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===Production===
==Clinical Use==
===Facial hirsutism in women===
Supplies of eflornithine are limited, as its manufacturer does not consider it cost effective.
[[Hirsutism]] affects between 5-15% of all women across all ethnic backgrounds. <ref>{{|author=Azziz R. |title=The evaluation and management of hirsutism. Obstet Gynaecol 2003; 101: 995 -1007}}</ref> Depending on the definition and the underlying data, estimates indicate that approximately 40% of women have some degree of unwanted facial hair. <ref>{{|author=Blume-Peytavi U, Gieler U, Hoffmann R, Shapiro J, |title=Unwanted Facial Hair: Affects, Effects and Solutions. Dermatology. 2007; 215(2): 139-46}}</ref>


Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine imbalance. <ref>{{|author=Blume-Peytavi U, Hahn S, |title=Medical treatment of hirsutism. Dermatol Ther. 2008 Sep-Oct; 21(5): 329-39. Review}}</ref> Hirsutism is a commonly presenting symptom in dermatology, endocrinology and gynaecology clinics, and one that is considered to be the cause of much psychological distress and social difficulty. <ref>{{|author=Barth JH, Catalan J, Cherry CA, Day A. |title=Psychological morbidity in women referred for treatment of hirsutism. J Psychosom Res. 1993 Sep; 37(6): 615-9}}</ref> Facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression. <ref>{{|author=Jackson J, Caro JJ, Caro G, Garfield F, Huber F, Zhou W, Lin CS, Shander D, Schrode K, and the Eflornithine HCl Study Group |title=The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981}}</ref>
Its production was halted by its manufacturer, [[Aventis]], in 1995 because the company did not consider it a profitable drug. The disease mainly affects poor people unable to pay for any sort of treatment.


Vaniqa is indicated for treatment of facial hirsutism in women. <ref>{{web cite|url=http://www.ukmi.nhs.uk/NewMaterial/html/docs/EflornithineNMP0504b.pdf|title=NHS and UKMi New Medicines Profile}}</ref> It is the only topical prescription treatment that slows the growth of facial hair. <ref>{{|author=Balfour JA, McClellan K. |title=Topical Eflornithine. Am J Clin Dermatol 2001; 2(3): 197-201}}</ref> It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. <ref>{{|author=Schrode K, Huber F, Staszak J, Altman DJ, and the Eflornithine Study Group |title=Evaluation of the long-term safety of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10-15 March, San Francisco; USA, Poster 294}}</ref> Positive results were seen after eight weeks. <ref>{{|author=Schrode K, Huber F, Staszak, J, Altman DJ, Shander D, Morton J, and the Eflornithine Study Group |title=Randomized, double-blind, vehicle-controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10-15 March, San Francisco; USA, Poster 291}}</ref>
In 2001, after lobbying at the WHO [[World Health Organization]] by [[Médecins Sans Frontières]] ("Doctors Without Borders"), the manufacturer resumed production of eflornithine, melarsoprol, and [[pentamidine]] in sufficient amounts to cover existing needs. This 5-year agreement with the WHO also envisaged MSF's working on the distribution of the drugs. The yearly value of the drugs donated by [[Aventis]] under this agreement is US$5 million. In addition, under the agreement, [[Bristol-Myers Squibb]], the manufacturer of Vaniqa, will pay for part of the eflornithine. The 5-year agreement expired in 2006.<ref>[http://www.ifpma.org/Health/other_infect/health_sleep.aspx IFPMA Health Initiatives: Sleeping Sickness<!-- Bot generated title -->]</ref> The trade name of eflornithine as manufactured for the treatment of sleeping sickness is '''Ornidyl'''.


Vaniqa and laser treatment have complementary mechanisms of action.<ref>{{|author=Hamzavi I, Tan E, Shapiro S, Harvey l. |title=A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57(1): 54-59}}</ref> As Vaniqa does not affect hair diameter, it does not decrease the efficacy of simultaneous or subsequent laser therapy<ref>{{|author=Hoffmann R |title=A 4-month, open-label study evaluating the efficacy of eflornithine 11.5% cream in the treatment of unwanted facial hair in women using TrichoScan. Eur J Dermatol 2008; 18(1): 65-70}}</ref>. Synergies between the two treatment methods lead to faster and better end results.<ref>{{|author=Hamzavi I, Tan E, Shapiro S, Harvey l. |title=A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57(1): 54-59}}</ref>
Once the five-year period is over, [[Sanofi-Aventis]] (its new name after merging with another drugs company, [[Sanofi-Synthélabo]]) would start transferring technology and giving technical assistance to any possible manufacturer willing to continue production on their own.<ref>{{es icon}} http://www.dndi.org.br/Espanhol/doenca_sono.aspx</ref>


Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.<ref>{{|author=Jackson J, Caro JJ, Caro G, Garfield F, Huber F, Zhou W, Lin CS, Shander D, Schrode K, and the Eflornithine HCl Study Group |title=The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981}}</ref>
As of September 2005, the World Health Organization reports that the [[India Institute of Chemical Technology]] in [[Hyderabad, India|Hyderabad]], [[India]] and [[ILEX Oncology]] in [[Texas]], [[United States]] are both working on new ways of making eflornithine more cheaply. The WHO goes on to say that ILEX is experimenting with an oral formulation of the drug as a treatment for cancer and that trials of the new oral formulation for efficacy against sleeping sickness are underway.


===Sleeping Sickness===
==Dosing==
Human [[African trypanosomiasis]] (HAT) is a parasitic disease spread by the tsetse fly. It is found only in subtropical and equatorial Africa. In 1995, the WHO estimated that 300,000 people were afflicted with the disease. In its 2001 report, the WHO set the figure of people at risk of infection at 60 million, of which only 4 to 5 million had access to any kind of medical monitoring. In 2006, the WHO estimated that about 70,000 people could have the disease, which, if left untreated, is always fatal.<ref>{{web cite|url=http://en.sanofi-aventis.com/binaries/RDD_2005_sanofi_EN_tcm28-1529.pdf|title=Sanofi-Aventis 2005 Sustainable Development Report}}</ref><ref>{{web cite|url=http://en.sanofi-aventis.com/binaries/brochure_aam_en_tcm28-18133.pdf|title=Sanofi-Aventis Access to Medicines Brochure}}</ref>
When used for sleeping sickness, eflornithine is given intravenously, 50 mg/kg every six hours for 14 days.<ref>{{cite journal |author=Van Nieuwenhove S, Schechter PJ, Declercq J, Boné G, Burke J, Sjoerdsma A |title=Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=79 |issue=5 |pages=692–8 |year=1985 |pmid=3938090 |doi=0.1016/0035-9203(85)90195-6 |url=}}</ref>


Sleeping sickness is treated with [[pentamidine]] in intramuscular injection in the first phase of the disease, and with [[melarsoprol]] and eflornithine in intravenous injection (50 mg/kg every six hours for 14 days [7]) in the second phase of the disease.<ref>{{web cite|url=http://en.sanofi-aventis.com/binaries/brochure_aam_en_tcm28-18133.pdf|title=Sanofi-Aventis Access to Medicines Brochure}}</ref>
[[Image:DFMO mechanism.png|thumb|450px|right|Chemical mechanism for irreversible inhibition of ornithine decarboxylase by DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from<ref name=Poulin>{{cite journal |author=Poulin R, Lu L, Ackermann B, Bey P, Pegg AE |title=Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites |journal=J. Biol. Chem. |volume=267 |issue=1 |pages=150–8 |year=1992 |pmid=1730582 |doi= |url=http://www.jbc.org/cgi/reprint/267/1/150}}</ref>]]


==Available forms and dosage==
===Vaniqa===
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.<ref>{{cite web|url=http://www.vaniqa.com/files/Vaniqa_Prescription_Info.pdf|title=Vaniqa US Patient Information Leaflet}}</ref> Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

===Ornidyl===
Ornidyl, intended for injection, is supplied in the strength of 200 mg eflornithine hydrochloride per ml.<ref>{{cite web|url=http://drugs-about.com/drugs-o/ornidyl.html|title=Ornidyl facts}}</ref>


==Hair growth inhibitor cream==
Eflornithine is also an effective hair growth inhibiting agent. As a topical application, the drug has been shown to be an effective hair growth retardant in some patients, and is sold under the brand name '''Vaniqa''' (eflornithine hydrochloride 13.9%). Efficacy data submitted to [[Food and Drug Administration]] (FDA) observed about 58% of women using it on facial hair had improvement.<ref>[http://www.fda.gov/cder/foi/label/2000/21145lbl.pdf Vaniqa package insert]</ref> This study suggested it may be particularly effective in postmenopausal women. One large published study on safety found the product rarely caused significant side effects such as acne, follicle irritation, itching or dryness.<ref>{{cite journal |author=Hickman JG, Huber F, Palmisano M |title=Human dermal safety studies with eflornithine HCl 13.9% cream (Vaniqa), a novel treatment for excessive facial hair |journal=Curr Med Res Opin |volume=16 |issue=4 |pages=235–44 |year=2001 |pmid=11268707 |doi= 10.1185/030079901750176735|url=http://openurl.ingenta.com/content/nlm?genre=article&issn=0300-7995&volume=16&issue=4&spage=235&aulast=Hickman}}</ref> This corroborates unpublished data submitted to FDA showing about 2% of subjects discontinued use due to adverse reactions.


