cite journal|last=Sirlak|first=Mustafa|last2=Akar|first2=A. Ruchan|last3=Eryilmaz|first3=Sadik|last4=Cetinkanat|first4=Elif Kuzgun|last5=Ozcinar|first5=Evren|last6=Kaya|first6=Bulent|last7=Elhan|first7=Atilla Halil|last8=Ozyurda|first8=Umit|date=2010-01-01|title=Micronized purified flavonoid fraction in pretreating CABG patients|journal=Texas Heart Institute Journal|volume=37|issue=2|pages=172–177|issn=1526-6702|pmc=2851420|pmid=20401289}}</ref> such as [[Alzheimer's disease]], and its anti-inflammatory and anti-apoptotic activity has been demonstrated in neuronal cells, in vitro.<ref>Sanjay L.Dholakiya, Kenza E. Benzeroual, Protective effect of Diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF- [alpha] expression, Toxicology in Vitro, In Press, Accepted Manuscript, Available online 6 April 2011.</ref>
Diosmin has been found to be effective in mitigating hyperglycemia in diabetic rats.<ref>Leelavinothan Pari, Subramani Srinivasan, Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats, Biomedicine & Pharmacotherapy, Volume 64, Issue 7, September 2010, Pages 477-481.</ref> It is also speculated that diosmin might have potential in the treatment of [[Neurodegeneration|neurodegenerative disease]]<nowiki/>s,<ref>{{Cite journal|last=Sirlak|first=Mustafa|last2=Akar|first2=A. Ruchan|last3=Eryilmaz|first3=Sadik|last4=Cetinkanat|first4=Elif Kuzgun|last5=Ozcinar|first5=Evren|last6=Kaya|first6=Bulent|last7=Elhan|first7=Atilla Halil|last8=Ozyurda|first8=Umit|date=2010-01-01|title=Micronized purified flavonoid fraction in pretreating CABG patients|journal=Texas Heart Institute Journal|volume=37|issue=2|pages=172–177|issn=1526-6702|pmc=2851420|pmid=20401289}}</ref> such as [[Alzheimer's disease]], and its anti-inflammatory and anti-apoptotic activity has been demonstrated in neuronal cells, in vitro.<ref>Sanjay L.Dholakiya, Kenza E. Benzeroual, Protective effect of Diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF- [alpha] expression, Toxicology in Vitro, In Press, Accepted Manuscript, Available online 6 April 2011.</ref>


=== Mechanisms ===
== Mechanisms ==
{{Unreferenced section|date=August 2008}}
{{Unreferenced section|date=August 2008}}
Diosmin prolongs the [[vasoconstrictor]] effect of [[norepinephrine]] on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and [[venous stasis]]. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.
Diosmin prolongs the [[vasoconstrictor]] effect of [[norepinephrine]] on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and [[venous stasis]]. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.
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Diosmin reduces the expression of [[endothelial adhesion molecules]] ([[ICAM1]], [[VCAM1]]), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and [[prostaglandins]] ([[PGE2]], PGF2a).
Diosmin reduces the expression of [[endothelial adhesion molecules]] ([[ICAM1]], [[VCAM1]]), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and [[prostaglandins]] ([[PGE2]], PGF2a).


=== Regulatory status ===
== Regulatory status ==
Diosmin is distributed in the U.S. as a dietary supplement and as a prescription [[medical food]].<ref>[http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0293-01-vol228.pdf Public Health Service memorandum], Sept. 13, 2005</ref> The [[Food and Drug Administration|FDA]] concluded in 2001 that there was inadequate evidence on which to base an expectation of safety.<ref>New Dietary Ingredients in Dietary Supplements, U. S. Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Nutritional Products, Labeling, and Dietary Supplements
Diosmin is distributed in the U.S. as a dietary supplement and as a prescription [[medical food]].<ref>[http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0293-01-vol228.pdf Public Health Service memorandum], Sept. 13, 2005</ref> The [[Food and Drug Administration|FDA]] concluded in 2001 that there was inadequate evidence on which to base an expectation of safety.<ref>New Dietary Ingredients in Dietary Supplements, U. S. Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Nutritional Products, Labeling, and Dietary Supplements
February 2001 (Updated September 10, 2001)
February 2001 (Updated September 10, 2001)

Revision as of 09:51, 7 November 2019

Diosmin
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		oral
ATC code
Identifiers
  • 5-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)- 7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy -6-[[(2R,3R,4R,5R,6S) -3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.537 Edit this at Wikidata
Chemical and physical data
FormulaC28H32O15
Molar mass608.545 g/mol g·mol−1
3D model (JSmol)
  • O=C\4c5c(O)cc(O[C@@H]2O[C@H](CO[C@@H]1O[C@H]([C@H](O)[C@@H](O)[C@H]1O)C)[C@@H](O)[C@H](O)[C@H]2O)cc5O/C(c3ccc(OC)c(O)c3)=C/4
  • InChI=1S/C28H32O15/c1-10-21(32)23(34)25(36)27(40-10)39-9-19-22(33)24(35)26(37)28(43-19)41-12-6-14(30)20-15(31)8-17(42-18(20)7-12)11-3-4-16(38-2)13(29)5-11/h3-8,10,19,21-30,32-37H,9H2,1-2H3/t10-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1 checkY
  • Key:GZSOSUNBTXMUFQ-YFAPSIMESA-N checkY
 ☒NcheckY (what is this?)  (verify)

Diosmin (diosmetin 7-O-rutinoside), a flavone derivative also known as venosmine, is a glycoside of diosmetin, which in turn is the 4'-methoxy derivative of luteolin. Diosmin is naturally occurring, mainly in the citrus family rutaceae, but also in herbs such as Teucrium gnaphalodes.[1]

Synthetic

Due to high demand for pharmaceutical use, it is also made semi-synthetically by dehydrogenation of hesperidin, e.g. with iodine in pyridine.[2] Diosmin has 10 stereocenters. It is an oral phlebotropic drug used in the treatment of venous disease, i.e., chronic venous insufficiency (CVI) including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. It is also used as a stand-alone or surgical adjunctive therapy in hemorrhoidal disease (HD).

