WO1998043644A1 - Formulations et procedes de traitement et de prevention de la myelo-encephalite equine due a des protozoaires - Google Patents

Formulations et procedes de traitement et de prevention de la myelo-encephalite equine due a des protozoaires Download PDF

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Publication number
WO1998043644A1
WO1998043644A1 PCT/US1998/006340 US9806340W WO9843644A1 WO 1998043644 A1 WO1998043644 A1 WO 1998043644A1 US 9806340 W US9806340 W US 9806340W WO 9843644 A1 WO9843644 A1 WO 9843644A1
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WO
WIPO (PCT)
Prior art keywords
diclazuril
triazine
epm
treatment
neurona
Prior art date
Application number
PCT/US1998/006340
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English (en)
Inventor
David Granstrom
Thomas Tobin
Original Assignee
David Granstrom
Thomas Tobin
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
Priority claimed from US08/908,257 external-priority patent/US5883095A/en
Application filed by David Granstrom, Thomas Tobin filed Critical David Granstrom
Priority to BR9808114-4A priority Critical patent/BR9808114A/pt
Priority to CA002285477A priority patent/CA2285477C/fr
Publication of WO1998043644A1 publication Critical patent/WO1998043644A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • Equine Protozoal Myeloencephalitis is the leading infectious neurologic disease of American horses. Consistendy safe and effective treatments for this disease are not available. Conventional therapy relies on relatively non-specific drug/medication combinations; these approaches are only partially effective and relapses and/or adverse reactions are common.
  • EPM is a New World disease and is the most common infectious neurological disease of horses in the Western hemisphere. It is caused by an "apicomplexan” parasite called Sarcocys ⁇ s neurona (S. neurona), which cycles naturally between opossums and birds. The horse is an aberrant host, becoming exposed when it consumes infectious material from opossum feces. In the horse, S. neurona makes its way to the brain and spinal cord, where it proliferates and causes clinical disease.
  • EPM occurs wherever opossums are found. All cases of EPM therefore trace to Western hemisphere exposure, and the incidence of EPM is likely greatest in areas with high opossum populations. However, clinical cases of EPM are found throughout the world, because horses who become infected with S. neurona while in opossum territories may be transported elsewhere.
  • neurona in the brain and spinal cord is a critical obstacle to treatment of EPM.
  • the brain and spinal cord are immunologically privileged; as such, immune responses are likely less effective in the brain than elsewhere.
  • Current treatments, as detailed below, do not directly kill S. neurona; as such they often fail to effect a "cure.”
  • the present treatment method directly kills S. neurona, making it dramatically different from previous treatments.
  • Previous therapy for EPM consists of administration of various combinations of sulfonamides, trimethoprim and pyrimethamine (Daraprim).
  • Daraprim pyrimethamine
  • many horses relapse when therapy ceases, probably because the current therapies do not cross the blood/brain barrier reliably and/or attack the organism directly. These agents only binder proliferation of 5. neurona and do not kill it The inability of current treatments to kill S. neurona likely contributes to the significant relapse rate after therapy ceases.
  • One of the major concerns about current therapeutic approaches to EPM is the difficulty in maintaining simultaneous minimum inhibitory concentrations (MICs) of pvrimethamine, trimethoprim and sulfonamides in the CNS.
  • MICs simultaneous minimum inhibitory concentrations
  • the present treatment methods utilize triazine-based anticoccidials, preferably diclazuril, to prevent and treat EPM, without the side effects of previous EPM treatments.
  • EPM and coccidiosis are both caused by "apicomplexan” parasites; however, coccidiosus does not affect the CNS as does EPM.
  • Triazine-based compounds have previously been used in the prophylaxis of coccidiosis in poultry in Canada, Europe, and South America. Vanparijs et. al, 129 Vet. Rec. 339 (1991); Driessen et. al., 72 Aust. Vet. 139 (1995). Diclazuril has been used to treat coccidiosus in turkeys, ducks, quail, guinea-fowl, pheasants, partridges, mice, rats, dogs, rabbits, cattle, and horses. Lindsay et al, 55 Am. J. Vet. Res. 976 (1994); Lindsay et al., 81(2) J. Parisitol.
  • U.S. Patent 4,952,570 also discloses the use of triazine-based compounds (including diclazuril) to treat protozoal infections, although neither Equine Protozoal Myelitis nor S. neurona are mentioned. Moreover, diclazuril, in particular is generally considered non-absorbable by the small intestine, and systemic treatment of protozoal infections not possible.
  • Diclazuril has been shown to be active against Neospora caninum, another apicomplexan organism, in vitro but not yet in vivo. Lindsay et. al., 55 Amer. V et. JR. 926 (1994) and Dubey and Lindsay, 67 Vet. Parisitol. 1 (1996). Diclazuril has also been shown to be effective against intestinal Eimeria spp. in many avian hosts and against intestinal and hepatic coccidiosis in rabbits. Vanparijs et. al., 32 Vet. Parisitol. 109 (1989).
  • diclazuril has been used in the prophylaxis and treatment of experimental T. gondii infection in mice. While diclazuril alone or in combination with pyrimethamine protected mice against death following inoculation with T. gondii, diclazuril, alone or in combination did not prevent tissue cyst formation, including brain tissue cyst formation in surviving mice. Based on this work in mice, Lindsay concluded that combinations of diclazuril and pyrirnethamine may be beneficial in the treatment of toxoplasmosis in man and animals Lindsay et. al., 81(2) J. Parisitol. 315 (1995).