It is partly the development of the hair removal market that encouraged Aventis to restart the manufacture of eflornithine, and which allowed it to once again become available for use in sleeping sickness.


==References==
==References==

Revision as of 12:44, 19 May 2010

Eflornithine
Clinical data
License data
Pregnancy
category
  • Category C for dermal cream
Routes of
administration		Intravenous (discontinued)
Dermal
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (Intravenous)
Negligible (Dermal)
MetabolismNot metabolised
Elimination half-life8 hours
ExcretionRenal
Identifiers
  • 2,5-diamino-2-(difluoromethyl)pentanoic acid
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC6H12F2N2O2
Molar mass182.2 g/mol g·mol−1

Eflornithine (α-difluoromethylornithine or DFMO) is a drug found to be effective in the treatment of facial hirsutism [1] (excessive hair growth) as well as in African trypanosomiasis (sleeping sickness) [2]. Eflornithine hydrochloride cream, which is for topical administration in women suffering from facial hirsutism, is marketed under the brand name Vaniqa by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. [3] Eflornithine for injection against sleeping sickness is manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. [4] Both are prescription drugs.

History

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but, while having little use in treating malignancies, it was found to be highly effective in reducing hair growth [5], as well as in treatment of African trypanosomiasis (sleeping sickness) [6], especially the West African form (Trypanosoma brucei gambiense).

Hirsutism

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the FDA granted a U.S. NDA for Vaniqa. The following year, the European Commission issued its Marketing Authorisation. Today, Vaniqa is marketed by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. [7]

Sleeping sickness treatment

In 2001, Aventis (now Sanofi-Aventis) and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Sanofi-Aventis, to be given to the WHO and distributed by the association Doctors Without Borders (aka MSF - Médecins sans Frontières) [8] [9] in countries where the sleeping sickness is endemic.

From 2001 through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives. This changed the epidemiological profile of the disease, meaning that eliminating it altogether can now be envisaged. [10]

Cancer treatment

In 2008, UC Irvine researchers reported a study indicating that, when combined with sulindac (an anti-inflammatory drug), DFMO significantly reduces the risk of recurring colorectal polyps. [11]

Mode of Action

Hirsuitism

Eflornithine topically applied is an irreversible inhibitor of ornithine decarboxylase (ODC), an enzyme that catalyses the conversion of ornithine to putrescine, which plays an important role in cell division and proliferation in the hair follicle. [12]

File:Hirsuitism.png

Sleeping sickness treatment

Eflornithine appears to kill trypanosomes by acting as a suicide inhibitor of the enzyme ornithine decarboxylase (EC 4.1.1.17). This enzyme regulates cell division by catalysing the first step in polyamine biosynthesis. As the inhibitor has a low half-life in humans, it is broken down rapidly while the parasite cannot metabolise it quickly enough. This means that it preferentially harms the parasite.


Clinical Use

Facial hirsutism in women

Hirsutism affects between 5-15% of all women across all ethnic backgrounds. [13] Depending on the definition and the underlying data, estimates indicate that approximately 40% of women have some degree of unwanted facial hair. [14]

Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine imbalance. [15] Hirsutism is a commonly presenting symptom in dermatology, endocrinology and gynaecology clinics, and one that is considered to be the cause of much psychological distress and social difficulty. [16] Facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression. [17]

Vaniqa is indicated for treatment of facial hirsutism in women. [18] It is the only topical prescription treatment that slows the growth of facial hair. [19] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. [20] Positive results were seen after eight weeks. [21]

Vaniqa and laser treatment have complementary mechanisms of action.[22] As Vaniqa does not affect hair diameter, it does not decrease the efficacy of simultaneous or subsequent laser therapy[23]. Synergies between the two treatment methods lead to faster and better end results.[24]

Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.[25]

Sleeping Sickness

Human African trypanosomiasis (HAT) is a parasitic disease spread by the tsetse fly. It is found only in subtropical and equatorial Africa. In 1995, the WHO estimated that 300,000 people were afflicted with the disease. In its 2001 report, the WHO set the figure of people at risk of infection at 60 million, of which only 4 to 5 million had access to any kind of medical monitoring. In 2006, the WHO estimated that about 70,000 people could have the disease, which, if left untreated, is always fatal.[26][27]

Sleeping sickness is treated with pentamidine in intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine in intravenous injection (50 mg/kg every six hours for 14 days [7]) in the second phase of the disease.[28]


Available forms and dosage

Vaniqa

Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.[29] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

Ornidyl

Ornidyl, intended for injection, is supplied in the strength of 200 mg eflornithine hydrochloride per ml.[30]


References

  1. ^ Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  2. ^ Pepin J, Milord F, Guern C, Schechter PJ ((1987).). Lancet 2 (8573): 1431–3. "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness". doi:10.1016/S0140-6736(87)91131-7. PMID 2891995. {{cite journal}}: Check |url= value (help); Check date values in: |year= (help); Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link) CS1 maint: year (link)
  3. ^ "Vaniqa US Patient Information Leaflet" (PDF).
  4. ^ "Ornidyl advanced consumer information". {{cite web}}: Text "Drugs.com" ignored (help)
  5. ^ {{Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}
  6. ^ Pepin J, Milord F, Guern C, Schechter PJ ((1987).). Lancet 2 (8573): 1431–3. "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness". doi:10.1016/S0140-6736(87)91131-7. PMID 2891995. {{cite journal}}: Check |url= value (help); Check date values in: |year= (help); Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link) CS1 maint: year (link)
  7. ^ Template:Vaniqa Training Programme Module 5
  8. ^ "IFPMA Health Initiatives: Sleeping Sickness".
  9. ^ "Sanofi-Aventis Access to Medicines Brochure" (PDF).
  10. ^ "Sanofi-Aventis Access to Medicines Brochure" (PDF).
  11. ^ "SAn effective colon cancer prevention treatment".
  12. ^ {{|author=Malhotra B, Noveck R, Behr D, Palmisano M. |title=Percutaneous absorption and pharmacokinetics of Eflornithine HCI 13.9% cream in women with unwanted facial hair. J Clin Pharmacol |year=2001; 41: 972-978.}}
  13. ^ {{|author=Azziz R. |title=The evaluation and management of hirsutism. Obstet Gynaecol 2003; 101: 995 -1007}}
  14. ^ {{|author=Blume-Peytavi U, Gieler U, Hoffmann R, Shapiro J, |title=Unwanted Facial Hair: Affects, Effects and Solutions. Dermatology. 2007; 215(2): 139-46}}
  15. ^ {{|author=Blume-Peytavi U, Hahn S, |title=Medical treatment of hirsutism. Dermatol Ther. 2008 Sep-Oct; 21(5): 329-39. Review}}
  16. ^ {{|author=Barth JH, Catalan J, Cherry CA, Day A. |title=Psychological morbidity in women referred for treatment of hirsutism. J Psychosom Res. 1993 Sep; 37(6): 615-9}}
  17. ^ {{|author=Jackson J, Caro JJ, Caro G, Garfield F, Huber F, Zhou W, Lin CS, Shander D, Schrode K, and the Eflornithine HCl Study Group |title=The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981}}
  18. ^ "NHS and UKMi New Medicines Profile" (PDF).
  19. ^ {{|author=Balfour JA, McClellan K. |title=Topical Eflornithine. Am J Clin Dermatol 2001; 2(3): 197-201}}
  20. ^ {{|author=Schrode K, Huber F, Staszak J, Altman DJ, and the Eflornithine Study Group |title=Evaluation of the long-term safety of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10-15 March, San Francisco; USA, Poster 294}}
  21. ^ {{|author=Schrode K, Huber F, Staszak, J, Altman DJ, Shander D, Morton J, and the Eflornithine Study Group |title=Randomized, double-blind, vehicle-controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10-15 March, San Francisco; USA, Poster 291}}
  22. ^ {{|author=Hamzavi I, Tan E, Shapiro S, Harvey l. |title=A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57(1): 54-59}}
  23. ^ {{|author=Hoffmann R |title=A 4-month, open-label study evaluating the efficacy of eflornithine 11.5% cream in the treatment of unwanted facial hair in women using TrichoScan. Eur J Dermatol 2008; 18(1): 65-70}}
  24. ^ {{|author=Hamzavi I, Tan E, Shapiro S, Harvey l. |title=A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57(1): 54-59}}
  25. ^ {{|author=Jackson J, Caro JJ, Caro G, Garfield F, Huber F, Zhou W, Lin CS, Shander D, Schrode K, and the Eflornithine HCl Study Group |title=The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981}}
  26. ^ "Sanofi-Aventis 2005 Sustainable Development Report" (PDF).
  27. ^ "Sanofi-Aventis Access to Medicines Brochure" (PDF).
  28. ^ "Sanofi-Aventis Access to Medicines Brochure" (PDF).
  29. ^ "Vaniqa US Patient Information Leaflet" (PDF).
  30. ^ "Ornidyl facts".
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