U.S. patent application number 15/537547 was filed with the patent office on 2017-12-07 for use of isoxazoline compounds for treating demodicosis.
This patent application is currently assigned to Intervet Inc.. The applicant listed for this patent is Intervet Inc.. Invention is credited to Regis Joel Alain Frenais, Anja Regina Heckeroth, Janina Tanzler, Heike Williams.
Application Number | 20170348286 15/537547 |
Document ID | / |
Family ID | 52146273 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170348286 |
Kind Code |
A1 |
Williams; Heike ; et
al. |
December 7, 2017 |
USE OF ISOXAZOLINE COMPOUNDS FOR TREATING DEMODICOSIS
Abstract
The present invention relates to methods of treating demodicosis
by administering an isoxazoline compound of formula (I).
##STR00001##
Inventors: |
Williams; Heike; (Offenbach
am Main, DE) ; Heckeroth; Anja Regina;
(Stadecken-Elsheim, DE) ; Tanzler; Janina;
(Nieder-Olm, DE) ; Frenais; Regis Joel Alain;
(Meignanne, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intervet Inc. |
Madison |
NJ |
US |
|
|
Assignee: |
Intervet Inc.
Madison
NJ
|
Family ID: |
52146273 |
Appl. No.: |
15/537547 |
Filed: |
December 21, 2015 |
PCT Filed: |
December 21, 2015 |
PCT NO: |
PCT/EP2015/080744 |
371 Date: |
June 19, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61P 33/14 20180101; A61K 9/0056 20130101; A61K 9/0053 20130101;
A61K 9/0019 20130101; A61K 31/42 20130101; A61K 31/422 20130101;
A61K 9/20 20130101 |
International
Class: |
A61K 31/42 20060101
A61K031/42; A61K 9/20 20060101 A61K009/20; A61K 9/00 20060101
A61K009/00; A61K 31/422 20060101 A61K031/422 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2014 |
EP |
14199562.1 |
Claims
1. Method of treating generalized demodicosis in mammals comprising
administering an effective amount of an isoxazoline compound of
formula (I) ##STR00020## wherein R.sup.1=halogen, CF.sub.3,
OCF.sub.3, CN, n=integer from 0 to 3,
R.sup.2=C.sub.1-C.sub.3-haloalkyl, T=5- or 6-membered ring, which
is optionally substituted by one or more radicals Y, Y=methyl,
halomethyl, halogen, CN, NO.sub.2, NH.sub.2--C.dbd.S, or two
adjacent radicals Y form together a chain; Q=X--NR.sup.3R.sup.4 or
a 5-membered N-heteroaryl ring, which is optionally substituted by
one or more radicals; X=CH.sub.2, CH(CH.sub.3), CH(CN), CO, CS,
R.sup.3=hydrogen, methyl, haloethyl, halopropyl, halobutyl,
methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl,
haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl,
ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,
haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,
tetrahydrofuryl, methylaminocarbonylmethyl,
(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,
cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,
haloethylaminocarbonylcyclopropyl, ##STR00021## ##STR00022##
wherein Z.sup.A=hydrogen, halogen, cyano, halomethyl (CF.sub.3);
R.sup.4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl,
ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl,
methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl,
ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or
R.sup.3 and R.sup.4 together form a substituent selected from the
group consisting of: ##STR00023## or a salt or solvate or N oxide
thereof.
2. The method according to claim 1 wherein the isoxazoline compound
of formula (I) is fluralaner.
3. The method according to claim 1 wherein the isoxazoline compound
is administered once, twice or three times.
4. The method according to claim 1 comprising a single
administration of the isoxazoline compound to a mammal.
5. The method according to claim 1 wherein the isoxazoline compound
is administered to the mammal orally
6. The method according to claim 1 wherein the isoxazoline compound
is administered to the mammal topically.
7. The method according to claim 1 wherein the isoxazoline compound
is administered to the mammal parenterally by injection.
8. The method according to claim 1 wherein the mammal is a
companion animal.
9. The method according to claim 1 wherein the companion animal is
a dog.
10. Method of controlling Demodex spp. mites in dogs after a single
administration of an isoxazoline compound of formula (I).
11. The method according to claim 10 wherein the isoxazoline
compound of formula (I) is fluralaner.
12. The method according to claim 10 wherein the Demodex spp. mites
are controlled for at least 56 days.