There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life.[3] There are no prospective studies in arterial disease.

Diosmin is currently a prescription medication in some European countries (tradenames Dio-PP, Venotec, Daflon, Detralex, Vasculera, Arvenum), containing 90% diosmin and 10% hesperidin, and sold as a nutritional supplement in the United States.

Diosmin has been found to be effective in mitigating hyperglycemia in diabetic rats.[4] It is also speculated that diosmin might have potential in the treatment of neurodegenerative diseases,[5] such as Alzheimer's disease, and its anti-inflammatory and anti-apoptotic activity has been demonstrated in neuronal cells, in vitro.[6]

Mechanisms

Diosmin prolongs the vasoconstrictor effect of norepinephrine on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and venous stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.

Diosmin improves lymphatic drainage by increasing the frequency and intensity of lymphatic contractions, and by increasing the total number of functional lymphatic capillaries. Furthermore, diosmin with hesperidine decreases the diameter of lymphatic capillaries and the intralymphatic pressure.

At the microcirculation level, diosmin reduces capillary hyperpermeability and increases capillary resistance by protecting the microcirculation from damaging processes.

Diosmin reduces the expression of endothelial adhesion molecules (ICAM1, VCAM1), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals and prostaglandins (PGE2, PGF2a).

Regulatory status

Diosmin is distributed in the U.S. as a dietary supplement and as a prescription medical food.[7] The FDA concluded in 2001 that there was inadequate evidence on which to base an expectation of safety.[8] As of 2013, the FDA did not revise this position, and all phlebotonics remain unapproved.[9] In the U.S., dietary supplements are regulated under Dietary Supplement Health and Education Act of 1994, which does not require proof of efficacy so long as no specific health claims are made.[10] Under FDA regulation, medical food products must obtain GRAS (Generally Recognized As Safe) status.[10] The enhanced version of diosmin, Vasculera, is sold as a medical food product with GRAS status and recognized efficiency in the management of chronic venous insufficiency.[11] A 2016 Cochrane review found that diosmin significantly reduced leg and ankle swelling and lower leg pain.[12]

See also

References

  1. ^ Flavonoid Aglycones and Glycosides from Teucrium gnaphalodes. F. A. T. Barberán, M. I. Gil, F. Tomás, F. Ferreres and A. Arques, J. Nat. Prod., 1985, 48 (5), pages 859–860, doi:10.1021/np50041a040
  2. ^ Studies in Organic Chemistry (1981), 11, 115-119
  3. ^ Jantet, G. (2002-06-01). "Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids". Angiology. 53 (3): 245–256. doi:10.1177/000331970205300301. ISSN 0003-3197. PMID 12025911.
  4. ^ Leelavinothan Pari, Subramani Srinivasan, Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats, Biomedicine & Pharmacotherapy, Volume 64, Issue 7, September 2010, Pages 477-481.
  5. ^ Sirlak, Mustafa; Akar, A. Ruchan; Eryilmaz, Sadik; Cetinkanat, Elif Kuzgun; Ozcinar, Evren; Kaya, Bulent; Elhan, Atilla Halil; Ozyurda, Umit (2010-01-01). "Micronized purified flavonoid fraction in pretreating CABG patients". Texas Heart Institute Journal. 37 (2): 172–177. ISSN 1526-6702. PMC 2851420. PMID 20401289.
  6. ^ Sanjay L.Dholakiya, Kenza E. Benzeroual, Protective effect of Diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF- [alpha] expression, Toxicology in Vitro, In Press, Accepted Manuscript, Available online 6 April 2011.
  7. ^ Public Health Service memorandum, Sept. 13, 2005
  8. ^ New Dietary Ingredients in Dietary Supplements, U. S. Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Nutritional Products, Labeling, and Dietary Supplements February 2001 (Updated September 10, 2001) [1], Memorandum [2]
  9. ^ Garg, Nitin; Gloviczki, Peter (2013). "55 - Chronic Venous Insufficiency". Vascular Medicine: A Companion to Braunwald's Heart Disease (Second Edition). Elsevier Health Sciences. pp. 652–666. ISBN 9781437729306.
  10. ^ a b "Guidance for Industry: Frequently Asked Questions About Medical Foods - Second Edition". fda.gov. May 2007. Retrieved 2019. {{cite web}}: Check date values in: |access-date= (help)
  11. ^ "Vasculera - diosmiplex 630mg". dailymed.nlm.nih.gov.
  12. ^ Martinez-Zapata, Maria José; Vernooij, Robin WM; Uriona Tuma, Sonia Maria; Stein, Airton T; Moreno, Rosa M; Vargas, Emilio; Capellà, Dolors; Bonfill Cosp, Xavier (6 April 2016). "Phlebotonics for venous insufficiency". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD003229.pub3. PMID 27048768. {{cite journal}}: Unknown parameter |lay-url= ignored (help)
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