Tegumentary leishmaniasis: researchers develop biocurative for less painful treatment
Treatment of leishmaniasis still has medications with potentially serious adverse effects10/09/2022
Considered a Neglected Tropical Disease (NTD) by affecting vulnerable populations, cutaneous or integumentary leishmaniasis is classified as a public health problem in Brazil. In 2019, 15,484 new cases were confirmed in the country, with a detection coefficient of 7.37 records per 100 thousand inhabitants, according to data from the Ministry of Health. The disease causes skin lesions with various clinical characteristics, from lesions with slow healing to permanent scars, resulting in social stigma and psychological disorders that negatively affect the quality of life of affected people.
Without treatment, the disease can have quite serious consequences. However, the treatment of cutaneous leishmaniasis depends on multiple injections of antimonate derivatives, which is already a problem, since the disease affects people living in rural areas far from urban centers, and who will need to travel daily for 20 to 30 days to take the injections. Currently several alternative therapies are under development in view of the challenges of antimoniate derivatives, which include injection site pain, high cost, adverse effects, variable efficacy, drug resistance. In addition, a treatment in which it is not necessary for the patient to undergo toxic treatments in hospitalizations and that can be applied at home, would be one of the greatest benefits that would directly impact the lives of those who suffer from skin lesions caused by cutaneous leishmaniasis.
The team of Dr. Camila Indiani, from Fiocruz Bahia, together with collaborators in the field of chemistry and clinical research, has carried out studies with the bandage based on Bacterial Cellulose (CB), a nanomaterial produced by gram negative bacteria, of various species of the genera Acetobacter, Pseudomonas, Achromobacter, Alcaligene, Aerobacter and Azotobacter. The researcher explains that structurally, BC is formed by a network of cellulose fibers composed of microfibrils, has high purity, high water content and excellent mechanical property, characteristics relevant to its practical application. Also according to her, BC is an ideal candidate to be tested as a biocurative, as it presents biocompatibility, absence of toxicity and favors healing. “Thus, the BC is indicated for the treatment of minor traumas, burns, among others. It can also be employed as a sustained release system, that is, drugs can be formulated in the CB, associating their healing properties with a microbicidal compound, for example,” she points out.
In this context, the team of Dr. Indiani, in collaboration with Dr. Hernane Barud, from the University of Araraquara (Uniara), conducted tests with diethyldithiocarbamate (DETC), a superoxide dismutase inhibitor. “Initially, we performed tests in the laboratory, in vitro systems, and then in a preclinical model of Leishmania infection, involving mice. In these trials, we showed that DETC associated with BC reduced the parasite load and negatively impacted the development of the lesion”, he signs. Still according to Dr. Indiani, these results motivated a pilot trial, proof of concept, in patients with cutaneous leishmaniasis, treated in the area of Corte de Pedra, municipality of Tancredo Neves, Bahia. “In collaboration with Dr. Edgar Carvalho (FIOCRUZ/BA) and his team, we recruited patients with CL caused by L. braziliensis to participate in a study whose objective was to evaluate the effectiveness of using a biocurative containing DETC as an adjunct to Glucantime (Sanofi-Aventis) in the treatment of CL, ” she adds. Efficacy was assessed by cure rate and cure time was also determined.
From the pilot trial, proof of concept, it was observed that 60 days after the beginning of treatment, the cure rate was 22% (2/9) in patients treated with Glucantime, 80% (8/10) in the group treated with Glucantime + biocurative and 70% in the group treated with Glucantime + Biocurative containing DETC. After 90 days, the cure rate was 55% (5/9) in the Glucantime group and remained at 80% (8/10) in the other two groups.
“These results showed that patients treated with BC (with or without DETC), in association with Glucantime, had a significantly higher cure rate. Although the presence of DECT did not increase the cure rate or cure time, the use of topically applied biocurative on skin lesions had a positive impact, significantly increasing the cure rate. Again, this was a small essay, proof of concept, but with very promising results”, celebrates Dr. Indiani.
Asked about the advantage of the biocurative in relation to conventional treatment, the researcher clarifies that the biocurative does not have an action to kill leishmania and thus should always be used with a leishmanicidal drug. The scientist recalls that the first choice treatment in Brazil is still pentavalent antimonial, applied intravenously, associated with side effects, and which cannot be applied in pregnant women. “Failure to treat with this drug (Glucantime) has increased and, today, about 50% of patients treated with CL do not present cure with a course of the drug. In addition, the cure time is between 60 and 120 days”, she points out while saying that the main effect of the biocurative is to reduce the cure time of the disease by mechanisms associated with wound healing. She also recalls that it was evaluated as an adjunct to treatment with Glucantime at the recommended dose.
As the pilot trial showed that the application of the biocurative itself already brings benefits to the patient, it is possible to associate other drugs with microbicidal activity for a topical treatment of CL. Another advantage of the biocurative is that it can be handled by the patient. However, in the study, the team chose to make the replacements at the health center. Asked about when the biocurative may be available, Dr. Indiani informs that a larger study with more patients is still needed to prove the effect of the biocurative in increasing the cure rate and also in reducing the cure time of the disease. Finally, she emphasizes that any new treatment strategy that has fewer side effects, is effective and can be managed autonomously by the patient will be revolutionary. The scientific community is committed to reaching these solutions and the biocurative is an alternative that she and her team are testing.
Cutaneous leishmaniasis is the most common form of leishmaniasis and is endemic in about 90 countries worldwide, with new cases reaching between 600 thousand and 1 million annually. According to the World Health Organization (WHO), more than 90% of the cases reported in 2019 were from Afghanistan, Algeria, Brazil, Colombia, the Islamic Republic of Iran, Iraq, Libya, Morocco, Pakistan, Peru, the Syrian Arab Republic and Tunisia. The disease is also known by the names of “Bauru ulcer”, “tapir nose”, “oriental button” and “angry wound”.
“A pilot and open trial to evaluate topical Bacterial Cellulose bio-curatives in the treatment of cutaneous leishmaniasis caused by L. braziliensis”
“DETC-based bacterial cellulose bio-curatives for topical treatment of cutaneous leishmaniasis”
In addition to the biocurative, other alternative forms of treatment have also been developed, including cryotherapy (with nitrogen), photodynamic therapy, allopurinol and miltefosine + thermotherapy combination. Topical amphotericin B is already in a very advanced stage and presents two formulations: one water-soluble, very toxic, and another, in fat particles, called nanoparticles, for hospital use and the presentations are quite expensive. Treatment with amphotericin B may be intravenous (IV) or intramuscular (IM). The use of intralesional glucantime and thermotherapy are already recommendations of the Ministry of Health and the Pan American Health Organization (PAHO). However, traditional IV and IM treatment used in Brazil as glucantime, an antimony of high toxicity, was probably responsible for many deaths of people who had only skin disease.
As we can see, there are several alternatives and the treatment of cutaneous leishmaniasis is not necessarily done by intravenous drugs. There is also no justification for Brazil to continue giving priority to parenteral treatment. We need to invest more and more in topical treatment, whether chemical, with these drugs, antibiotics or heat treatment.