13. The method according to claim 10 wherein the isoxazoline
compound is administered to the mammal orally.
14. The method according to claim 10 wherein the isoxazoline
compound is administered to the mammal topically.
15. The method according to claim 10 wherein the isoxazoline
compound is administered to the mammal parenterally by
injection.
16. The method according to claim 1 wherein the isoxazoline
compound is afoxalaner.
17. The method according to claim 1 wherein the isoxazoline
compound is sarolaner.
18. The method according to claim 1 comprising a single
administration of 10-40 mg/kg bodyweight fluralaner to dogs that
have been diagnosed with generalized demodicosis.
19. The method of claim 1, where n is 1, 2 or 3.
20. The method of claim 1, wherein R.sup.2 is CF.sub.3 or
CF.sub.2Cl.
21. The method of claim 1, wherein two adjacent radicals Y form
together a three or four membered chain.
Description
FIELD OF INVENTION
[0001] The present invention relates to the prevention or treatment
of parasitic arthropod infestations of animals.
BACKGROUND OF INVENTION
[0002] Demodex spp. mites are normal commensals of the skin of a
number of animals parasitising within the sebaceous glands
connected to the hair follicles. Should their numbers increase
dramatically, they are capable of producing a disease known as
demodicosis or demodectic mange.
[0003] Demodicosis is a non contagious inflammatory parasitic
dermatosis caused by overpopulation of the follicular Demodex
mites. Demodicosis can be classified as localized or generalized
according to the extent of the lesions. Localized demodicosis is a
benign disease and most cases resolve spontaneously within six to
eight weeks.
[0004] Generalized demodicosis is a severe disease with generalized
lesions that are usually aggravated by secondary bacterial
infections (pyodemodicosis). Accompanying pododermatitis is common.
Dogs can have systemic illness with generalized lymphadenopathy,
lethargy, and fever when deep pyoderma, furunculosis, or cellulitis
is seen. Diagnosis is not difficult, as deep skin scrapings or hair
plucking reveal mites, eggs, and larval forms in high numbers.
[0005] Chronic generalized demodicosis is a frustrating and
difficult skin disease to treat. In dogs that are otherwise
healthy, the generalized form of the disease is unlikely to resolve
without therapy.
[0006] Therapeutic options that are currently available include
amitraz, ivermectin, milbemycin oxime, moxidectin orally and
moxidectin topically, mostly to be given at multiple occasions
(daily, weekly or monthly) for periods of three months or more.
[0007] To be effective, these treatment regimens require high owner
compliance over an extended period of time. Owner compliance can be
an important factor in treatment success when multiple doses of a
treatment spread over a long period of time are required in order
to achieve a satisfactory outcome.
[0008] A problem frequently encountered with the treatment of
demodicosis in dogs is the inability to ensure that a dog is
absolutely free from mites after treatment and re-infestation can
be detected months after completion of a treatment that was
initially considered to be successful.
[0009] Therefore it is desirable to provide a method to treat
Demodex spp. infestation and demodicosis in animals, especially
dogs, that effectively controls mites and is convenient to
administer and therefore supports owner compliance and prevents
re-infestation and relapse of the disease.
SUMMARY OF THE INVENTION
[0010] The current invention provides to use an isoxazoline
compound of formula (I)
##STR00002##
wherein
[0011] R.sup.1=halogen, CF.sub.3, OCF.sub.3, CN,
[0012] n=integer from 0 to 3, preferably 1, 2 or 3,
[0013] R.sup.2=C.sub.1-C.sub.3-haloalkyl, preferably CF.sub.3 or
CF.sub.2Cl,
[0014] T=5- or 6-membered ring, which is optionally substituted by
one or more radicals Y,
[0015] Y=methyl, halomethyl, halogen, CN, NO.sub.2,
NH.sub.2--C.dbd.S, or two adjacent radicals Y form together a
chain, especially a three or four membered chain;
[0016] Q=X--NR.sup.3R.sup.4 or a 5-membered N-heteroaryl ring,
which is optionally substituted by one or more radicals;
[0017] X=CH.sub.2, CH(CH.sub.3), CH(CN), CO, CS,
[0018] R.sup.3=hydrogen, methyl, haloethyl, halopropyl, halobutyl,
methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl,
haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl,
ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,
haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,
tetrahydrofuryl, methylaminocarbonylmethyl,
(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,
cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,
haloethylaminocarbonylcyclopropyl,
##STR00003## ##STR00004##
[0019] wherein Z.sup.A=hydrogen, halogen, cyano, halomethyl
(CF.sub.3);
[0020] R.sup.4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl,
ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl,
methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl,
ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl;
[0021] Or R.sup.3 and R.sup.4 together form a substituent selected
from the group consisting of:
##STR00005##
[0022] or a salt or solvate or N-oxide thereof for the manufacture
of a medicament for the treatment of demodicosis in mammals,
especially companion animals, especially dogs.
[0023] This invention also is directed to the isoxazoline compound
as described in this application or a pharmaceutical composition
comprising such isoxazoline compound for use in the treatment of
generalized demodicosis in animals comprising an effective amount
of an isoxazoline compound as described in this specification, and,
in case of the pharmaceutical formulation, a pharmaceutically
acceptable carrier.
[0024] The current invention further provides a method of
controlling Demodex spp. mites in dogs comprising a single
administration of an isoxazoline compound as described in this
specification.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The inventors of the current invention discovered that
demodicosis of mammals can be treated by administering an effective
amount of an isoxazoline compound as described in this application.
It has been found that a single administration of such an
isoxazoline compound resulted in a complete miticidal effect
against Demodex spp. mites and a high efficacy against generalized
demodicosis in dogs.
[0026] As it has been shown in the example, after single
administration of fluralaner as Bravecto.RTM. chewable tablets to
dogs, mite numbers in skin scrapings were reduced by 99.8% on Day
28 and by 100% on Days 56 and 84 after administration.
Statistically significantly (P 0.05) fewer mites were found on Days
56 and 84 on the Bravecto.RTM. treated dogs compared to the dogs
that received the prior art Advocate.RTM. (imidacloprid/moxidectin)
treatment on three occasions in 28 day intervals.
[0027] The prior art methods for the control of generalized
demodicosis require all multiple treatments (daily or very frequent
administration) of either amitraz or macrocyclic lactones such as
milbemycin oxime, moxidection, ivermectin, doramectin or selamectin
over a long time period.
[0028] Such multiple treatments are very burdensome as frequent
handling is necessary, that require cooperation of the treated
animal, which is not always the case.
[0029] A further downside of the prior art methods and reason of
limited owner compliance is the high cost associated with such
treatment regimens.
[0030] The prior art administration of the compounds additionally
bear a high risk of side effects of such treatments because
relatively high dosages of the miticidal compounds over an extended
time period resulted in some cases in severe toxic side effects in
treated animals, especially for ivermectin sensitive breeds of dogs
such as e.g. collies.
[0031] Especially the prior art bath treatment with amitraz
additionally required the owner to take special measures to avoid
contact with the compound and bathing should be done in a
well-ventilated area. Furthermore clipping of the dog's hair coat
was required for full efficacy.
[0032] However I, in case the necessary treatment schedule is not
completed, because of lack of owner compliance, the risk of a
relapse of the demodicosis is very high. Another reason for
treatment failure is that the used compounds had limited efficacy
and some Demodex mites survived the treatment.
[0033] The current inventors surprisingly found that such
disadvantages of the prior art can be prevented, if an isoxazoline
compound as described in this application, especially fluralaner is
used.
[0034] By the method of the current invention, that requires
administration of an effective dosage of an isoxazoline compound
according to the current invention, a premature treatment cessation
by owners will be avoided.