  • mice in these experiments died from pneumonia and hepatitis; there is no evidence from the Lindsay experiments to suggest that diclazuril is effective in the treatment of encephalitis.
  • the data show that diclazuril did not prevent tissue cyst formation in the CNS.
  • a triazine- based anti-coccidial such as clazuril, diclazuril, toltrazuril or letrazuriL
  • EPM means equine protozoal myelitis or equine protozoal myeloencephalitis or a disease which manifests as symptoms of either equine protozoal myelitis or equine protozoal myeloencephalitis, or closely related apicomplexan-based neurological diseases of horses.
  • the present invention provides formulations of triazine-based anticoccidials for the use in preventing and/or treating EPM.
  • a horse-feed based formulation is preferred.
  • a horse-feed formulation which comprises diclazuril.
  • an oral formulation is preferred.
  • a most preferred oral formulation is one which is administered as a paste.
  • an oral formulation which comprises a triazine-based anticoccidial is administered as a paste, and further comprises other desirable therapeutics, such as anti-inflammatories, sulfonamides, tximethoprim, pyrimethamine and/or other anti-protozoals is considered within the scope of the present invention.
  • the present invention also provides methods to treat EPM in a horse in need of such treatment, comprising administering a pharmaceutically acceptable amount of a triazine-based anticoccidial.
  • Preferred is a method to treat EPM using clazuril, diclazuril, toltrazuril or letrazuril. Most preferred is a method to treat EPM using toltrazuril or diclazuril.
  • the present invention also provides methods to prevent S. neurona infection in horses comprising administering a prophylactic amount of a triazine-based anticoccidial.
  • a method to prevent S. neurona infection by administering clazuril, diclazuril, toltrazuril or letrazuril.
  • Most preferred is a method to prevent S. neurona infection using toltrazuril or diclazuril.
  • the treatments provided are able to completely kill all 5. neurona present in the animal. A considerable portion of the recovery from the clinical symptoms of infection, however, occurs after treatment because clearance of dead S. neurona organisms, reduction of inflammatory response and repair of damaged neurons normally takes up to a year. Exercise and anti- inflammatory medication play a positive role in the repair process. In order to diagnose a horse with clinical EPM, it should be both CSF positive for S. neurona antibodies and show a history and clinical signs consistent with EPM. Other non- S. neurona-basod causes of neuropathy must also be excluded. A further sign is response and/or relapse following standard therapy, if the information is available.
  • the horse will: be grade 3-4 on a five point scale neurological exam; asymmetric in muscle vitality; positive for EPM on spinal tap by Western blot; have exhibited relapse after current treatment, with all other potential causes of ataxia excluded.
  • the triazine-based anticoccidials can be purchased from commercial sources, such as Janssen Pharmaceutica in Belgium (clazuril, letrazuril and diclazuril) or Bayer AG in Leverkusen, Germany (toltrazuril). However, one skilled in the art is aware how to synthesize these compounds de novo using conventional methods.
  • Formulations can be made using conventional formulation technology.
  • Horse food composition is well known in the art.
  • the present formulation comprises adding at least one triazine-based anti-coccidial to the feed as it is made or after it is made, so as to provide an overall composition consistent with the dosages necessary for prophylaxis or treatment, depending on the use. For instance, for a feed which would be useful as a prophylactic treatment the following formulation could be made (all percentages are by weight, not less than the numbers given):
  • a feed which would be useful as a treatment of clinical EPM could have the following composition, for instance: Toltrazuril 0.1- 0.5% protein 10% fat 3.5% fiber 6.0% calcium 0.6% phosphorus 0.45% copper 35 ppm zinc 140 ppm selenium 0.6 ppm vitamin A 3,000 IU ⁇ b
  • Simple oral formulations may also be made using available Clinacox, oats and molasses, or Clinacox, oats, sweet feed, bran and water, for example.
  • any formulation which comprises a triazine-based anti-coccidial and prior EPM treatment methods is considered within the scope of the present invention.
  • sulfonamides, trimethoprim and pyrimethamine (Daraprim) added to the above formulations are within the purview of the present invention.
  • the formulation would have to be adjusted for the appropriate pharmaceutically-acceptable percentage of final concentration of all ingredients.
  • paste formulations are the generally preferred mode of administration of orally-bioavailable compounds, a paste formulation acceptable to horses is hereby provided.
  • Any carriers or excipients preferably those which enhance absorption, can also be included in the present formulations.
  • One such absorption-enhancing carrier is lactose.
  • Other carriers known in the art may also be used.
  • Sweetners or other flavor-enhancers may be used as well.
  • Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl-and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations may be made so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art
  • the formulations are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to 10% active ingredient by weight, more usually about 0.25 to 5% of the active ingredient
