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SPECIAL REPORT: AT LAST, DFMO MOVES TO THE FRONT OF THE LINE
By Ann G. Sjoerdsma, © Aug. 28, 2008

Starting with SerotoninMore than twenty-five years after it first cured patients stricken with deadly West African sleeping sickness, Médecins Sans Frontières (MSF) physicians have blessed the Sjoerdsma research team’s DFMO as the drug of choice for treatment of the late-stage parasitic disease. (1)

Not only is MSF (Doctors Without Borders) recommending that DFMO, also known as eflornithine, replace the highly toxic and increasingly ineffective arsenical, melarsoprol, which has been in front-line use against trypanosomiasis since 1949, but it is also promoting DFMO combination therapy in order to protect “The Resurrection Drug” from trypanosome resistance.

By 2010, writes Francesco Checchi, formerly with MSF and now at the London School of Hygiene and Tropical Medicine, DFMO, administered with the Chagas disease drug, nifurtimox, “could become the therapeutic mainstay.” (2)

African trypanosomiasis is transmitted to humans by the bite of an infected tsetse fly. Left untreated, the disease is always fatal. West African trypanosomiasis, which is caused by the Trypanosoma brucei (T. brucei) gambiense strain of trypanosomes, becomes life-threatening in the late or meningoencephalitic stage, after the parasites have crossed the blood-brain barrier. Patients with central nervous system infection can appear somnolent, hence the disease’s characterization as sleeping sickness. DFMO earned its resurrection nickname because it dramatically revives sufferers in near-death comas.

Starting with Serotonin author Ann G. Sjoerdsma recently interviewed Dr. Cyrus Bacchi, the Pace University biochemist who discovered DFMO’s trypanocidal effect in mice infected with an animal strain of the parasite. (3)

According to Bacchi, “Eflornithine is now the first-line drug, and melarsoprol is used only in situations where they [MSF doctors] can’t get it. . . . It has a greater than 90 percent success rate with low relapse and low toxicity. Melarsoprol doesn’t compare.”

Although synthesized in 1973 by Dr. Philippe Bey at the Centre de Researche Merrell International in Strasbourg, France, under the direction of Dr. Albert Sjoerdsma, DFMO did not “find its use” against tryps until Bacchi obtained a sample of the compound from Dr. Peter McCann, Merrell’s liaison to outside researchers, and tested it.

Adopting a “scorched-earth approach” to DFMO’s development, Sjoerdsma, who later became president of the former Merrell Dow Research Institute, freely supplied hundreds of scientists with compound upon their request. Initially showing promise as an anti-cancer agent, DFMO irreversibly inhibits the enzyme, ornithine decarboxylase, which is critical to the formation of polyamines, chemical components of cell growth. Polyamines are, in turn, critical to the physiology, the replication, of trypanosomes.

“If you stop ornithine decarboxylase in trypanosomes, you stop trypanosomes,” says Sjoerdsma.

(Starting with Serotonin captures the exciting play-by-play of DFMO’s synthesis, research, and development, from the lab to the clinic to the African bush, and beyond to its 1990 FDA approval as the orphan drug, Ornidyl®.)

It has been known since the 1970s that melarsoprol induces an encephalopathy that kills between 3 and 10 percent of all patients who receive it. More recently, the European drug has proved to be alarmingly ineffective in trypanosomiasis-endemic areas, such as Angola, the Democratic Republic of Congo, Sudan, and Uganda—with a failure rate approaching 30 percent. (4) Melarsoprol’s relapse rate is similar, says Bacchi, who participates in Drugs for Neglected Diseases Initiative (DNDi), a non-profit health consortium dedicated to developing new drugs.

Why did it take so long for melarsoprol’s obviously tarnished star to fall and for DFMO’s to rise? Bacchi speculates that “Clinicians [in the field] become entrenched,” preferring to use drugs that they’ve always used, and “they believe that Americans can’t develop a drug for tropical diseases.”

DFMO also lost its champion, after Sjoerdsma was forced into retirement and emeritus status at age 65 in 1989, and Marion Laboratories bought Merrell Dow. The newly organized Marion Merrell Dow immediately sought to unload the humanitarian, but unprofitable “Third World” drug, offering to transfer it to the World Health Organization, which, over ten years, repeatedly stumbled in efforts to find an alternate producer. In the 1990s, with serious lapses in disease surveillance because of civil war, government incompetence, and benign neglect by the WHO, the incidence of T. brucei gambiense trypanosomiasis soared to 300,000. Today, the WHO estimates that 50,000 to 70,000 new cases occur annually.

The World Health Organization, which supports MSF’s endorsement of DFMO, long argued that the Merrell drug was too expensive and difficult to administer in Africa because of its protocol: four intravenous infusions per day for fourteen days. But, compared to Western standards, the per capita expense for DFMO was always minimal: about $140 in 1990 and $600 in 2000.
 
Currently, MSF doctors are responsible for the supply and distribution of all African trypanosomiasis drugs, which the Paris-based international pharmaceutical company, Sanofi-Aventis, by virtue of corporate merger, now owns and donates. A five-year pact between Sanofi-Aventis and the WHO guarantees that MSF will receive free kits with the requisite supply of DFMO through 2011.

Sjoerdsma has contended that an exclusively oral form of DFMO should work just as well as an intravenous form and would eliminate some of the problems associated with infusions (e.g., continuous nursing care). But WHO attempts to establish an oral protocol never panned out, and attention has shifted to combination therapy. When combined with nifurtimox for ten days, clinical trials suggest that patients need only one week of DFMO infusions twice a day. (5)

“Years ago, we told them [the WHO] to use a combination, but they didn’t listen,” says Bacchi.

