Research Network Natural Products against Neglected Diseases - ResNet NPND

Green medicine for the poorest of the poor

Neglected tropical diseases - The diseases of the poor

Neglected tropical diseases are a group of poverty-related diseases, often deadly or at least life-threatening, sometimes disfiguring, in all cases destroying life-quality. The World Health Organization currently recognizes 17 such diseases and estimates that at least 1 billion people world-wide suffer from at least one of them. Please take a few moments to learn about NTDs on the WHO website:  

http://www.who.int/neglected_diseases/diseases/en/

Since NTDs affect the poorest of the world’s population in many tropical countries, there is no economic interest to invest into research and development of new drugs. Furthermore, there is no public awareness of these diseases! That means: Even though most of them could be treated and even eradicated, their existence is perpetuated by disregard and neglect!

Neglected tropical diseases and the potential of natural products in developing new therapies

Many NTDs are infectious parasitic diseases caused by multicellular organisms (worms and related animals) or by unicellular parasites (protozoans). Some are also caused by bacteria and a few by viruses.

Bacterial infections can be treated successfully with antibiotics. Most people are not aware that most antibiotics, starting from Penicillins and Cephalosporins over Erythromycins and Streptomycins to the Tetracyclins and many others, are not synthetic chemicals but actually natural products, produced by bacteria and fungi. In fact, the “bacterial NTDs” can be treated with antibiotics which, however, are usually not available to those who suffer from these diseases. 

Treatment of viral infections with drugs is a very difficult task. Quite interestingly, however, the recently developed drugs against viral flu such as Tamiflu and Relenza were actually inspired by natural products. 

In case of most NTDs caused by worms (scientifically called “helminths”), efficient therapies exist (including natural product-derived drugs such as ivermectin) which are relatively safe to the patient and easy to use. In fact, many of these diseases would be easy to control, if the circumstances of daily life (access to clean water, hygienic environment) could be made available to the affected populations. 

Protozoan NTDs 

NTDs caused by unicellular “animal-like” parasites sometimes called “protozoans” (in fact they are only “animal-like” because they can move and “behave” more like animals than like plants; they aren't much more closely related to animals than plants, and even more distinct from animals than fungi) are among the severest (if untreated) and most dangerous NTDs. The organisms causing them are a particular type of protozoans called “Kinetoplastids” or, more specifically “Trypanosomatids”. There are two types of such pathogenic Trypanosomatids, namely, Trypanosoma and Leishmania. The former are the cause of Human African Trypanosomiasis (more popularly called “Sleeping Sickness”, caused by Trypanosoma brucei) and of the South American Trypanosomiasis called Chagas’ Disease (caused by Trypanosoma cruzi). Leishmania are a diverse group of closely related parasites causing various kinds of diseases subsumed under the term “Leishmaniasis” which can affect the skin, mucous membranes as well as the inner organs. These diseases are hardly known in the “western civilized world”. Existing drugs against the Trypanosomatid diseases are old (some were developed during colonial times!), usually quite toxic to the patients and in some cases simply not available or not applicable in remote rural areas where the diseases prevail.

Another “protozoan” tropical disease is Malaria, caused by parasites of another group, termed Plasmodium. Even though it is not on the WHO list of NTDs, because safe and efficient drugs actually exist (some of the most important ones being natural products), Malaria does represent a major problem for millions of people who do not have access to proper treatment. Increasing development of resistance of the causative parasite against existing treatments also calls urgently for new useful drugs in case of Malaria which is the reason why this disease is on the list of ResNet NPND.

 

Mycetoma

Mycetoma is a chronic, granulomatous, progressive and disfiguring inflammatory disease. It is caused by certain bacteria (e.g. Streptomyces somaliensis and Nocardia brasiliensis) or fungi (e.g. Madurella mycetomatis) and hence it is usually classified into actinomycetoma and eumycetoma, respectively.

The disease is usually manifested as a painless subcutaneous mass with sinus formation and purulent discharge that contains grains is pathognomonic of mycetoma. The mass may spread from the skin to involve deep structures, resulting in destruction, deformity, and occasionally it can be fatal. The foot and hand are the most frequently affected sites seen in 82% of cases (Madurella foot). In endemic areas, other parts of the body may be involved such as the knee, arm, leg, head and neck, thigh and perineum. No age is exempted in mycetoma; however, it occurs more frequently in young adult men in the age range 20–40 years and almost 30% of reported patients were young students.

The worldwide distribution of mycetoma varies widely; it is endemic in many tropical and subtropical regions and prevails in the mycetoma belt, which stretches in a band from the latitudes of 15°S to 30°N. The belt includes the countries of Sudan, Somalia, Senegal, India, Yemen, Mexico, Venezuela, Columbia, Argentina, and a few others. The African continent seems to have the highest burden and prevalence of the disease. It has also been extensively reported from India. However, mycetoma has been reported in many temperate regions as well. There are a few reports on mycetoma from the USA, Sri Lanka, Germany, Egypt, Turkey, Philippines, Japan, Lebanon, Thailand, Saudi Arabia, Morocco, Tunisia and Iran.

Globally, only two large epidemiological studies have been performed to estimate the disease prevalence. These studies were performed by Abbott in Sudan during the period 1952–1955 and accordingly the estimated prevalence in Sudan was 4.6 per 100,000 inhabitants whiles it was estimated in Mexico (between 1956 and 1985) by Lopez Martinez and colleagues to be 0.6 per 100,000 inhabitants . This grossly underestimated prevalence is comparable to those from other neglected tropical diseases such as Buruli ulcer, African trypanosomiasis, dracunculiasis and leprosy. Surprisingly, Mycetoma is not yet included among Neglected Tropical Diseases. Nevertheless, mycetoma has very recently recognized by the Neglected Tropical Department/WHO as a neglected disease (WHO 2013).

Currently, the mean antifungal treatment duration for eumycetoma is one and half year and treatment is associated with serious side effects beside it is not affordable to a wide segment of patients in endemic areas. This was further aggravated by the disappointingly poor treatment outcome which is characterized by low cure rate and high recurrence rates which eventually lead to amputation. Therefore, there is an urgent need for novel effective and potent antifungals for eumycetoma.