[0035] The isoxazoline compound for use in the current invention
can be described by Formula (I):
##STR00006##
[0036] wherein
[0037] R.sup.1=halogen, CF.sub.3, OCF.sub.3, CN,
[0038] n=integer from 0 to 3, preferably 1, 2 or 3,
[0039] R.sup.2=C.sub.1-C.sub.3-haloalkyl, preferably CF.sub.3 or
CF.sub.2Cl,
[0040] T=5- or 6-membered ring, which is optionally substituted by
one or more radicals Y,
[0041] Y=methyl, halomethyl, halogen, CN, NO.sub.2,
NH.sub.2--C.dbd.S, or two adjacent radicals Y form together a chain
CH--CH.dbd.CH--CH, N--CH.dbd.CH--CH, CH--N.dbd.CH--CH,
CH--CH.dbd.N--CH, or CH--CH.dbd.CH--N, HC.dbd.HC--CH,
CH--CH.dbd.CH, CH.dbd.CH--N, N--CH.dbd.CH;
[0042] Q=X--NR.sup.3R.sup.4 or a 5-membered N-heteroaryl ring,
which is optionally substituted by one or more radicals Z.sup.A,
Z.sup.B Z.sup.D;
[0043] X=CH.sub.2, CH(CH.sub.3), CH(CN), CO, CS,
[0044] R.sup.3=hydrogen, methyl, haloethyl, halopropyl, halobutyl,
methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl,
haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl,
ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,
haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,
tetrahydrofuryl, methylaminocarbonylmethyl,
(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,
cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,
haloethylaminocarbonylcyclopropyl,
##STR00007## ##STR00008##
[0045] R.sup.4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl,
ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl,
methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl,
ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl;
or
[0046] R.sup.3 and R.sup.4 together form a substituent selected
from the group consisting of:
##STR00009##
[0047] wherein Z.sup.A=hydrogen, halogen, cyano, halomethyl
(CF.sub.3).
[0048] In one preferred embodiment in Formula (I) T is selected
from
##STR00010## ##STR00011## ##STR00012##
[0049] wherein in T-1, T-3 and T-4 the radical Y is hydrogen,
halogen, methyl, halomethyl, ethyl, haloethyl.
[0050] In an preferred embodiment in Formula (I) Q is selected
from
##STR00013##
[0051] wherein R.sup.3, R.sup.4, X and Z.sup.A are as defined
above.
##STR00014## ##STR00015##
[0052] Preferred isoxazoline compounds of Formula (I) for use in
the current invention are:
TABLE-US-00001 (R.sup.1).sub.n R.sup.2 R.sup.3 R.sup.4 T Y Q Z X
3-Cl, 5Cl CF.sub.3 CH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-2 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-CF.sub.3,
5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O)
3-CF.sub.3, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 --
Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 -- T-2 -- Q-6 Z.sup.B-7 3-Cl, 5Cl
CF.sub.3 -- -- T-2 -- Q-7 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 --
Q-5 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 -- Q-2 Z.sup.D-1 3-Cl,
5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 --
C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CC H T-3 CH.sub.3 Q-1
-- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CN H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3
CH.sub.3 Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H
T-3 CH.sub.3 Q-1 -- C(O) 3-Cl, 4-Cl, CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 5-Cl
3-Cl, 4-Cl, CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3 CH.sub.3
Q-1 -- C(O) 5-Cl 3-Cl, 4-F, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
4-F, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-20 -- Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 CH.sub.3 T-20 --
Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 CH.sub.3 T-20 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-20 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 --
C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3
H T-21 -- Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl,
5-Cl CF.sub.3 CH.sub.2CH.sub.2SCH.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl,
4-Cl, CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 -- CH.sub.2 5-Cl 3-Cl,
4-Cl, CF.sub.3 C(O)CH(CH.sub.3).sub.2 H T-22 F Q-1 -- CH.sub.2 5-Cl
3-Cl, 4-Cl, CF.sub.3 C(O)-cyclo-propyl H T-22 F Q-1 -- CH.sub.2
5-Cl 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 -- CH.sub.2
3-Cl, 4-Cl, CF.sub.3 C(O)CH.sub.2CH.sub.3 H T-22 F Q-1 -- CH.sub.2
5-Cl 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 Cl Q-1 --
CH.sub.2 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-1
CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl,
5-Cl CF.sub.3 R.sup.3-1 (Z) H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 R.sup.3-1 (E) H T-1 CH.sub.3 Q-1 -- C(O)
[0053] Especially preferred isoxazoline compounds for use in the
