Therapy Analysis - Leishmaniasis
Absence of research
Although the effects of leishmaniasis can be devastating, pharmaceutical companies are reluctant to fund research into a disease that occurs in economically poor areas. The current treatments, which have existed since the 1940s, are antimony-containing compounds such as meglumine antimoniate and sodium stibogluconate. These are very expensive (approximately US$150 per treatment) and so are not commonly provided by local health services. Furthermore, side-effects can be severe, and because it is expensive, most patients do not complete the course, which causes an increased rate of resistant disease. Alternatively, pentamidine or amphotericin B may be used, but the side-effects related to these drugs, which include heart problems, low blood pressure and high or low blood sugar, are even more severe, while the daily, often painful injection regime discourages patients still further.
There is no clearly defined pharmacological approach in treating leishmaniasis; however, the most commonly employed is permeability enhancement, which encompasses 23.1% of the compounds listed (Graph 1).
Drugs in development for leishmaniasis are shown in Table 1. Paromomycin, an ointment designed to treat the cutaneous form of leishmaniasis, has proved effective so far, along with aminosidine, both of which have a relatively low incidence and severity of sideeffects. Severe cases of resistant leishmaniasis are treated with the general antibacterial amphotericin B, which is also used for treating severe fungal and bacterial infections. Gilead Sciences and Fujisawa Healthcare have jointly developed a liposomal formulation, AmBisome, which is launched in France and the US, while BioDelivery Sciences' oral formulation is in preclinical studies.
Perhaps leading pharmaceutical company GlaxoSmith-Kline will supply a more imminent breakthrough. Its compound sitamaquine, a monthly oral treatment, is expected to reach Phase III clinical trials in 2007. GSK's vaccine, also in its pipeline, is extremely promising, as it would provide cost-effective protection for a whole population at risk. Funding for this highly-regarded project has been provided by the Bill and Melinda Gates Foundation since 2000, with an additional donation expected this year to further a 6 year development programme.
The newest drug launched for leishmaniasis, miltefosine, was originally launched for the treatment of skin metastases in breast cancer patients in Germany in 1993, and in other European countries and the Philippines in 2001. It wasn't until 2003 that the Indian government approved the launch of this drug under the name Impavido for use in patients with visceral leishmaniasis. It was heralded as a significant step, particularly as it was the first oral drug for this potentially fatal form of the disease. Swiftly following on from this was its launch in Colombia for all forms of the disease, and in the EU, also for the visceral form. In addition, in a Phase IV trial conducted in India, it showed similar cure rates and safety profile to preregistration trials in hospitalized patients, leading to the conclusion that it was suitable to integrate into a public use programme. The Ministry of Health in India estimated in 2002 that 70,000 treatments of this drug per year would be required to address the high infection rates, especially in highly endemic areas and those bordering Nepal and Bangladesh. It is hoped that these high demands will be met, and certainly an agenda is in place to ensure that they are. The intention is that miltefosine is distributed free-of-charge to district and primary healthcare clinicians and private clinics in endemic areas, initially through their existing systems for drug delivery, such as those used for leprosy and tuberculosis. The drug will be prescribed by doctors only and monitored for use and side-effects during the implementation phase.
..actual elimination of leishmaniasis is still a distant dream..Also reassuring to note is that the Kala Azar Elimination Programme, run by the Indian National Anti Malaria programme, is expected to amend the current drug policy for treating the disease, removing the use of antimonial compounds and amphotericin B and replacing them with miltefosine as a first-line treatment. It is planned to extend this programme to cover Nepal and Bangladesh. With this most recent development, it is hoped that leishmaniasis will eventually be eradicated. Many government officials are looking to utilise prevention methods that do not involve the elimination of potential animal reservoir species, such as dogs, and miltefosine has, to date, provided promise here too. The implementation of practical measures has also helped to control the disease and reduce its transmission. Insecticide spraying controls sandfly populations, whilst bednets impregnated with insecticide can be used in 'at risk' areas, and pyrethroid-impregnated collars for dogs are popular in some local communities to prevent the animals becoming reservoirs for the disease. Improved detection methods are also being investigated to support elimination programmes in the areas most severely affected. The use of generic, and thus cheaper, versions of other effective treatments in India is being considered for the poorest communities, so that they at least have the chance to complete a course of treatment.
But despite these methods, actual elimination of leishmaniasis is still a distant dream, and additional novel ideas can only be welcomed. One therapeutic area which has not been investigated is that of gene targeting: a study published in 2000 noted a relationship with mucosal leishmaniasis to tumour necrosis factors alpha (TNFα) and beta (TNFβ) and cutaneous leishmaniasis and the major histocompatability complex. We can only hope that in the future, this research and that currently underway will spell the end of this modern plague.
Rebecca Bridge
Pharmaprojects Analyst
