Leishmania

Leishmania

THE DISEASEPREVALENCETREATMENT AND DIAGNOSISLINES OF RESEARCHRESEARCH TEAMPUBLICATIONS

THE DISEASE

Leishmaniasis is a disease caused by a Protozoan parasite of the Leishmania genus, with more than 20 different species. It is transmitted to humans by the bite of an infected female sand fly. The disease can have three clinical manifestations: visceral (the more serious, known as kala-azar, which can be fatal), cutaneous (the most common) and mucocutaneous.

The ISTUN lines of research focus on the design of new compounds, elaboration of strategies for more effective pharmaceutical formulations, as well as the search for new therapeutic targets and the improvement of diagnostic techniques.

PREVALENCE

According to WHO (WHO 2013), there is an estimate of 1.3 million new cases per year, and 20-30 thousand deaths.  However, this data is probably underestimated, since many cases are not diagnosed and the number of people infected but asymptomatic is greater than the evident cases.  The disease is associated with environmental changes, malnutrition, population displacements, poor housing and weakness of the immune system. It affects the poorest people on the planet and is present at the Mediterranean basin (including Spain), South-East Asia, East Africa and Latin America. It is important to note that Spain is the country of the Mediterranean basin with greater reporting of cases of co-infection with Leishmania and HIV/AIDS, in which patients present a clinical picture that is indistinguishable from that observed in patients infected with Leishmania alone.

Treatment and diagnosis

Leishmaniasis treatment depends of several factors: the presentation of the disease, the species of Leishmania that produces it and the geographic location in which it is present. Currently there is a set of relatively effective drugs available but they are not exempt of disadvantages such as the emergence of resistance, difficult administration and high toxicity. Today, it is a priority to identify therapeutic targets, design and develop new drugs that can be administered by oral or topical route which should be less toxic and less expensive.

In terms of diagnosis, it includes, among others invasive tests as well as the study of clinical manifestations of the development of the disease.  However, clinical manifestations in the case of cutaneous leishmaniasis are nonspecific and may be confused with other diseases with cutaneous involvement. In addition, especially in the visceral form, many infected patients are asymptomatic, hence the importance of an early diagnosis to detect the presence of parasites in these individuals.

Lines of research

  • 1. New formulations

    Our line of research studies the possibilities of using pharmaceutical formulation (nanoparticles) strategies to solve some of the problems of current leishmaniasis treatments. Nanoparticles can enable drugs to be effective at lower and less toxic doses by directing them to the target in a selective manner, since they are naturally captured by macrophages that also harbour parasites. In addition, they can also allow treatments to be administered orally or topically to favour drug crossing of the different biological barriers.

    Concretely we study:

    • The relationship between the physical-chemical properties of nanoparticles (material and surface charge) and its ability to activate macrophages and thereby eliminate parasites. This combines the chemotherapy of the drug transported with its inmunostimulating capacity. It also permits the use of nanoparticles as vaccination adjuvant, another pending great challenge in the fight against leishmaniasis.

    •  The usefulness of the nanoparticles to overcome resistance to conventional treatments such as antimonial derivates, improving intracellular penetration.

    • Topical formulations for the local treatment of cutaneous leishmaniasis using Photodynamic therapy.

    • Bio adhesive nanoparticles to favour oral absorption of drugs with low bioavailability by this route of administration

  • 2. Pharmacotherapy

    Our leishmaniasis pharmacotherapy working group proposes the approach to this pathology through the design, synthesis and identification of new families of drugs with this activity and its optimization from the study of  the relationship between biological structure and chemical activity.

    In concrete, we focus on the synthesis of new symmetrical and asymmetrical molecules with a structure containing S and/or Se, in various states of oxidation, as well as fragments of proven leishmania killing efficacy through the implementation of the strategy "Medicinal Chemical Hybridization". Structural modulation will be designed to optimize the power, improve selectivity and ADME properties. In relation with the possible mechanism of action, inhibition of the tripanotion reductase and other enzymes involved in parasite redox processes are proposed.

  • 3. Therapeutic targets and Molecular Diagnosis

    Molecular Diagnosis: The knowledge of the genome of several species of Leishmania facilitates confrontation with diagnostic problems. Our research group focuses on solving these problems through the search, study and characterization of genes that can be used as diagnostic markers for early detection of disease.