  • unit dosage form refers to physically discrete unites suitable as unitary dosages for mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • Formulations of the present invention could therefore also contain acceptable amounts of the following ingredients: grain products, molasses products, plant protein products, soybean oil, calcium carbonate, salt, attapulgite clay, dicalcium phosphate, sodium selenite, propionic acid, choline chloride, tetrasodium pyrophosphate, calcium pantothenate, vitamin E supplement, riboflavin supplement vitamin B-12 supplement, niacin supplement, vitamin A supplement, vitamin D-3 supplement, ferrous carbonate, manganous oxide, zinc oxide, copper sulfate, magnesium oxide, calcium iodate and cobalt carbonate.
  • these compounds may be administered in any formulation which allows EPM to be treated.
  • feed formulations it is important to give enough feed to the animal to ensure ingestion of the required dose. For example, it is necessary to take into account wasted feed that is left in the feeding area and inaccessible to the animal.
  • the compounds and/or formulations may be administered via any acceptable method or route.
  • the compounds and/or formulations may be administered in the feed, through formulation with the feed, or via liquid or solid (ie. powder) added at the time of feeding.
  • the compounds and/or formulations can also be administered intravenously, transdermally, sublingually, transmucosaUy, via tablet, pill, powder, lozenge, sachet cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment soft or hard gelatin capsule, suppository, sterile injectable solution, sterile packaged powder and transdermal patch.
  • the dosage for treatment of EPM will preferably vary according to the weight of the horse (ie. 3-15 mg/kg/day, preferably 5-10 mg kg/day), for from 20-40 days or longer if required, but can be administered in the following common dosage range: 1.5 - 10 grams of drug per day.
  • EPM-effective dose or duration of treatment is within the scope of the invention.
  • the dosage can be time release, which can be any of the above, except that it is formulated so as to release a certain dose continuously or intexmittently over a period of time. It is also a preferred embodiment to administer the drug as an injection, one or more times per day, at the same dose as above.
  • diclazuril Because diclazuril has a relatively long plasma half-life in horses, it takes about 5-7 days of a standard 5 mg kg/21 day treatment for the blood and cerebro-spinal fluid concentrations of diclazuril to attain steady-state.
  • the present invention includes a method to treat EPM wherein steady-state is acheived by administering larger doses ("loading doses") in the first day or first few days of treatment
  • loading doses larger doses
  • the dosage for prophylaxis of EPM can be less than that necessary for treating EPM, but may be the same, depending on the need of the individual horse.
  • a typical preventative dose of the triazine-based anti-coccidials herein disclosed would be 0.3 - 0.15 mg/kg/day, preferably 0.5 - 0.1 mg/kg/day, however, it can be administered via a feed formulation of 0.0002% - 0.002% active ingredient or 1 mg/kg- 1 in feed or 200 g of 0.5% Clinacox pre-mix per ton of feed as well.
  • Horses can be fed formulations herein described on a schedule consistent with their needs.
  • a full treatment plan for an animal with EPM would comprise the following sequential approaches: a.) reduce of the local inflammatory response in the CNS; b.) kill the S.neurona in the CNS; and c.) provide nerve-strengthening stimulus.
  • NSAID medication is effective; especially if started two days before the triazine-based anti-coccidial is started. Banamine, phenylbutazone or similar drugs seem to be optimal.
  • In order to kill S. Neurona 2.5 grams of diclazuril per day for three weeks seems to be sufficient and may be optimal.
  • Example 1 The Disposition And Pharmacokinetics Of Toltrazuril. The following were initial studies to determine the bioavailability of toltrazuril in non-EPM infected horses. Five horses were given 5 grams/1000 lbs body weight toltrazuril by stomach tube and blood levels were determined at various time periods after administration. Toltrazuril was very well-absorbed after administration, with peak plasma concentrations occurring at 24 hours after drug administration. Additionally, this agent was shown to have a long plasma half-life (54 hours). The long plasma half life facilitated maintainenance of plasma concentrations at consistently high ( ⁇ g/ml) concentrations for weeks. Under these conditions of continuous high plasma concentrations, the opportunity for the drug to enter the CNS was maximized.
  • Pharmacokinetic projections based on these kinetics were that single daily doses of 5 gms/horse will yield plasma concentrations of about 30 ⁇ g/ml of toltrazuril after 15 days. Administered every second day, this same dose yields steady state plasma concentrations of about 15 ⁇ g/ml.
  • the mare was discharged with a diagnosis of EPM with presumptive secondary trauma at the second cervical vertebra. It was recommended that treatment continue for 30 to 60 days. Prior to discharge, the horse had great difficulty walking, and when exiting the stall she reared and fell on her poll. Phenylbutazone was prescribed, presumably for the local trauma and to reduce the inflammatory response in the CNS.
  • this mare has not relapsed or re-infected, despite being in an infectious environment. Clinically, and effectively, this mare continues to improve and has shown no signs of relapse. At twelve months post treatment, this mare is clinically sound and her most recent CSF tap suggest that the amount of anti- S. neurona antibody in her CSF is declining. This mare is likely to go CSF negative for S. neurona eventually.

