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Leishmaniasis. Patient’s needs driven R & D Agenda. Increasing Devastation of Leishmaniasis. 88 countries in tropical and temperate regions 72 of them developing or least developed Two million cases occur annually About 350 million people are at risk prevalence of 12 million - PowerPoint PPT Presentation
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Patient’s needs driven R & D Agenda
Increasing Devastation of Leishmaniasis 88 countries in tropical and temperate regions 72 of them developing or least developed Two million cases occur annually About 350 million people are at risk prevalence of 12 million human leishmaniasis is on the increase worldwide
—Outbreaks in New areas—Disease moving towards urban areas —Increase in the number of cases in VL & CL—100,000 died of 280,000 in Sudan in 80s
Pentavalent Antimony Pentavalent antimonials (Sbv) have been the
mainstay of all forms of leishmaniasis for seven decades
Branded products and generic products are similar in safety and efficacy
Antimony remains the most important antileishmanial compound in the world for all forms of leishmaniasis
However, toxicity profile of antimony warrants search for safer drugs to replace it as first line drug in other parts of the world as well as least for VL
Antimony toxicity Serious and fatal antimony toxicity not
infrequent even with standard products (3-6% deaths in VL) Ahasan et al 1996, Bangladesh; Thakur et al, 1998; Sundar et
al, 2000, India; Moore et al 2001, Kenya; Singh et al; 1989, India; Delgado et al, 1999, Spain 12% )
Cardiotoxicity (Thakur et al, 1998, India; Laguna et al, 1999, Spain; Ribiero
et al, 1999 Brazil; Sundar et al, 2000, India) Pancreatitis especially in HIV co-infected
(Aronson et al 1998, US military, Delgado et al, 1999, Spain, Gasser et al, 1994 [CL]Peru;)
Drug Failure in India Indian Epidemic is unique where large
scale primary antimony & pentamidine failure has occurred
Once the resistance is established, it escalates rapidly due to anthroponotic nature of transmission
Evidences suggest emergence of antimony refractory strains in India
Response to Antimony Therapy in Indian Kala-azar
0
20
40
60
80
100
70s 80s 92-93 94-97Years
Perc
enta
ge C
ure
Rate
10 mg/Kg20 mg/Kg
Impact of Antimony Resistance
Sb was the only affordable drug in India
(Cost for 50 kg Patient – US $ 35)
Very few can afford anything priced above
Delayed or no cure leading to increased
morbidity and mortality
Amphotericin B Effective but toxic drug Use restricted to hospitals Prolonged hospitalisation of 5-6
weeks Expensive (Drug cost – 5 thousand) Clinical & lab. Monitoring is required Not affordable for most patients
Lipid Associated Amphotericin B in Kala-azar
Important advance in chemotherapy Deoxycholate replace by other lipids Drug accumulates in RE system, no organ
toxicity Extremely attractive, few side-effects High dose over short period can be given Shorter courses
Reduce the hospitalization cost Possible to treat larger number of
patients
Lipid Amphotericin B Not much to choose in terms of efficacy AmBisome is safest, nearly free of adverse
events and followed by Abelcet > Amphocil Can be used in presence of renal or hepatic
insufficiency, in very sick patients Commercial formulations (cost for a 15 mg/kg
dose for 50 kg person) – Market retail price AmBisome, Gilead, USA (US $ 3000.00) Abelcet, Liposome co, USA(US $ 1700.00) Amphocil, Intermune, USA (US $ 2200.00)
Paramomycin (Aminosidine)• An aminoglycoside (parenteral)• Good antileishmanial activity, earlier used for
bacterial & Parasitic infections• In several phase II studies 16 mg/kg for 3 weeks
cured 93% VL patients• Will be licensed after the ongoing multicenter
Phase III trial results ( dose 15 mg/kg x 21 days)• Safe, Good alternative to antimony as first line
Tt • Likely to be produced in India• Could be the cheapest antileishmanial drug (~
10-15 US$)
Miltefosine -• First oral drug for leishmaniasis• Approved in India, Germany & Colombia• Dose: 100 mg (>25 kg); 50 mg (<25 kg); Children
2.5mg/kg, Duration: Four weeks • Long term cure rates 94%• Side – effects:
• Vomiting occurs in ~40%, diarrhea in ~20%. • Skin allergy, nephrotoxicity are occasionally seen
• Can not be used in pregnant females [teratogenic], and those refusing contraception (for the treatment period and another two months)
• Cost – US$ 145.00, Freely available over the counter in India
Future Needs Limited therapeutic options available More drugs (better, safer & cheaper) are
needed Cheaper lipid amphotericin B needed
preferably AmBisome Combination multidrug treatment
urgently needed especially for Indian subcontinent, eventually globally
Short duration therapy to improve compliance & prevent resistance
Access is important – Drug should be free to patients
Miltefosine is an example – No access to poor patients