    Therapeutic targets: our research team analyzes Leishmania genes involved in cell proliferation and cell differentiation and infectivity. We study its expression throughout the lifecycle of the parasite and infective forms. The implication of this gene in cell differentiation mechanisms relates it to the acquisition of infectivity by the parasite. Interpreting this mechanism is essential in order to understand the transmission and progression of the disease and it would allow us to characterize new therapeutic targets in the fight against these diseases.

"New formulations" Research team

Investigator team "Compound Synthesis"

  • María Font Arellano (PhD) María Font Arellano (PhD)
    Investigator
    Telephone: + 34 948 425600 Extension: x6509-635 Email: mfont@unav.es
  • Juan Antonio Palop Cubillo (PhD) Juan Antonio Palop Cubillo (PhD)
    Emeritus Investigator
    Telephone: + 34 948 425600 Extension: x6358 Email: jpalop@unav.es
  • Daniel Plano (PhD) Daniel Plano (PhD)
    Investigator
    Telephone: + 34 948 425600 Email: dplano@unav.es
  • Ylenia Baquedano Pérez (PhD) Ylenia Baquedano Pérez (PhD)
    Investigator
    Telephone: + 34 948 425600 Extension: x6292 Email: ybaquedano@alumni.unav.es

"Molecular Diagnosis and Therapeutic Targets" Investigator team

  • Paul Nguewa (PhD) Paul Nguewa (PhD)
    Principal Investigator
    Telephone: + 34 948 425646 Extension: x6434 Email: panguewa@unav.es

Publications

  • Publicaciones

    APPROPRIATENESS FOR TOTAL JOINT REPLACEMENT: PERSPECTIVES OF DECISION-MAKERS
    Clavel N, De Coster C, Pomey MP, Sanmartin C, Bohm É, Dunbar MJ, Frank CY, Hawker G, Noseworthy T.

    Healthc Policy. 2016 Feb;11(3):80-92.
    PMID: 27027795 [PubMed - as supplied by publisher

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    NOVEL HETEROARYL SELENOCYANATES AND DISELENIDES AS POTENT ANTILEISHMANIAL AGENTS
    Baquedano Y, Alcolea V, Toro MÁ, Gutiérrez KJ, Nguewa P, Font M, Moreno E, Espuelas S, Jiménez-Ruiz A, Palop JA, Plano D, Sanmartín C.
    Antimicrob Agents Chemother. 2016 Apr 11. pii: AAC.02529-15. [Epub ahead of print]
    PMID: 27067328 [PubMed - as supplied by publisher

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    ORAL DELIVERY OF CAMPTOTHECIN USING CYCLODEXTRIN/POLY (ANHYDRIDE) NANOPARTICLES
    Huarte J, Espuelas S, Lai Y, He B, Tang J, Irache JM.

    Int J Pharm. 2016 Apr 18. pii: S0378-5173(16)30331-3. doi: 10.1016/j.ijpharm.2016.04.045. [Epub ahead of print]
    PMID: 27102993 [PubMed - as supplied by publisher]

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    NOVEL SELENO- AND THIO-UREA DERIATIVES WITH POTENT IN VITRO ACTIVITIES AGAINST SEVERAL CANCER CELL LINES
    Alcolea V, Plano D, Karelia DN, Palop JA, Amin S, Sanmartín C, Sharma AK.
    Eur J Med Chem. 2016 Feb 18;113:134-144. doi: 10.1016/j.ejmech.2016.02.042. [Epub ahead of print]
    PMID: 26922233 [PubMed - as supplied by publisher]

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    SELENOCYANATES AND DISELENIDES: A NEW CLASS OF POTENT ANTILEISHMANIAL AGENTS.
    Plano, D.; Baquedano, Y.; Moreno-Mateos, D.; Font, M.; Jiménez-Ruiz, A.; Palop, J.A.; Sanmartín, C. Eur. J. Med. Chem., 2011, (in press).
    ScienceDirect - European Journal of Medicinal Chemistry

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    TECHNOLOGICAL PERSPECTIVES IN LEISHMANIASIS. 
    Espuelas, S., D. Oliveira, O. Bruna-Romero. Chapter book. 2011 (in press)

