[Leish-l] miltefosine for diffuse leishmaniasis

[Anthony Bryceson]

Dear Carlos
As you are well aware DCL is very difficult to treat. The big problem is that the defect in specific CMI is more profound than that in VL and may never recover, in contrast with the defect in VL which bounces back quickly. 

To have any chance of curing the patient, treatment  should be monitored by quantitative slit skin smears (as for splenic aspirates in VL) from multiple pre-selected sites, every week or two weeks, and treatment continued until negativity and for some weeks or months longer.  When slit skin smears become negative, hunt for any nodular or infiltrated lesions and take deep biopsies and look for amastigotes there. Keep on hunting and smearing. Sometimes, at the end of all this, evidence of CMI may appear, and cure becomes a possibility. I am sure that the method of treating is more important than the choice of drug - so long of course that the parasite is susceptible to the drug.

Hannah Akuffo has sent you the abstract relating to 3 patients treated by Sabawork Teklemariam in Addis Abeba. That article details this approach.

Do you know the species of Leishmania causing Maria's DCL, and its sensitivities? In Addis Abeba parasites were cultured from two of the patients and sensitivities determined and isobolograms drawn to look for synergy. The isolates were sensitive to paromomycin and sodium stibogluconate was synergistic. It would be worth while to make cultures before you start any new treatment and have the isolate tested in this way. I expect that you have a lab that could do this; if not, Simon Croft might be able to advise.

Miltefosine has been very successful in a number of situations in South American CL and showed promise for DCL,  but patients relapsed despite prolonged treatment. 
1. Zerpa O, Ulrich M, Blanco B, et al. Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses. Br J Dermatol. 2007;156:1328-1335.

In a few patients with VL-HIV confection whom I treated in London, miltefosine worked well at first, but the patients relpased while still on treatment and drug resistance was supected but not tested. Miltefosine has a pharmacokinetic profile with a long tail that might make it susceptible to the devlopment of resistance, especially if the therapeutic window for a given isolate was narrow. So you might want to think about adding a second drug to go with miltefosine from the beginning. I am not sure what might be the best drug for combination; perhaps Josh Berman might have an opinion. It is of course essential to ensure contraception.

You could also consider the combination of paromomycin and low dose SSG. In view of Maria's poor renal function you might need to modify the dose of paromomycin and to monitor function.

Robert Vinson is CEO of Paladin Labs, and would I am sure help you locate miltefosine. <rvinson at paladin-labs.com>

Richard Chin is CEO of One World Health,  and would, I am equally sure, help you locate paromomycin, should you consider that path.  http://www.oneworldhealth.org/contact-us  Phone: +1 415-421-4700 Fax: +1 415-421-4747

I wish you and Maria all the best in this venture.
Anthony


Dear Jennie
Immunotherapy proved rather disappointing in VL. It seems that the patient needs a decent immune response in the first place to benefit from immuno-boosting. 
Sadly
Anthony


On 6 Jul 2011, at 20:04, Carlos Costa wrote:

> Dear all,
> 
> Maria Cleudimar has cutaneous diffuse leishmaniasis due to Leishmania amazonensis. She used to be a long time patient form Dr. Jackson Costa, in the countryside of Maranhão State, Brazil, since she was 10 years old, after a disease that started when she was just five. Now, she is under my and Dorcas care, at the age of 30, living in the city of Teresina.
> 
> Her long time DCL does not respond to the treatment antimonium anymore. Although we still prescribe liposomal amphotericin B at very low dose (3mg/kg/once a week), her situation is deteriorating progressively, her renal function does not allow any additional dosing since creatinine is presently above 3mg/dL, and previous biopsy had shown tubular damage apparently secondary to the drug, without evidence of amyloidosis. We tried several combinations of different drugs, without success. Her situation worsened a lot during her recent pregnancy (the baby is eight months old now).
> 
> Our hope now stands only in miltefosine, for oral chronic use, but the drug is not licensed or available in Brazil yet (to my knowledge).
> 
> With her permission I attached some of her pictures, hoping to sensitize critical people in order to help me to get miltefosine and the permission for prescription in Brazil (or any other oral drug with promising efficacy, and without nephrotoxicity, if known). Moreover, we need to know about the dose adjustment for the renal impairment, and how long the drug could safely be used.
> 
> One picture shows her face before treatment, and another after the pregnancy, with the baby. One shows the situation of her thighs, another the calf of the leg and the last one the infiltration of the palate.
> 
> Hoping a little from friends, my kindest regards,
> 
> Carlos.
> 
> PS. Please understand that the pictures are allowed not for publication or public presentation. Cleudimar permission is restricted to this forum.
> 
> 
> -- 
> Carlos H. N. Costa, MD, DSc.
> President
> Sociedade Brasileira de Medicina Tropical 
> (Brazilian Society of Tropical Medicine)
> Instituto de Doenças Tropicais Natan Portella
> Universidade Federal do Piauí
> Rua Artur de Vasconcelos 151-Sul
> 64049-750 Teresina-PI
> Brazil
> Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).
> 
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