current invention are
TABLE-US-00002 (R.sup.1).sub.n R.sup.2 R.sup.3 R.sup.4 T Y Q Z X
3-Cl, 5Cl CF.sub.3 CH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 --
C(O) 3-CF.sub.3, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2
-- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 -- T-2 -- Q-6 Z.sup.B-7 3-Cl, 5Cl
CF.sub.3 -- -- T-2 -- Q-7 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 --
Q-5 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 -- Q-2 Z.sup.D-1 3-Cl,
5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 --
C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CC H T-3 CH.sub.3 Q-1
-- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CN H T-3 CH.sub.3
Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
4-Cl, CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 --
C(O) 5-Cl 3-Cl, 4-F, CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3
CH.sub.3 Q-1 -- C(O) 5-Cl 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 CH.sub.3 T-20 --
Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 --
C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 --
Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2CH.sub.2SCH.sub.3 H T-21 --
Q-1 -- C(O) 3-Cl, 4-Cl, CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 --
CH.sub.2 5-Cl 3-Cl, 4-Cl, CF.sub.3 C(O)CH(CH.sub.3).sub.2 H T-22 F
Q-1 -- CH.sub.2 5-Cl 3-Cl, 4-Cl, CF.sub.3 C(O)-cyclo-propyl H T-22
F Q-1 -- CH.sub.2 5-Cl 3-Cl, 4-F, CF.sub.3 C(O)CH.sub.3 H T-22 F
Q-1 -- CH.sub.2 5-Cl 3-Cl, 4-Cl, CF.sub.3 C(O)CH.sub.2CH.sub.3 H
T-22 F Q-1 -- CH.sub.2 5-Cl 3-Cl, 4-F, CF.sub.3 C(O)CH.sub.3 H T-22
Cl Q-1 -- CH.sub.2 5-Cl 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl,
5-Cl CF.sub.3 R.sup.3-1 (Z) H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 R.sup.3-1 (E) H T-1 CH.sub.3 Q-1 -- C(O)
[0054] A more preferred isoxazoline compound for use in the current
invention has the Formula (II),
##STR00016##
[0055] wherein
[0056] R.sup.1a, R.sup.1b, R.sup.1c are independently from each
other hydrogen, Cl or CF.sub.3, preferably R.sup.1a and R.sup.1c
are Cl or CF.sub.3 and R.sup.1b is hydrogen,
[0057] T is
##STR00017##
[0058] wherein
[0059] Y is methyl, bromine, Cl, F, CN or C(S)NH.sub.2, and
[0060] Q is as described above.
[0061] In another preferred embodiment in Formula (II) R.sup.3 is H
and R.sup.4 is --CH.sub.2--C(O)--NH--CH.sub.2--CF.sub.3,
--CH.sub.2--C(O)--NH--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CF.sub.3 or --CH.sub.2--CF.sub.3
[0062] In a preferred embodiment the isoxazoline compound is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN
864731-61-3--USAN fluralaner).
[0063] In another embodiment the isoxazoline compound is
(Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-
-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN
928789-76-8).
[0064] In another embodiment the isoxazoline compound is
4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl--
N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed
in WO2009/0080250.
[0065] In another embodiment the isoxazoline compound is Ethanone,
1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethy-
l)-3-isoxazolyl]spiro[azetidine-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsu-
lfonyl)--(Sarolaner) (CAS RN-- 1398609-39-6).
##STR00018##
[0066] In another embodiment the isoxazoline compound is
2-Thiophenecarboxamide,
5-((5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxa-
zolyl)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)--(INN
Lotilaner) (CAS RN-- 1369852-71-0).
##STR00019##
[0067] In another preferred embodiment the isoxazoline compound is
4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-
-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalen-
ecarboxamide (CAS RN 1093861-60-9, USAN--afoxolaner) that was
disclosed in WO2007/079162--.
[0068] In another embodiment the isoxazoline compound is
5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-
-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxam-
ide (CAS RN 1231754-09-8) that was disclosed in WO2010/070068.
[0069] Isoxazoline compounds and their use as antiparasitics are
e.g. described in US patent application US 2007/0066617, and
International Patent applications WO 2005/085216, WO 2007/079162,
WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068 and
WO 2010/079077.
[0070] The method (or use) of this invention comprises to use
racemic mixtures, for example, equal amounts of the enantiomers of
such isoxazoline compounds as described above. In addition, the
method of this invention includes isoxazoline compounds that are
enriched compared to the racemic mixture in an enantiomer of
Formula 1. Also included are the essentially pure enantiomers of
such isoxazoline compounds.
[0071] When enantiomerically enriched, one enantiomer is present in
greater amounts than the other, and the extent of enrichment can be
defined by an expression of enantiomeric excess ("ee"), which is
defined as (2x-I)-100%, where x is the mole fraction of the
dominant enantiomer in the mixture (e.g., an ee of 20% corresponds
to a 60:40 ratio of enantiomers). Preferably the compositions for
use in the current invention have at least a 50% enantiomeric
excess; more preferably at least a 75% enantiomeric excess; still
more preferably at least a 90% enantiomeric excess; and the most
preferably at least a 94% enantiomeric excess of the more active
isomer. Of particular note are enantiomerically pure embodiments of
the more active isomer.
[0072] Isoxazoline compounds as described above can comprise
additional chiral centers. The method of this invention comprises
racemic mixtures as well as enriched and essentially pure stereo
configurations at these additional chiral centers.
[0073] The reference to isoxazoline compound in this specification
includes enantiomers, salts and solvates as well as N-oxides
thereof that can be produced by conventional methods.
[0074] By "treating" or "treat" or "treatment" is intended the
application or administration of a compound or composition to an
animal that has a parasitic infestation for the eradication of the
parasite or the reduction of the number of parasites, infesting the
animal (eliminate existing parasites). The effect can be e.g.
ovicidal, larvicidal nymphicidal, or adulticidal or a combination
thereof. The effect can manifest itself directly, i.e. killing the
parasites either immediately or after some time has elapsed, for
example when molting occurs, or by destroying their eggs, or
indirectly, e.g. reducing the number of eggs laid and/or the
hatching rate.
[0075] An "effective amount," is the amount or quantity of an
isoxazoline compound as described above that is required to treat
Demodex spp. infestations of animals, i.e. to alleviate or reduce
parasite numbers on an animal, and/or to inhibit the development of
parasite infections on an animal, in whole or in part.
[0076] This amount is readily determined by observation or
detection of the parasite numbers on the animal both before and
after administering an isoxazoline compound as described above to
such animals, e.g. the parasite count is reduced, after a first
administration, by 5% to about 100%, preferably more than 50%, more
than 70%, more than 90%, more than 95%, more than 99%, especially
100%.
[0077] Preferably the effective amount results in microscopical
cure, i.e. that no Demodex spp. mites are present in the deep skin
scrapings of affected skin (preferably three to five scrapings of
most severely affected areas), preferably taken at several time
points.
[0078] The effective amount for treatment of generalized
demodicosis additionally leads to diminishing or resolution of
clinical signs of demodicosis as described in this application.
[0079] Typically effective (dosage) amount of isoxazoline
compounds, are between 1 mg/kg bodyweight of the treated animal and
50 mg/kg bodyweight, or 5 mg/kg bodyweight to 45 mg/kg bw, or 10
mg/kg bw to 40 mg/kg bw, or 20 to 30 mg/kg bw. In one embodiment
the effective dosage is 25 mg/kg bodyweight.
[0080] In one embodiment a single dose of an effective amount of
the isoxazoline compound is administered to a mammal, especially
dog, that is infested with Demodex spp. mites.
[0081] In one embodiment a single dose of an effective amount of
the isoxazoline compound is administered to a dog that has been
diagnosed with a generalized canine demodicosis.
[0082] In another embodiment two doses of an effective amount of
the isoxazoline compound are administered to a mammal, especially
dog, that is infested with Demodex spp. mites.
[0083] In one embodiment a two doses of an effective amount of the
isoxazoline compound are administered to a dog that has been
diagnosed with a generalized canine demodicosis.
[0084] In another embodiment three doses of an effective amount of
the isoxazoline compound are administered to a mammal, especially
dog, that is infested with Demodex spp. mites.
[0085] In one embodiment a three doses of an effective amount of
the isoxazoline compound are administered to a dog that has been
diagnosed with a generalized canine demodicosis.
[0086] Preferred is the systemic administration of the isoxazoline
compounds. "Systemic administration" is an administration at a site
remote from a site wherein at least a portion of the target
parasites reside. With systemic administration, at least a portion
of the isoxazoline compound reaches the target parasite via the
animal recipient's bloodstream, other body fluids (lymph fluids),
and/or tissues (e.g., skin or fat tissue). This is in contrast to
"contact activity" were the surface of the parasite body is
directly exposed to the isoxazoline compound. Typically, the
parasite ingests the systemic administered isoxazoline along with
the animal recipient's blood, other body fluids, and/or tissue.
Systemic administration may be achieved in several forms, e.g.
oral, parenteral or via topical administration wherein the
isoxazoline compound is transdermally absorbed.