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    ANTILEISHMANIAL ACTIVITY OF IMIDOTHIOCARBAMATES AND IMIDOSELENOCARBAMATES. PARASITOLOGY RESEARCH.
    Moreno, D., D. Plano, Y. Baquedano, A. Jimenez-Ruiz, J.A. Palop, and C. Sanmartin, 2011. 108(1): p. 233-239.
    ABSTRACT CORTESÍA DE PUBMED

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    POLY(ANHYDRIDE) NANOPARTICLES AS ADJUVANTS FOR MUCOSAL VACCINATION.
    Irache, J.M., H.H. Salman, S. Gomez, S. Espuelas, and C. Gamazo, Front Biosci (Schol Ed), 2010. 2: p. 876-90.
    ABSTRACT CORTESÍA DE PUBMED

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    DELIVERY SYSTEMS FOR THE PREVENTION AND TREATMENT OF LEISHMANIOSIS.
    Espuelas, S. Gazeta Médica da Bahía 2009, 79: 75-83 (Suppl. 3).

    SYNTHESIS AND PHARMACOLOGICAL SCREENING OF SEVERAL AROYL AND HETEROAROYL SELENYLACETIC ACID DERIVATIVES AS CYTOTOXIC AND ANTIPROLIFERATIVE AGENTS.
    Sanmartin, C., D. Plano, E. Dominguez, M. Font, A. Calvo, C. Prior, I. Encio, and J.A. Palop, Molecules, 2009. 14(9): p. 3313-38.
    ABSTRACT CORTESÍA DE PUBMED

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    CO-ENCAPSULATION OF AN ANTIGEN AND CPG OLIGONUCLEOTIDES INTO PLGA MICROPARTICLES BY TROMS TECHNOLOGY.
    San Roman, B., J.M. Irache, S. Gomez, N. Tsapis, C. Gamazo, and M.S. Espuelas, Eur J Pharm Biopharm, 2008. 70(1): p. 98-108.
    ABSTRACT CORTESÍA DE PUBMED

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    MANNOSE-TARGETED SYSTEMS FOR THE DELIVERY OF THERAPEUTICS.
    Irache, J.M., H.H. Salman, C. Gamazo, and S. Espuelas, Expert Opin Drug Deliv, 2008. 5(6): p. 703-24.
    ABSTRACT CORTESÍA DE PUBMED

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    ALLERGEN IMMUNOTHERAPY WITH NANOPARTICLES CONTAINING LIPOPOLYSACCHARIDE FROM BRUCELLA OVIS.
    Gomez, S., C. Gamazo, B. San Roman, M. Ferrer, M.L. Sanz, S. Espuelas, and J.M. Irache, Eur J Pharm Biopharm, 2008. 70(3): p. 711-7.
    ABSTRACT CORTESÍA DE PUBMED

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    INFLUENCE OF LIGAND VALENCY ON THE TARGETING OF IMMATURE HUMAN DENDRITIC CELLS BY MANNOSYLATED LIPOSOMES.
    Espuelas, S., C. Thumann, B. Heurtault, F. Schuber, and B. Frisch, Bioconjug Chem, 2008. 19(12): p. 2385-93.
    ABSTRACT CORTESÍA DE PUBMED

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    GAMMA INTERFERON LOADED ONTO ALBUMIN NANOPARTICLES: IN VITRO AND IN VIVO ACTIVITIES AGAINST BRUCELLA ABORTUS.
    Segura, S., C. Gamazo, J.M. Irache, and S. Espuelas, Antimicrob Agents Chemother, 2007. 51(4): p. 1310-4.
    ABSTRACT CORTESÍA DE PUBMED

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    INTRADERMAL IMMUNIZATION WITH OVALBUMIN-LOADED POLY-EPSILON-CAPROLACTONE MICROPARTICLES CONFERRED PROTECTION IN OVALBUMIN-SENSITIZED ALLERGIC MICE.
    Roman, B.S., S. Espuelas, S. Gomez, C. Gamazo, M.L. Sanz, M. Ferrer, and J.M. Irache, Clin Exp Allergy, 2007. 37(2): p. 287-95.
    ABSTRACT CORTESÍA DE PUBMED

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    POTENTIAL OF ALBUMIN NANOPARTICLES AS CARRIERS FOR INTERFERON GAMMA.
    Segura, S., S. Espuelas, M.J. Renedo, and J.M. Irache, Drug Dev Ind Pharm, 2005. 31(3): p. 271-80.
    ABSTRACT CORTESÍA DE PUBMED