Epidemiologist Dr. Gerardo Priotto, of MSF’s Epicentre headquarters in Paris, oversaw the study that significantly boosted DFMO’s first-line status. Priotto and his team analyzed a much larger patient cohort than those in previous studies: 1055 adults and children newly diagnosed with stage-two T. brucei gambiense trypanosomiasis in MSF’s Sudan program. Patient followup varied between one and two years. (6)

Priotto also has pushed for DFMO-nifurtimox combination therapy, announcing in 2006 that with the simpler and safer treatment it permits, “Countries should not settle for a drug [melarsoprol] that kills one out of every twenty patients.” (7) 

“DFMO forever,” says Sjoerdsma.

Notes:

1) The principal MSF report is Gerardo Priotto, Loretxu Pinoges, Isaac Badi Fursa, Barbara Burke, Nathalie Nicolay, Guillaume Grillet, Cathy Hewison, and Manica Balasegaram, “Safety and Effectiveness of First Line Eflornithine for Trypanosoma brucei gambiense Sleeping Sickness in Sudan: Cohort Study,” British Medical Journal 336 (March 29, 2008): 705-8. Francesco Checchi and Michael P. Barrett summarize the Priotto et al study in their editorial, “African Sleeping Sickness: Eflornithine should be the drug of choice for stage 2 disease, but resistance must be monitored,” British Medical Journal, ibid, pp. 679-80.

See also J. Robays, M.E. Raguenaud, T. Josenando, and M. Boelaert, “Eflornithine Is a Cost-Effective Alternative to Melarsoprol for the Treatment of Second-Stage Human West African Trypanosomiasis in Caxito, Angola,” Tropical Medicine and International Health 13 (Feb. 2008): 265-71; Francois Chappuis, “Melarsoprol-Free Drug Combinations for Second-Stage Gambian Sleeping Sickness: The Way to Go,” Clinical Infectious Diseases 45 (Dec. 2007): 1443-5; Manica Balasegaram, Steve Harris, Francesco Checchi, Sara Ghorashian, Catherine Hanel, and Unni Karunakara, “Melarsoprol Versus Eflornithine for Treating Late-Stage Gambian Trypanosomiasis in the Republic of the Congo,” Bulletin of the World Health Organization 84 (Oct. 2006): 783-91; and Francois Chappuis, Nitya Udayraj, Kai Stietenroth, Ann Meussen, and Patrick A. Bovier, “Eflornithine Is Safer Than Melarsoprol for the Treatment of Second-Stage Trypanosoma brucei gambiense Human African Trypanosomiasis,” Clinical Infectious Diseases 41 (Sept. 2005): 748-51.

2) See Checchi and Barrett, note 1, above, at 680. Nifurtimox is taken orally and sold by Bayer as Lampit®. When given alone, nifurtimox has limited effectiveness against African trypanosomiasis, but it is useful in acute-phase Chagas disease, also called American trypanosomiasis. Although common in South America, Central America, and Mexico, Chagas disease, which is transmitted to humans through the feces of an infected reduvid bug, has spread in recent years to the southern United States. In its chronic phase, it can cause serious heart and digestive problems.

3) The breakthrough article on DFMO in trypanosomes was C.J. Bacchi, H.C. Nathan, S.H. Hutner, P.P. McCann, and A. Sjoerdsma, “Polyamine Metabolism: A Potential Therapeutic Target in Trypanosomes,” Science 210 (1980): 332-4. Many other papers tracking DFMO’s progress are documented in the endnotes to Starting with Serotonin, chiefly chapters 19 and 25.

4) See, e.g., Jo Robays, Gaspard Nyamowala, Claude Sese, Victor Betu Ku Mesu Kande, Pascal Lutumba, Wim Van der Veken, and Marleen Boelaert, “High Failure Rates of Melarsoprol for Sleeping Sickness, Democratic Republic of Congo,” Emerging Infectious Diseases,June 2008, available at http://www2a.cdc.gov/EID/content/14/6/966.htm.

Melarsoprol also causes liver toxicity, severe enterocolitis, and diffuse peripheral neuropathy.

5) Reports on DFMO-nifurtimox combination therapy include:

    • G. Priotto, S. Kasparian, D. Ngouama, “Nifurtimox-Eflornithine Combination Therapy for Second-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo,” Clinical Infectious Diseases 45 (2007): 1435-42.
    • Francesco Checchi, Patrice Piola, Harriet Ayikoru, Florence Thomas, Dominique Legros, and Gerardo Priotto, “Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series,” Public Library of Science [PLoS] Neglected Tropical Diseases 1 (2007): e64, available online at http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000064.
    • Gerardo Priotto, Carole Fogg, Manica Balasegaram, Olema Erphas, Albino Louga, Francesco Checchi, Salah Ghabri, and Patrice Piola, “Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda,” PLoS Clinical Trials 1 (2006): e39, at http://clinicaltrials.ploshubs.org/article/info:doi/10.1371/journal.pctr.001003.

6) See Priotto et al, “Safety and Effectiveness of First Line Eflornithine for Trypanosoma brucei gambiense Sleeping Sickness in Sudan: Cohort Study,” cited in note 1, above.

7) Priotto’s quote appeared in a Médecins Sans Frontières press release, Nov. 15, 2006, “New Study Shows Potential for Shorter and Safer Sleeping Sickness Treatment,” at http://www.doctorswithoutborders.org/pr/release_print.cfm?id=1890.

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