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WO2007066130A2 - Composition veterinaire - Google Patents

Composition veterinaire Download PDF

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Publication number
WO2007066130A2
WO2007066130A2 PCT/GB2006/004597 GB2006004597W WO2007066130A2 WO 2007066130 A2 WO2007066130 A2 WO 2007066130A2 GB 2006004597 W GB2006004597 W GB 2006004597W WO 2007066130 A2 WO2007066130 A2 WO 2007066130A2
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WO
WIPO (PCT)
Prior art keywords
flukes
closantel
medicament
endoparasites
salicylanilide
Prior art date
Application number
PCT/GB2006/004597
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English (en)
Other versions
WO2007066130A3 (fr
Inventor
Alistair Couper
Mona Ferry
Lillian Cromie
Willy Blakely
Original Assignee
Norbrook Laboratories Limited
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 Norbrook Laboratories Limited filed Critical Norbrook Laboratories Limited
Publication of WO2007066130A2 publication Critical patent/WO2007066130A2/fr
Publication of WO2007066130A3 publication Critical patent/WO2007066130A3/fr

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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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • This invention relates to the use of veterinary compositions for controlling endoparasites in animals, and in particular livestock.
  • the invention to be more
  • the invention therefore offers improvements in the prevention or reduction of re-infection of pasture with parasite eggs thereby reducing or eliminating parasitic infection of grazing cattle.
  • Closantel is a salicylanilide anthelmintic that binds almost exclusively to plasma albumin (Res. Vet. Science, 44, 229- 232, Michiels et al 1987) . As a result of its activity, it is mainly directed against blood-feeding internal parasites such as Fasciola hepatica, Haemonchus contortus and Oestrus ovls. It has been combined with the macrocyclic lactone anthelmintic ivermectin in an injectable combination
  • An object of the present invention is to provide a
  • veterinary composition which is useful for the inhibition of the reproductive capability of developing endoparasites and the resulting mature form in livestock including, but not limited to Fasciola hepatica (liver flukes) , Haemonchus contortus and Oestrus ovis, especially Fasciola hepatica.
  • "Developing" endoparasites is a term commonly used in the field of veterinary science to include early immatures (0 to 5 weeks old) and immatures (6 to 9 weeks old) .
  • a further object of the invention is to provide a method of treating livestock infected by endoparasites susceptible to treatment with a veterinary composition comprising a
  • salicylanilide which inhibits the reproductive capacity of developing stages of endoparasites.
  • composition comprising a reproductive inhibitor effective in the inhibition of the reproductive capability of developing parasites wherein said inhibitor comprises a salicylanilide, in a physiologically tolerable vehicle.
  • a reproductive inhibitor which comprises a salicylanilide for the manufacture of a veterinary medicament for the inhibition of the reproductive capability of developing endoparasites and the resulting mature form infecting an animal host.
  • the treatment comprises administering to the infected animal a veterinary medicament in a physiologically tolerable vehicle comprising a salicylanilide.
  • the salicylanilide can be closantel, tribromsalan,
  • the salicylanilide is closantel.
  • the salicylanilide can be present in an amount of from about 1 to about 30% (w/v) , preferably in an amount of from about 5 to about 20% (w/v) , more preferably in an amount of from about 10 to about 20% (w/v) and most preferably in an amount of either about 20% (w/v), 12.5% (w/v) or about 10% (w/v).
  • a salicylanilide preferably closantel
  • closantel a salicylanilide, preferably closantel
  • composition may include another
  • antiparasiticidal agent which is capable of inhibiting energy and/or protein production in early immature
  • a different flukicide may be used, e.g. a
  • benzenesulphonamide and/or a benzimidazole when a broad spectrum agent is used in conjunction with the preferred flukicide (s) , it may be a macrolactone e.g. an avermectin or milbemycin.
  • the benzenesulphonamide can be clorsulon.
  • the benzimidazole can be albendazole, fenbendazole,
  • the benzenesulphonamide and/or a benzimidazole can be present in an amount of from about 1 to about 30% (w/v) , preferably in an amount of from about 1 to about 15% (w/v) , more preferably in an amount of either about 10% (w/v) or about 5% (w/v) , and most preferably in an amount of about 5% (w/v) .
  • the benzenesulphonamide and/or a benzimidazole can be present in an amount of about 5% (w/v) .
  • the benzenesulphonamide and/or a benzimidazole can be present in an amount of about 10% (w/v) .
  • the avermectin can be ivermectin, abamectin, aversectin C, doramectin, eprinomectin, selamectin, e ⁇ iamectin or mixtures thereof.
  • the avermectin is ivermectin.
  • the avermectin can be present in an amount of from about 0.1 to about 10% (w/v) , preferably in an amount of from about 0.1 to about 2% (w/v) , and most preferably in an amount of about 0.5% (w/v) .
  • the milbemycin can be milbemycin oxime, moxidectin or mixtures thereof.
  • the milbemycin is moxidectin.
  • the milbemycin can be present in an amount of from about 0.1 to about 10% (w/v) , preferably in an amount of from about 0.1 to about 2% (w/v), and most preferably in an amount of about 0.5% (w/v) .
  • the moxidectin can be present in an amount of about 1% (w/v), 0.5% (w/v) and 0.1% (w/v) when the composition is a parenteral formulation, pour-on
  • the agents may be presented as a parenteral, oral or topical (e.g. "Pour-On") combination product, with the broad
  • salicylanilide for subsequent (later parasite life cycle stage) administration, or an optional additional flukicide and / or the broad spectrum agent.
  • composition is in the form of a parenteral
  • the preferred dose rates of the salicylanilide, and in particular closantel, for cattle is between about 1 to about 20 mg/kg, more preferably between about 2.5 and about 10 mg/kg, even more preferably either about 5 or 10 mg/kg and most preferably about 5 mg/kg. If an avermectin, preferably ivermectin, is present it can be given at a dose rate of about 100 ug to about 1 mg/kg and preferably about 200 ug/kg.
  • composition in the form of a parenteral formulation the salicylanilide
  • preferably closantel is present in an amount of about 12.5% (w/v) .
  • composition in the preparation of a 0.5% (w/v) ivermectin parenteral solution the composition can comprise the following: 0.5% w/v Ivermectin
  • composition in the preparation of a 0.5% (w/v) ivermectin parenteral solution the composition can comprise the following:
  • composition in the preparation of a 0.5% (w/v) ivermectin parenteral solution the composition can comprise the following:
  • polyvinyl pyrrolidone PVP
  • PEG Polyethylene glycol 200
  • closantel is then introduced with stirring as required.
  • the solution is sterilised by membrane filtration and packaged aseptically.
  • the delivery system comprises at least 20% v/v of one or more alcohols.
  • the preferred alcohols are monohydric aliphatic or aromatic alcohols, more preferably lower alkanols (Ci-C ⁇ )•
  • the most preferred delivery system comprises at least 20% v/v ethanol with isopropanol being additionally used to bring the formulation to 100% v/v for use.
  • the preferred dose rates of the salicylanilide, and in particular closantel, for cattle is between about 1 to about 30 mg/kg, more preferably between about 5 and about 25 mg/kg, even more preferably either about 10 or 20 mg/kg and most preferably about 20 mg/kg.
  • an avermectin preferably ivermectin
  • it can be given at a dose rate of about 100 ug to about 1 mg/kg and preferably about 500 ug/kg.
  • the salicylanilide preferably closantel
  • such a delivery system can further comprise a polymeric moiety selected from polyethylene glycol (PEG) , polyvinylpyrrolidone (PVP) and
  • the delivery system comprises PEG, PVP, or a poloxamer
  • the delivery system may be made for use with typical
  • auxiliaries such as surfactants, embittering denaturants (anti-licking) , preservatives, spreading aids, penetration or occlusion enhancers, and antioxidants, such as butylated hydroxyl toluene (BHT) , butylated hydroxyl anisole (BHA), or sodium formaldehyde-sulphoxylate .
  • BHT butylated hydroxyl toluene
  • BHA butylated hydroxyl anisole
  • sodium formaldehyde-sulphoxylate sodium formaldehyde-sulphoxylate
  • such a delivery system can comprise a lower aliphatic alcohol such as ethanol with a glycol solvent such as a PEG solvent, to which is added isopropanol to bring the solution to 100% (v/v) for use.
  • a lower aliphatic alcohol such as ethanol
  • a glycol solvent such as a PEG solvent
  • PEG solvents according to molecular weight is commercially available, and any of these, or others that may yet be made available, may be chosen for convenience
  • a preferred delivery system comprises the solvents PEG 200 with ethanol and isopropanol, together with a polymeric moiety (e.g. polyethylene glycol, polyvinyl pyrrolidone and poloxamers) to enhance permeability.
  • the polymeric moiety can be present in an amount of from about 0.1 % (W/v) to about 80% (w/v) , preferably from about 3% (w/v) to about 20% (w/v) .
  • the preferred polymeric moiety is polyvinyl pyrrolidone (PVP) . A proportion of the PVP may be substituted by higher
  • molecular weight polyethylene glycols up to molecular weight of 20000.
  • Crodamol CAP emollient ester mix
  • a drench or paste When presented as an oral formulation, a drench or paste, preferably a drench, can be used or oral formulations using polyvinyl pyrrolidone according to WO-A-03/072113 can be employed in order to obtain long acting levels of the salicylanilide in the blood plasma of the treated animal.
  • the preferred dose rates of the salicylanilide, and in particular closantel, for cattle is between about 1 to about 20 mg/kg, more preferably between about 2.5 and about 10 mg/kg, even more preferably either about 5 or 10 mg/kg and most preferably about 5 mg/kg. If an avermectin, preferably ivermectin, is present it can be given at a dose rate of about 100 ug to about 1 mg/kg and preferably about 200 ug/kg.
  • the invention offers advantages in challenging developing flukes, and inhibits the reproductive capacity in the flukes, thereby interrupting their life cycle, and rendering the mature flukes more susceptible to challenge by a
  • endoparasite burden on the animal is limited by restriction of the natural life cycle of the parasite in the treated animal host whereby its ability to develop and reproduce is inhibited.
  • the treatment is carried out in a period estimated to coincide with onset of maturity of the predicted parasitic infection of the animal and comprises administration of a salicylanilide in an amount effective for inhibiting
  • the proposed treatment has the following benefits.
  • Infecting endoparasites may be killed in some cases within a short time after infection, or prevented from infecting the host at all, but essentially for those endoparasites which mature, the proposed treatment is effective as discussed herein to reduce the ability of surviving parasites to reinfect the pasture.
  • the treatment is most effective against Fasciola hepatica, Haemonchus contortus and Oestrus ovis, especially Fasclola hepatica.
  • Friesian X of mixed sexes approximately six months of age. Although they had never grazed on pasture faeces samples were taken to ensure that they were not excreting any helminth eggs and therefore unlikely to be infected. It was proposed to test closantel in combination with a leading macrolactone broad spectrum product (ivermectin) which is considered to have no recognised activity as a flukicide (fasciolicide) .
  • ivermectin/closantel to be administered to those selected for treatment. After weighing they were assigned to
  • treatment groups A and B according to descending weight. Those of identical weight were further allocated by
  • Group A were injected subcutaneously in the neck with the ivermectin/closantel injection at a dose rate of 200 ⁇ gkg ⁇ 1 of ivermectin and ⁇ mgkg "1 of closantel.
  • Group B remained as untreated
  • parenchymal tissue were removed manually and placed in normal saline at 37 °C until the fluke collection from that liver was complete. Standard procedures were followed in preparation of the flukes for staining and histology.
  • the aim of the fluke recovery procedure is to evaluate the size, reproductive organ development, egg production and egg hatching after treatment using the aforesaid
  • hatched and un-hatched eggs were allowed to sediment in a jar. Sub-samples of this sediment were examined using a dissecting microscope, and approximately 500 eggs from each batch were scored as ⁇ hatched' or ⁇ un- hatched' . The proportion of hatched eggs was recorded as a percentage of total eggs scored for each batch.
