WO1994006439A1 - Composition antileishmania pour application topique - Google Patents

Composition antileishmania pour application topique Download PDF

Info

Publication number
WO1994006439A1
WO1994006439A1 PCT/US1993/008979 US9308979W WO9406439A1 WO 1994006439 A1 WO1994006439 A1 WO 1994006439A1 US 9308979 W US9308979 W US 9308979W WO 9406439 A1 WO9406439 A1 WO 9406439A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
leishmaniasis
paromomycin
gentamicin
leishmania
Prior art date
Application number
PCT/US1993/008979
Other languages
English (en)
Inventor
Max Grogl
Lawrence Fleckenstein
Patrick Mcgreevy
Brian Schuster
Original Assignee
Department Of The Army, United States Government
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Department Of The Army, United States Government filed Critical Department Of The Army, United States Government
Publication of WO1994006439A1 publication Critical patent/WO1994006439A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a means of effectively inhibit- ing leishmania infections by topical application of composi ⁇ tions containing paromomycin and gentamicin.
  • Leishmania species are hemoflagellate protozoa which are transmitted by the bite of the sandfly. In man, the organisms grow and multiply in tissues of the reticuloendothelial system. Some of these species of parasites of genus Leishmania cause cutaneous lesions which usually appear as chronic, ulcerative skin lesions. Dermotropic species like L. tropica. L. aethiopica. and L. major are most prevalent in the Old World, while L. peruviana, L. mexicana. L. quvanensis, L. amazonensis, L. panamensis. and L. braziliensis are found in the New World. L. panamensis and L.
  • braziliensis may metastasize to the oral- nasal mucosa to cause mucosal leishmaniasis.
  • Both L. aethio ⁇ pica and L. mexicana cause diffuse cutaneous leishmaniasis. No vaccine or other prophylaxis against these diseases is currently available.
  • Drugs most commonly used against these parasites contain the pentavalent antimony.
  • the sodium stilbogluconate (Pent- ostam) and the meglumine antimonate (Glucanti e) are commonly used. These drugs are toxic to the liver, kidneys, pancreas and heart. The most serious effects are pancreatitis and cardiac arrhythmias. A photericin B and Pentamidine are also used, but are equally toxic. Ketocanazole is effective against some species.
  • the present treatment of choice required injections of pentavalent antimonies for 10 - 28 days under hospital care, since such treatment often results in side effects such as cardiac arrhythmias, pancreatitis and hepati ⁇ tis.
  • U.S. Patent 4,595,901 to El-On, et al. discloses a composition containing a mixture of paromomycin or a salt thereof with dimethylsulfoxide or quaternary ammonium salts, especially methylbenzethonium chloride. These compositions are effective against some Leishmania species, but are ineffective against others. The compositions of that patent have been found to be essentially ineffective against most New World strains and against some of the Old World strains. Gentamicin was tried in some of the El-On compositions, but were essen ⁇ tially ineffective when formulated in accord with the teaching of El-On. The claimed compositions of El-On are toxic to many patients when given at therapeutic levels.
  • the instant invention provides compositions containing as active agents paromomycin in combination with gentamicin. When given in combination, the compositions appear much more effective than when given alone or with other ammonium salts as taught by El-On. Furthermore, the compositions of the invention were found to be effective against several species of Leishmania that were not effectively inhibited by the prior art compositions.
  • compositions of the invention contain as active agents an antileishmania-effective amount of paromomycin or a salt thereof and a paromomycin-potentiating effective amount of gentamicin.
  • the active agents used in the compositions are in amounts of up to 40% paromomycin and up to 5% gentamicin in a carrier to provide a composition appropriate for topical application.
  • Carriers used must be nontoxic. Addition of penetration agents was also found to be beneficial.
  • Several of the commercially available carriers, including Aquaphilic, Aquacide, Aquaphor, Unibase and PEG base were found to be effective, as were some nonionic emulsion basis. Addition of known penatrants such as urea were also used.
  • compositions of the invention proved to be particularly effective against both Old World and New World species of Leishmania.
  • the gentamicin appears to act as a potentiation agent, enhancing the effect of the paromomycin.
  • the gentamicin also acts as a bacteriostatic and bacteriocidal agent.
  • the synergistic effect of the combination of active agents has not previously been known.
  • the compositions of the invention can prevent progression of the papule into a full ⁇ blown lesion.
  • compositions have also been found to be especially effective in treatment of diffuse cutaneous leishmaniasis caused by L. aethiopic and L. mexicana and in treating and preventing metastasis of L. panamensis and L. braziliensis to the oral-nasal mucosa.
  • Materials and Methods The four species of Leishmania selected for testing were
  • L. major (Strain Code MHOM/SU/74/WR779, L. amazonensis (Strain Code MH0M/BR/73/WR669) , L. panamensis (Strain Code MHOM/CR/87/ WR746) and L. mexicana (Strain Code MHOM/US/90/ WR972-B) .
