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Cure for fatal tropical disease, Oral treatment of Leishmaniasis

Max Planck Society : 18 February, 2000  (Technical Article)
Leishmaniasis, also known as 'kala-azar', 'black fever' or 'black sickness', is a widespread infectious disease in tropical or subtropical regions, which is spreading into Southern Europe. Cases of Leishmaniasis have also appeared in other European countries, for example several hundred per year in Switzerland. The death rate is high and alarming because of an increasing resistance against the classical therapy with antimonials.
A new cure for this fatal disease has been discovered in Göttingen/Germany by Prof. Hansjörg Eibl, Max Planck Institute for biophysical Chemistry, and Prof. Clemens Unger, a former member of the University Hospital. The possible help for millions of infected people comes from Miltefosine, a structurally simple molecule. Cure rates of nearly 100 percent have now been observed in patient studies in India.

Leishmaniasis is one of several names for various tropical diseases, which are caused by flagellates of the genus Leishmania. The parasites are transmitted by sandflies, blood-sucking insects of the tropical and subtropical zones. The manifestation of the disease may be visceral (kala-azar), mucocutaneous (American Leishmaniasis) or cutaneous (Aleppo boil). The incubation time varies from several weeks to months. More than 12 million people suffer from the disease, many of them even die as a result of the lack of a successful therapy. The main drawback of the different treatment strategies is the development of antimonial drug resistance in combination with the complicated intravenious administration.

The illness is predominantly found in tropical and subtropical zones, but is spreading to Spain, southern France, and Italy, reaching 88 countries world wide. Three hundred and fifty million people are currently living in endangered areas. About two million people are newly infected every year, of whom about 500.000 suffer from visceral leishmaniasis - a particularly serious, and without treatment, always fatal form of the disease. The number of those affected is increasing.

The disease has no geographical limit like malaria does and in the temperate zones of southern Europe leishmaniasis is on the rise. New reports look into the increasing expansion of leishmaniasis. Many people in Spain, for example, are infected with leishmania donovani. The disease remains latent and without symptoms. The pathogens live in the marrow and are kept under control by the immune system. However, if the immune system is weakend, for example by infection with the AIDS virus HIV, the leishmaniasis parasites reproduce in an explosive way. The pathogens enter the blood system and attack the liver, spleen and skin, which without treatment results in death. Every second leishmaniasis patient in Spain was diagnosed with AIDS. Therefore, experts predict that the number of leishmaniasis patients will increase with the expansion of AIDS.

There are various forms of leishmaniasis. A particularly dangerous and often fatal form is visceral leishmaniasis, which is caused by the pathogen leishmania donovani. The parasites live in the liver, spleen and marrow and reproduce rapidly. Without treatment the infection results in death. In addition to the visceral form, there are also various forms of cutaneous leishmaniasis ('oriental sores' or 'oriental buttons'), which cause skin ulcers and sometimes lead to a total disfigurement of the face. However, these forms usually heal by themselves and are not lethal. Sandflies of the Phlebotomus genus transmit the disease between humans, between animals and from animals to humans or vice versa. Typical symptoms of visceral leishmaniasis are fever, tiredness, and rheumatism along with general weakness which ends in a gradual but complete destruction of the liver and spleen. If left untreated, the patient will die in six to 24 months.

About 30 years ago scientists began to develop different vaccines against visceral leishmaniasis. Despite many attempts, they have remained unfruitful to this day. The success of any vaccine is contingent on the surface structure in the membrane. The pathogens of leishmaniasis are able to change their surface structure in the membrane at any time, eliminating any hope for a successful vaccine. Therefore, the usual form of treatment of leishmaniasis is still an intravenous therapy using highly poisonous antimony compounds, e.g. pentostam. According to Prof. Wernsdorfer (University of Vienna), 15% of the patients die from these injections, i.e. the therapy causes death in the advanced stage of the disease. In addition, patients are increasingly not reacting to the conventional poisonous antimonials. According to rough estimates, about 40% of the infected persons in India are already resistant to this therapy. Similar observations in Sudan support these reports. In recent years about 100.000 out of 300.000 patients have died in leishmaniasis epidemies. Reports of the organisation 'Medecins Sans Frontieres' are alarming. Despite heroic efforts, only 1000 patients have been treatable, far too few, due to the complicated intravenous form of therapy, which, even when applied, often fails due to resistance.