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    ALBUMIN NANOPARTICLES FOR THE INTRAVITREAL DELIVERY OF ANTICYTOMEGALOVIRAL DRUGS.
    Irache, J.M., M. Merodio, A. Arnedo, M.A. Camapanero, M. Mirshahi, and S. Espuelas, Mini Rev Med Chem, 2005. 5(3): p. 293-305.
    ABSTRACT CORTESÍA DE PUBMED

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    EFFECT OF SYNTHETIC LIPOPEPTIDES FORMULATED IN LIPOSOMES ON THE MATURATION OF HUMAN DENDRITIC CELLS.
    Espuelas, S., A. Roth, C. Thumann, B. Frisch, and F. Schuber, Mol Immunol, 2005. 42(6): p. 721-9.
    ABSTRACT CORTESÍA DE PUBMED

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    ALBUMIN NANOPARTICLES IMPROVED THE STABILITY, NUCLEAR ACCUMULATION AND ANTICYTOMEGALOVIRAL ACTIVITY OF A PHOSPHODIESTER OLIGONUCLEOTIDE.
    Arnedo, A., J.M. Irache, M. Merodio, and M.S. Espuelas Millan, J Control Release, 2004. 94(1): p. 217-2.
    ABSTRACT CORTESÍA DE PUBMED

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    FLUCONAZOLE ENCAPSULATION IN PLGA MICROSPHERES BY SPRAY-DRYING.
    Rivera, P.A., M.C. Martinez-Oharriz, M. Rubio, J.M. Irache, and S. Espuelas, J Microencapsul, 2004. 21(2): p. 203-11.
    ABSTRACT CORTESÍA DE PUBMED

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    SYNTHESIS OF AN AMPHIPHILIC TETRAANTENNARY MANNOSYL CONJUGATE AND INCORPORATION INTO LIPOSOME CARRIERS.
    Espuelas, S., P. Haller, F. Schuber, and B. Frisch, Bioorg Med Chem Lett, 2003. 13(15): p. 2557-60.
    ABSTRACT CORTESÍA DE PUBMED

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    POLYMERIC CARRIERS FOR AMPHOTERICIN B: IN VITRO ACTIVITY, TOXICITY AND THERAPEUTIC EFFICACY AGAINST SYSTEMIC CANDIDIASIS IN NEUTROPENIC MICE.
    Espuelas, M.S., P. Legrand, M.A. Campanero, M. Appel, M. Cheron, C. Gamazo, G. Barratt, and J.M. Irache, J Antimicrob Chemother, 2003. 52(3): p. 419-27.
    ABSTRACT CORTESÍA DE PUBMED

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    BOVINE SERUM ALBUMIN MODIFIED THE INTRACELLULAR DISTRIBUTION AND IMPROVED THE ANTIVIRAL ACTIVITY OF AN OLIGONUCLEOTIDE.
    Arnedo, A., J.M. Irache, G. Gonzalez Gaitano, M. Valganon, and S. Espuelas, J Drug Target, 2003. 11(4): p. 197-204.
    ABSTRACT CORTESÍA DE PUBMED

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    EFFICACY OF GANCICLOVIR-LOADED NANOPARTICLES IN HUMAN CYTOMEGALOVIRUS (HCMV)-INFECTED CELLS.
    Merodio, M., M.S. Espuelas, M. Mirshahi, A. Arnedo, and J.M. Irache, J Drug Target, 2002. 10(3): p. 231-8.
    ABSTRACT CORTESÍA DE PUBMED

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    IN VITRO ANTILEISHMANIAL ACTIVITY OF AMPHOTERICIN B LOADED IN POLY(EPSILON-CAPROLACTONE) NANOSPHERES.
    Espuelas, M.S., P. Legrand, P.M. Loiseau, C. Bories, G. Barratt, and J.M. Irache, J Drug Target, 2002. 10(8): p. 593-9.
    ABSTRACT CORTESÍA DE PUBMED

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    IN VITRO REVERSION OF AMPHOTERICIN B RESISTANCE IN LEISHMANIA DONOVANI BY POLOXAMER 188.
    Espuelas, S., P. Legrand, P.M. Loiseau, C. Bories, G. Barratt, and J.M. Irache. Antimicrob Agents Chemother, 2000. 44(8): p. 2190-2. 
    ABSTRACT CORTESÍA DE PUBMED.