  • L. major is an Old World species, while the other strains are New World species.
  • Balb/c mice were selected because of their high susceptibility to leishmania and the progressive, nonhealing nature of their lesions due to the inability of their immune systems to mount an effective cellular response. Most other mammalian species, including humans and C3He mice develop an immune response which serves to increase the efficacy of the antileishmanial agents.
  • mice weighed approximately 20 grams, were 8-12 weeks old, and individually ear-tagged. The hair near the base of the tail of each experimental animal was clipped. On day one the bare skin inoculated with 5-20 million Leishmania (stationary phase) promastigotes of the appropriate species. After 60 days, an ulcerated lesion approximately 50 mm square developed. Ten and 30 mice were assigned to the control and test groups, respectively. From day 61 to day 70 the animals were treated with the formulation. Some animals were treated twice daily for ten days. Some animals infected with L. major were also treated two times daily for two days or one time daily for five days. The mice in the control groups were treated with the carrier without the paromomycin and gentamicin.
  • the formula ⁇ tion of the invention contained 15% paromomycin and 0.5% gentamicin.
  • a formulation of El-On containing 15% paromomycin and 12 % methylbenzethoniu chloride in white soft paraffin were also tested.
  • the dosages administered to the individual animal depended on the size of the lesions as shown in the table below: Table I
  • the drug efficacy was determined based on three criteria: (a) the area of the lesion after the termination of treatment (b) the number of viable amastigotes per gram of lesion after termination of treatment, and (c) the number of animals healed/the number tested. Animals were considered clinically healed when lesions were completely resolved, the skin was normal and there was hair growth. The animals were considered clinically cured when the skin and hair growth remained normal for at least 70 days after beginning of treatment whether or not parasites could be detected in the skin. Animals having normal skin with hair growth in which no viable amastigotes were detected were considered parasitically cured. To determine the number of viable amastigotes per gram of lesion required sacrificing the animals. The viable amastigotes were measured using fluorescein diacetate-ethyl benzine staining. The actual formulation used contained the following:
  • the Aquaphilic components as disclosed by the manufacturer are: sorbitol 4% lactic acid 0.5% distilled water: 39.85% propylene glycol 6% sodium lauryl sulfate 0.75% isopropyl palmitate 0.5% stearyl alcohol 19.0' white petrolatum 19.0% propyl paraben 0.15% methyl paraben 0.25'
  • the Aquaphilic was formulated then with urea before formulation with the antileishmanial agents.
  • mice Thirty Balb/c mice were infected with 5 x 10° stationary phase L. major promastigotes at the base of the tail on day 1.
  • the lesion area on controls was approximately 80 mm at day 61 and increased thereafter to about 300 mm by day 105.
  • the treated animals had no lesions at day 105 (45 days after treatment) , though one animal showed a small lesion resulting from metastasis 80 days after treatment ceased (day 140) .
  • the number of amastigotes per gram of lesion was determined.
  • Example 2 The test above was repeated treating the animals with the compositions of El-On instead of the compositions of the invention. In this instance, the animals continued to have a drop in lesion area until day 30, when lesions appeared days healed.
  • Example 3 The preferred compositions of El-On were compared with the compositions of the invention and were tested against several strains of Leishmania in the manner described above. The data is seen in Table II.
  • Test I refers to the preferred composi ⁇ tion of El-On containing 15% paromomycin and 12% methyl- benzenthionium Chloride while Test II refers to the composi ⁇ tion of the invention containing 15% paromomycin and 0.5% gentamicin. Drug efficacy is given as # of mice healed/# of mice tested.
  • the combination compositions of the invention were tested in the hamster model using L. donovani, an organisms which causes visceral leishmaniasis in this animal model.
  • the response to treatment with gentamicin, paromomycin, and with the combination of the invention was compared.
  • the antimonial, Glucantime was given at usual doses which are acceptable for therapy by injection in hospital.
  • compositions were tested on both immune suppressed (Balb/c mice) and a healing model (hamsters) . Both models responded well to the combination compositions.
  • the composi ⁇ tions of the invention result in more rapid closing of lesions, more permanent healing and considerably improved cosmetic results than prior art compounds.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un moyen d'inhibition efficace d'infections dues à la leishmania par application topique de compositions renfermant de la paromomycine et de la gentamicine.
PCT/US1993/008979 1992-09-22 1993-09-21 Composition antileishmania pour application topique WO1994006439A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94853392A 1992-09-22 1992-09-22
US07/948,533 1992-09-22