With this in mind, Dr. Barbara Herwaldt wrote an article called 'Miltefosine - The Long Awaited Therapy For Visceral Leishmaniasis?', which appeared in the December 1999 edition of the journal 'The New England Journal of Medicine'. In this article she explains miltefosine in detail - a new medicine for treating leishmaniasis - the first effective oral treatment ever. This drug first alleviates the pain of these people suffering from high fever and weakness and cures the disease within about four weeks. Taking a tablet a day with normal food will very probably defeat this fatal tropical disease.

The active substance miltefosine, its chemical name being hexadecylphosphocholine, has a simple molecular structure.

It was discovered in Goettingen by Prof. Hansjörg Eibl from the Max Planck Institute for biophysical Chemistry, and Prof. Clemens Unger, then working at the University Hospital and now at the Clinic for Tumor Biology at the Albert Ludwig University in Freiburg. They found it by studying the effect of structural modification in (alkyl)-lysolecithins on the antineoplastic activity of these compounds. Surprisingly, some of the compounds like hexadecylphosphocholine or octadecylphosphocholine were highly effective in animal models after oral application and therefore were prepared for clinical studies. In many years of work Eibl’s and Unger’s research groups have developed the world-wide first medicament that is based on the structure of a phospholipid molecule. It was also the first drug from a Max Planck Institute that gained official approval. Eibl and Unger then also tested miltefosine, which has now also been successfully used against skin metastases in breast cancer, for its effects against leishmaniasis and malaria in cell culture experiments and in animal tests.

Miltefosine showed good effects against leihmania donovani in the cell culture. However, its application in animal experiments was problematic. Injecting miltefosine intravenously, the most direct way, did not come into question, as doing this resulted in hemolysis and significant changes in the tissue. Neither was injecting it directly underneath the skin an alternative, because it caused extensive and intolerable ulcers and changes in the skin around the puncture point. In addition, the effect was almost worse than that of the treatment with the conventional antimonials.

Eibl and Unger finally found the solution to the problem in the oral intake of the substance, a simple method that was particularly ideal for treating leishmaniasis. Taking miltefosine via the alimentary canal works well. After some time high serum and organ levels of miltefosine are measurable, especially in the liver and the spleen, the destination organs for the fatal visceral leishmaniasis. This excellent concentration of the substance at the critical location is optimal for an effective treatment.

In systematic animal tests a group of infected animals was kept as an untreated control group and another group was treated with miltefosine. Two to three weeks after infection with leishmania donovani the control group presented the usual symptoms of the disease: an enormous enlargement of the liver and the spleen. The animals died after six weeks. In comparison with the control group, the group that was treated with miltefosine presented no symptoms at any stage of the experiment. Neither were parasites found in the liver and spleen of the test animals. Obviously, the parasites are not capable of living in the presence of miltefosine.

Now the decisive question arose whether animals of the control group with very serious symptoms, could be cured by treatment with orally given miltefosine. The results were exciting and very revealing: the typical symptoms of the disease, enlargement of the liver and the spleen - did actually disappear rapidly. In comparison with the conventional pentostam therapy, the effect of miltefosine was at least 600 times better, a result which no one had even dared to dream of after the negative experiences with the intravenous or subcutane administration method.

While conducting the animal tests, Eibl and Unger also gave miltefosine to cancer patients who weren’t yielding to treatment, to take orally. They were able to give 26 patients miltefosine in oral doses of 50 mg to 200 mg without any significant side-effects. That is equivalent to a daily intake of 0.8 to 3.3 mg per kg on the basis of an average body weight of 60 kg. This is the basis on which the doses for the oral therapy of leishmaniasis were determined. The studies began with daily doses of 50 mg, 100 mg, and 150 mg (0.8 to 2.5 mg/kg/day) in various clinical centres in India, the Kala-Azar Research Centre in Brahmpura, and at the Kala-Azar Medical Research Centre, Banaras Hindu University in Varanasi. The studies were introduced and supervised by staff of the Asta Medica, Frankfurt, and by the World Health Organisation in Geneva. In addition, a respected expert on leishmaniasis, Dr. Murray of the Cornell Medical College, New York, supervised the progress of the study and the analysis of the clinical results.

Studies that look into finding the right dosis of miltefosine for the most effective therapy were published by Jha et al., also in the 'New England Journal of Medicine' in December 1999. These scientists suggest a dosis of 100 mg per day over a period of four weeks. However, they say the dosis should be adapted to the body weight and not exceed 2.5 mg/kg/day. This dosis led to a success rate of 98%.

This means the first oral treatment method for an often fatal tropical disease has been found. The treatment is easy to apply and is convincingly effective. The likelihood is high that this new drug may be able to conquer and eradicate black fever.
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