  • Flukes that had been fixed with 70% ethanol were processed according to a recognised procedure and left to stain for 24hours.
  • the flukes were then rinsed with 35% ethanol and de-stained with frequent changes of acidified ethanol, until the flukes just retained an overall pink colour. They were then rinsed in non-acidified 70% ethanol and transferred through two 3-hour changes of absolute ethanol to xylene.
  • Testis representation and thickness of the dendritic tubules comprising the testicular tissue in the posterio- medial region of the body.
  • Vitellaria distribution and density of catechol-induced tanning in the posterior and posterio-lateral regions of the body.
  • Uterus presence and abundance of tanned eggs immediately posterior to the acetabulum.
  • Ovary representation and thickness of the dendritic tubules comprising the ovarian tissue that lies in a pre-testicular position to the observer's left of the uterus (with the acetabulum facing the observer) .
  • the size measurements and the individual scores for the reproductive structures for each fluke were recorded for subsequent statistical analysis.
  • the ⁇ size index' was the product of the length and width measurements.
  • Each formalin-fixed fluke was transected at the level of the Menus' gland (at the posterior margin of the uterus, where the width of the body is greatest) and the posterior and anterior ends were processed separately through conventional procedures of alcohol-dehydration and wax-embedding for histological sectioning.
  • the ten posterior ends in each batch were aligned together in a single wax block so that the plane of section was parallel to the planes of
  • each fluke section transection of the flukes.
  • the ten anterior ends were aligned similarly in a separate wax block.
  • the dimensions of each fluke section reflected the width and thickness of the fluke.
  • Histological sections 3 micrometers thick were cut from each wax block and stained with haematoxylin and eosin following conventional procedures.
  • sections of the posterior ends of the flukes were used to study histological variations in testis and vitelline structure in different individuals, whilst sections of the anterior ends revealed details relating to the ovary and uterus.
  • dendritic tubules were assessed as (i) well defined and turgid throughout the posterio-medial field; (ii) those where the tubules were less defined and at least in some areas appeared shrunken or collapsed; (iii) and those flukes in which the testis tubules could not be distinguished from the ramifying gut caeca. Vitellaria:
  • Catechol acts as a substrate for phenol oxidase, an enzyme associated with the shell precursor proteins in mature vitelline cells and involved in the quinone-tanning process during maturation of the eggs in the uterus.
  • the intensity and distribution of dark brown staining in the posterior and posterio-lateral regions of flukes incubated in catechol was taken to reflect the abundance and localisation of mature cells in the vitelline tissue. Scoring for those flukes showing dense staining throughout the vitelline field was 3. In some cases the intensity of staining was reduced or patchy in distribution for which flukes were scored 1 or 2 for vitelline development. The smallest flukes often showed no evidence of catechol tanning, and these were given a score of 0.
  • Uterus
  • a score of 3 was given to those individuals in which the antero-medial area of the body was occupied by a thick, extensively coiled uterine tube packed with tanned eggs. Flukes in which the uterine tube was narrower containing fewer eggs, were given a score of 2. If only a few tanned eggs were evident a score of 1 was considered appropriate, whilst flukes with no eggs in the uterine area were given a score of 0.
  • Plasma closantel concentrations At 7 and 14 days post treatment the mean plasma concentrations of closantel in Group A were 36.2 (S. D 5.4) and 26.7 (S. D. 6.7) ⁇ gml "1 .
  • the geometric mean fluke count of the untreated Group B was 184.6 (range 93-281), whilst that of Group A was 105.8 (range 51-226). The reduction in fluke count in Group A was 42.6%.
  • the mean size index for control Group B was 186.3mm 2
  • the egg shedding score for Group B was 4.62 (S. D. 1.2).
  • the corresponding score for Group A was 2.25 (S. D 1.3).
  • the score for Group B was 4.62 (S. D. 1.2).
  • spermatocytes which undergo the two divisions of meiosis, and the spermatids.
  • Sections of narrower flukes i.e. those with a lower size score
  • Sections of narrower flukes i.e. those with a lower size score
  • tubules often contained fewer cells and considerable 'empty' (non- cellular) space.
  • the cells present were predominantly primary and secondary spermatogonia. Fewer tertiary
  • spermatogonia, spermatocytes and spermatids were present than in the densely packed tubules described above.
  • Vitelline follicles were present towards the lateral margins of all the sections examined, and were clustered in a broad zone in the parenchyma immediately beneath the peripheral musculature and tegumental perikarya.
  • Each follicle comprised a small group of 10 to 20 cells, amongst which three types were distinguishable at light microscope level.
  • the S (stem) cells were located
  • Profiles of the coiled uterine tube were a conspicuous feature in sections of the anterior portions of flukes. In general, these profiles encompassed sections of many eggs, each of which was enveloped with a thin shell (often broken or displaced during processing) and contained mature
  • vitelline cells The eggs usually appeared distorted due to dehydration.
  • the wall of the uterus itself was a thin cytoplasmic layer enclosing elongated nuclei at intervals and exhibiting fine microvilli or microlamellae on the lumenal aspect.
  • the uterine profiles often appeared as empty spaces, with no evidence of eggs. This corresponded with the appearance of the uterine field in whole mount preparations of small flukes, which often received a score of 0 for presence of eggs .
  • Profiles of the dendritic tubules of the ovary were located dorso-lateral to the uterus in sections of the anterior portions of flukes. The diameter of these profiles varied from fluke to fluke, and to some extent within each
  • each ovarian tubule had thicker ovarian tubules than small flukes with a low reproductive score.
  • the wall of each ovarian tubule was relatively thick, containing muscle tissue lined with ⁇ nurse cells' .
  • Oogonia which are small cells with densely basophilic nuclei and a high nucleo- cytoplasmic ratio, were distributed peripherally in each tubule.
  • Primary oocytes derived from the oogonia by mitotic division and subsequent differentiation, were located towards the centre of each tubule. The primary oocytes were relatively large, rounded cells with abundant pale-staining vesiculated cytoplasm.
  • closantel Whilst ivermectin is not effective as a fasciolicide, closantel is known to act as an uncoupler of oxidative phosphorylation in flukes and in addition is believed to have a significant neurotoxic effect, causing spastic paralysis, detachment from the food source in vivo and starvation (Fairweather and Boray, "Fasciolosis” Ch.7 ed. J. P. Dalton, 277-305, CABI Publ . UK 1998).
  • closantel which by its inhibitory effects on feeding and intermediary metabolism in flukes reduces the availability of ATP for the energy-demanding processes of gametogenesis and oogenesis, causes down-regulation of egg production but does not appear to induce functional defects in the gonads or accessory reproductive organs.
  • the spurt in growth and reproductive development in the bile ducts may be facilitated by reduction in the need to constantly renew the surface glycocalyx of the tegument in the face of humoral and cell mediated attack by the host (Hughes, Hanna and Symonds, Exp. Parasitology, 52, 271-279, 1981).
  • Newly excysted juvenile flukes rely on aerobic metabolism and are dependant on Kreb's cycle activity. During the period of migration in the liver parenchyma, the activity of Kreb's cycle decreases and acetate becomes the major end- product, but oxygen is still required to re-oxidise NADH.
  • Adult flukes in the bile ducts are anaerobes, utilizing malate dismutation to re-oxidise NADH (Tielens, Ch.8
  • flukes in the hepatic parenchyma might have an advantage over those in the bile ducts because even if paralyzed they would still lie in a nutritive medium and energy substrates such as glucose could still enter by diffusion across the tegument.
  • spermatogenesis and spermiogenesis which involve mitotic and meiotic divisions as well as cellular differentiation, proceed at rates dictated by the availability of ATP.
  • testis follicles of larger flukes which predominated in the control populations, generally had numerous cell types, representing all stages in the process of spermatogenesis.
  • spermatogonia and spermatocytes were more abundant than primary spermatogonia.
  • a full account of spermatogenesis and spermiogenesis in Fasciola hepatica has been given by Stitt and Fairweather, Parasitology, 101, 395-407 (1990) .
  • histological sections of the ovary in small flukes were narrow in comparison to those in larger flukes. They contained numerous peripheral oogonia (the equivalent of stem cells ) but few primary oocytes, which packed the core of ovarian tubules in flukes with a high reproductive score. The narrow diameter of the ovarian tubules in small flukes was also evident in the whole-mount preparations. The predominance of oogonia in the ovarian tubules of flukes with a low reproductive score reflects a reduced level of functional activity including cellular division and
  • oogonia undergo a number of mitotic divisions to form primary oocytes which are much larger than the oogonia ( 25 micrometers in
  • ivermectin/closantel to be administered to those selected for treatment. After weighing they were assigned to
  • ivermectin/closantel combination pour-on at a dose rate of 500 ⁇ gkg "1 ivermectin and 10 mgkg "1 closantel.
  • Group Y remained as untreated controls.
  • Blood samples were taken from group X on days +7 and +14 to monitor closantel plasma concentrations.
  • concentrations for the pour-on formulations in Group X were 41.9 (S. D. 8.8) and 31.8 (S. D.8.2) ⁇ gml "1 .
  • the reduction in size for Group X when compared to Group Y was 35.6%. After conversion to logarithms for analysis there was a significant difference between the sizes of Groups X and Y. F. hepatica reproductive score
  • the egg shedding score for Group Y was 4.62 (S. D. 1.2).
  • the corresponding score for Group X was 3.1 (S. D. 1.7). After non-parametric analysis there was no difference between between Groups X and Y.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'un inhibiteur de la reproduction comprenant un salicylanilide pour la fabrication d'un médicament vétérinaire destiné à l'inhibition de la capacité reproductrice des endoparasites en développement et de la forme mature résultante infectant un hôte animal.
PCT/GB2006/004597 2005-12-09 2006-12-08 Composition veterinaire WO2007066130A2 (fr)

Applications Claiming Priority (2)

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GB0525093.1 2005-12-09
GBGB0525093.1A GB0525093D0 (en) 2005-12-09 2005-12-09 Veterinary composition

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WO2007066130A2 true WO2007066130A2 (fr) 2007-06-14
WO2007066130A3 WO2007066130A3 (fr) 2007-08-16

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FR2991173A1 (fr) * 2012-06-04 2013-12-06 Virbac Composition veterinaire a administration cutanee a base d'oxyclozanide
EA022327B1 (ru) * 2013-01-04 2015-12-30 Общество С Ограниченной Ответственностью "Рубикон" Инъекционное ветеринарное средство в форме раствора для борьбы с полиинвазиями животного и способ его получения
WO2017157997A1 (fr) * 2016-03-16 2017-09-21 Antibiotx Aps Compositions topiques non aqueuses comprenant un salicylanilide halogéné
US9949988B2 (en) 2014-09-12 2018-04-24 Antibiotx A/S Antibacterial use of halogenated salicylanilides
EP3403652A1 (fr) * 2017-05-18 2018-11-21 Veterinärmedizinische Universität Wien Prévention et traitement de troubles associés au facteur de croissance 23 des fibroblastes (fgf23) incluant la maladie rénale chronique (ckd)
IT201800004309A1 (it) * 2018-04-09 2019-10-09 Trattamenti topici per la miasi oculare
US10463680B2 (en) 2015-05-29 2019-11-05 UNION therapeutics A/S Halogenated salicylanilides for treating clostridium infections
US11419834B2 (en) 2019-02-25 2022-08-23 Rhode Island Hospital Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide

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Publication number Priority date Publication date Assignee Title
ZA944191B (en) * 1993-06-15 1995-02-08 Univ Australian Synergistic anthelmintic compositions
US6340672B1 (en) * 2000-02-16 2002-01-22 Phoenix Scientific, Inc. Parasiticidal formulation and a method of making this formulation

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AR058298A1 (es) 2008-01-30

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