Publications (1)

Publication Number Publication Date
WO1994006439A1 true WO1994006439A1 (fr) 1994-03-31

Family

ID=25487967

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/008979 WO1994006439A1 (fr) 1992-09-22 1993-09-21 Composition antileishmania pour application topique

Country Status (2)

Country Link
IL (1) IL107077A0 (fr)
WO (1) WO1994006439A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831863A1 (fr) * 1995-06-07 1998-04-01 Biogaia Biologics Ab Procede permettant d'ameliorer la sante des animaux
US6180612B1 (en) * 1997-10-31 2001-01-30 The University Of Virginia Patent Foundation Methods and compositions for targeting DNA metabolic processes using aminoglycoside derivatives
CN102811992A (zh) * 2010-10-19 2012-12-05 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505901A (en) * 1982-03-29 1985-03-19 Orvet B.V. Compositions and methods for topical treatment of cutaneous leishmaniasis with paromomycin

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505901A (en) * 1982-03-29 1985-03-19 Orvet B.V. Compositions and methods for topical treatment of cutaneous leishmaniasis with paromomycin

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831863A1 (fr) * 1995-06-07 1998-04-01 Biogaia Biologics Ab Procede permettant d'ameliorer la sante des animaux
EP0831863A4 (fr) * 1995-06-07 1999-01-13 Biogaia Biolog Ab Procede permettant d'ameliorer la sante des animaux
US6180612B1 (en) * 1997-10-31 2001-01-30 The University Of Virginia Patent Foundation Methods and compositions for targeting DNA metabolic processes using aminoglycoside derivatives
US6531306B1 (en) 1997-10-31 2003-03-11 University Of Virginia Patent Foundation Polynucleotides encoding mammalian DNA-dependent ATPase A polypeptides
US6537791B1 (en) 1997-10-31 2003-03-25 University Of Virginia Patent Foundation Mammalian DNA-dependent ATPase a polypeptides and fusions thereof
US6573060B1 (en) 1997-10-31 2003-06-03 University Of Virginia Patent Foundation Methods and compositions for targeting DNA metabolic processes using aminoglycoside derivatives
CN102811992A (zh) * 2010-10-19 2012-12-05 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药
CN102811992B (zh) * 2010-10-19 2015-06-17 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药

Also Published As

Publication number Publication date
IL107077A0 (en) 1993-12-28

Similar Documents

Publication Publication Date Title
US4091090A (en) Potentiated anesthetics
CA2334344C (fr) Procede et composition pour le traitement d'irritations et d'infections epidermiques
US4006218A (en) Potentiated medicaments
US4321257A (en) Potentiated medicaments
CA2070685C (fr) Methode de traitement des affections douloureuses, inflammatoires ou allergiques
US4197318A (en) Potentiated antimicrobial medicaments
US4942041A (en) Pharmaceutical compositions effective for treating skin to destroy eggs of enterobius vermicularis
US4474748A (en) Medicaments potentiated with phenyl alkanols
US4078058A (en) Cerium sulfadiazine for treating burns
NL8102369A (nl) Preparaat van een antimicrobisch middel en werkwijze ter bereiding daarvan.
US6863898B2 (en) Method and composition for treating hairy hoof warts
CA2186867C (fr) Methodes d'utilisation de chelates contenant du fer pour diminuer les atteintes dues aux radicaux libres chez les mammiferes
EP0484112A2 (fr) Utilisation du lithium dans le traitement ou la prophylaxie du Molluscum contagiosum
WO1994006439A1 (fr) Composition antileishmania pour application topique
US6284739B1 (en) Antileishmanial composition for topical application
US4505901A (en) Compositions and methods for topical treatment of cutaneous leishmaniasis with paromomycin
EP0105448B1 (fr) Utilisation de l'acide undécylénique pour la préparation d'une composition pour le traitement de l'Herpès labialis
US11351146B2 (en) Topical compositions for the treatment of cutaneous leishmaniasis
JPS61500844A (ja) シラミの防除方法および防除用組成物
DD141995A5 (de) Verfahren zur herstellung detoxifizierter zubereitungen von cytostatika
CA1174169A (fr) Tolciclate et tolnaftate administres par voie orale
JPH05112457A (ja) 馬ウイルス感染に関する医薬組成物及びその治療方法
CA1207238A (fr) Utilisation de l'haloprogine dans le traitement de l'herpes des levres
US5200402A (en) Anti microbial mafenide-phosphanilate compound, pharmaceutical compositions and method of use therefor
US4438134A (en) Use of tolnaftate to treat herpes labialis

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA