[Leish-l] miltefosine for diffuse leishmaniasis

Pierre BUFFET pierre.buffet at upmc.fr
Fri Jul 8 16:37:23 BRT 2011


Anthony,


because there are only a few options left, would you consider at one  
point low dose pentamidine (3 mg/kg every week or so, as you did in  
DCL patinets in Ethiopia in the 70s if I remember)? Could be used  
either to stabilize the situation before starting on a  
coadministration, or as a maintenance after the co-administration, in  
both cases with careful monitoring of kidney function ?

Pierre


  Anthony Bryceson <a.bryceson at doctors.org.uk> a écrit :

> 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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