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Abstract

La présente invention porte sur des formulations utilisées pour traiter la myélo-encéphalite équine due à des protozoaires (EPM), ainsi que sur des procédés de traitement de cette maladie affectant un cheval. Ces procédés consistent à administrer une quantité thérapeutiquement efficace d'un agent anti-coccidien à base de triazine. Cette invention porte également sur des procédés de traitement d'EPM utilisant clazuril, diclazuril, toltrazuril ou létrazuril, ainsi que sur des procédés de prévention des infections S. neurona affectant les chevaux, ces procédés consistant à administrer une quantité prophylactique d'un agent anti-coccidien à base de triazine. Un procédé préféré de prévention des infections S. neurona consiste à utiliser clazuril, diclazuril, toltrazuril ou létrazuril, seul ou en combinaison avec une autre thérapeutique connue.
PCT/US1998/006340 1997-03-31 1998-03-31 Formulations et procedes de traitement et de prevention de la myelo-encephalite equine due a des protozoaires WO1998043644A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR9808114-4A BR9808114A (pt) 1997-03-31 1998-03-31 Formulação de ração para cavalos utilizável para tratar epm, processos para tratar pm em um cavalo que necessita deste tratamento, para prevenir infecção com s. neutrona em cavalos, e, para exterminar s. neurona em cavalos
CA002285477A CA2285477C (fr) 1997-03-31 1998-03-31 Formulations et procedes de traitement et de prevention de la myelo-encephalite equine due a des protozoaires

Applications Claiming Priority (4)

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US4247397P 1997-03-31 1997-03-31
US60/042,473 1997-03-31
US08/908,257 1997-08-07
US08/908,257 US5883095A (en) 1997-08-07 1997-08-07 Formulations and methods to treat and prevent equine protozoal myeloencephalitis

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062519A1 (fr) * 1998-06-02 1999-12-09 Bayer Aktiengesellschaft Preparations aqueuses semi-solides de sulfone de toltrazurile pour application orale
WO2000020016A1 (fr) * 1998-10-06 2000-04-13 Mars U.K. Limited Stereotypie chez l'animal
WO2000023058A2 (fr) * 1998-10-16 2000-04-27 Vitabiotics Limited Methode de traitement
WO2000037064A2 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
WO2000037084A1 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
WO2000037063A2 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
US6255308B1 (en) 1996-07-17 2001-07-03 Blue Ridge Pharmaceuticals, Inc. Treatment of equine protozoal myeloencephalitis
EP1385525A2 (fr) * 2001-03-30 2004-02-04 Robert F. Hofmann Formulation therapeutique oxydative cible
WO2004062673A1 (fr) * 2003-01-16 2004-07-29 Janssen Pharmaceutica N.V. Compositions anti-protozoaires comprenant du diclazuril
US20090181040A1 (en) * 1999-12-03 2009-07-16 Bayer Aktiengesellschaft Triazinone compounds for treating diseases resulting from infestation with parasitic protozoans
WO2010013129A1 (fr) * 2008-07-31 2010-02-04 Laboratorio Avi-Mex, S.A. De C.V. Combinaison coccidicide à usage vétérinaire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4952570A (en) * 1986-01-30 1990-08-28 Janssen Pharmaceutica N.V. 5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4952570A (en) * 1986-01-30 1990-08-28 Janssen Pharmaceutica N.V. 5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6255308B1 (en) 1996-07-17 2001-07-03 Blue Ridge Pharmaceuticals, Inc. Treatment of equine protozoal myeloencephalitis
US6448252B1 (en) * 1996-07-17 2002-09-10 Idexx Pharmaceuticals, Inc. Treatment of equine protozoal myeloencephalitis
US6436935B1 (en) 1998-06-02 2002-08-20 Bayer Aktiengesellschaft Semi-solid aqueous preparations for oral applications of toltrazuril sulphone
WO1999062519A1 (fr) * 1998-06-02 1999-12-09 Bayer Aktiengesellschaft Preparations aqueuses semi-solides de sulfone de toltrazurile pour application orale
WO2000020016A1 (fr) * 1998-10-06 2000-04-13 Mars U.K. Limited Stereotypie chez l'animal
WO2000023058A2 (fr) * 1998-10-16 2000-04-27 Vitabiotics Limited Methode de traitement
WO2000023058A3 (fr) * 1998-10-16 2000-07-06 Vitabiotics Limited Methode de traitement
WO2000037063A2 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
US6150361A (en) * 1998-12-22 2000-11-21 Bayer Corporation Triazineone compounds for treating diseases due to sarcosystis, neospora and toxoplasma
WO2000037063A3 (fr) * 1998-12-22 2000-10-19 Bayer Ag Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
WO2000037084A1 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
WO2000037064A2 (fr) * 1998-12-22 2000-06-29 Bayer Corporation Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
JP2002532545A (ja) * 1998-12-22 2002-10-02 バイエル・コーポレーシヨン 肉胞子虫、早生胞子虫及びトキソプラズマの故の疾患の処置のためのトリアジンオン化合物
WO2000037064A3 (fr) * 1998-12-22 2000-10-26 Bayer Ag Composes de triazineone utilises pour traiter les maladies dues aux sarcosystis, neospora et toxoplasme
AU770108B2 (en) * 1998-12-22 2004-02-12 Bayer Corporation Triazineone compounds for treating diseases due to sarcosystis, neospora and toxoplasma
JP4806121B2 (ja) * 1998-12-22 2011-11-02 バイエル・コーポレーシヨン 肉胞子虫、早生胞子虫及びトキソプラズマの故の疾患の処置のためのトリアジンオン化合物
US20090181040A1 (en) * 1999-12-03 2009-07-16 Bayer Aktiengesellschaft Triazinone compounds for treating diseases resulting from infestation with parasitic protozoans
US9399037B2 (en) * 1999-12-03 2016-07-26 Bayer Intellectual Property Gmbh Triazinone compounds for treating diseases resulting from infestation with parasitic protozoans
EP1385525A2 (fr) * 2001-03-30 2004-02-04 Robert F. Hofmann Formulation therapeutique oxydative cible
EP1385525A4 (fr) * 2001-03-30 2006-06-14 Robert F Hofmann Formulation therapeutique oxydative cible
WO2004062673A1 (fr) * 2003-01-16 2004-07-29 Janssen Pharmaceutica N.V. Compositions anti-protozoaires comprenant du diclazuril
WO2010013129A1 (fr) * 2008-07-31 2010-02-04 Laboratorio Avi-Mex, S.A. De C.V. Combinaison coccidicide à usage vétérinaire

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BR9808114A (pt) 2000-03-08
CA2285477A1 (fr) 1998-10-08

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