Ефлорнитине: Ұйықтау ауруы мен шаш өсуін емдеуге арналған дәрі

Chemical compound

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the second stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously (injection into a vein) or topically. It is on the World Health Organization's List of Essential Medicines. In the United States the injectable form can be obtained from the US Centers for Disease Control and Prevention.

Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets. Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second stage sleeping sickness Trypanosoma brucei gambiense. Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite's low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense. Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox eflornithine combination was the most promising first line theory regimen. A randomized control trial was conducted in Congo, Côte d'Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7 day intravenous regimen was as efficient as the standard 14 day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease. Nifurtimox eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.

After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host. The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes. If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients. It is the only topical prescription treatment that slows the growth of facial hair. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. Positive results were seen after eight weeks. However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks. Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.

In the US, eflornithine is indicated to reduce the risk of relapse in people with high risk neuroblastoma. Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses. Adequate and well controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus. No teratogenic effects have been detected.

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

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 U. S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.

The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990. In 2001, 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 Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders) in countries where sleeping sickness is endemic. According to Médecins sans Frontières, this only happened after "years of international pressure," and coinciding with the period when media attention was generated because of the launch of another eflornithine based product (Vaniqa, for the prevention of facial hair in women), 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, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission among others, is currently the only topical prescription treatment that slows the growth of facial hair.

It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells. However, several clinical trials demonstrated minor results. It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited. This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder. Bacchi et al. 1980 found the drug to be curative in T. b. brucei infection of mouse and it is generally without toxicity. Klug et al. 2016 are of the opinion that this demonstrates good promise for oral treatment. However although Jansson et al. 2008 also effectively treated mice with it they found the pharmacokinetics of oral administration in rats very negative. Brun et al. 2010 are of the opinion that Jansson's results have killed the prospects for oral treatment.