[0087] In some embodiments, the isoxazoline compound is
systemically administered via an oral route in a unit dosage form,
such as, for example, a soft or hard capsule, a pill, a powder,
granules, a tablet (e.g., a chewable tablet), a paste, a solution,
a suspension (aqueous or non-aqueous), an emulsion (oil-in-water or
water-in-oil), an elixir, a syrup, a bolus, a drench, or via the
animal recipient's feed or drinking water. Alternatively oral
administration can be performed via the animal recipient's feed or
drinking water e.g. it may be intimately dispersed in the animal
recipient's regular feed, used as a top dressing, or in the form of
pellets or liquid that is added to the finished feed.
[0088] One form of oral administration is a dosage form, e.g. a
chewable composition, such as a chewable tablet. Examples of
chewable tablets comprising isoxazoline compounds of formula (I)
were described in WO2013/150052 and WO2013/150055. The composition
of the chewable tablets that is disclosed in the examples of these
documents is incorporated by reference. Alternative chewable
tablets are described in WO2013/119442.
[0089] Oral veterinary compositions in the form of a "chewable
tablet", sometimes referred to as "soft chewable compositions" or
"soft chew", are usually convenient to administer to certain
animals, particularly cats and dogs, preferably dogs, and may be
used effectively to dose veterinary medicine to these animals.
[0090] A "Chewable tablet", "Soft chew" or "Soft chewable
pharmaceutical product" is intended to mean a pharmaceutical unit
dose that is solid at room temperature and that is after oral
administration soft to chew by the animal and which is functionally
chewy because the product has some plastic texture during the
process of mastication in the mouth. Such soft chews have a
softness that is similar to a cooked ground meat petty. The
chewable tablet or soft chew comprises a carrier and other
non-active ingredients.
[0091] The isoxazoline compound alternatively (or additionally) may
be systemically administered topically using a transdermal
formulation (i.e., a formulation that passes through the skin).
Alternatively (or additionally), the composition may be
systemically administered topically via the mucosa. The isoxazoline
composition alternatively (or additionally) may be systemically
administered parenterally, such as via intramuscular injection,
intravenous injection, subcutaneous injection, implant (e.g.,
subcutaneous implant), infusion, bolus, etc.
[0092] The animals may receive an isoxazoline compound as defined
earlier once, two times or three times until the Demodex mite
infestation is controlled and the generalized demodicosis is
successfully treated. One treatment provides effectiveness against
Demodex spp. mites for at least 4 weeks, 8 weeks, 12 weeks, 16
weeks or 20 weeks, or 24 weeks.
[0093] In general the isoxazoline compound can be administered to
all species of animals that have Demodex spp. infestation or
require treatment of a demodicosis.
[0094] The recipient of the product may be a livestock animal, e.g.
sheep, cattle, pig, goat; or a companion animal, e.g. dog, cat, or
horse. Especially preferred is the use in companion animals, e.g.
dogs or cats, especially dogs.
[0095] Demodex spp. mites that can be controlled by the use
according to the current invention are e.g. Demodex canis, Demodex
injai, Demodex cornei, Demodex. cati, Demodex gatoi, Demodex bovis,
Demodex ovis, Demodex caprae, Demodex aries.
[0096] A "Demodex mite infestation" refers to the presence of
parasites in numbers that pose a risk of r harm to animals.
[0097] By using the isoxazoline compounds as described in this
application disadvantages of the prior art can be avoided, because
a single (or maximal two or three times, depending on the
isoxazoline compound used) administration of the compound would be
necessary to achieve the desired effect.
[0098] Demodicosis is diagnosed by clinical evaluation and deep
skin scrapings that is analysed using a microscope for mites
present. Demodicosis is considered generalized when five or more
areas of localized disease are observed, or pododemodicosis is
observed on two or more feet, or when an entire body region is
involved. Demodicosis can also be categorized as either juvenile
(dogs up to 18 months of age), adult onset (dogs generally older
than four years of age with no previous history of disease), or
chronic generalized (persisting disease for at least six
months).
[0099] Depending on the specific isoxazoline compound used, the
administration allows to completely inhibit or kill the Demodex
spp. mites present on the animal that cause the demodicosis.
Preferably, microscopic cure, i.e. multiple skin scrapings without
any Demodex mites (eggs, larvae, nymphs and adults) is obtained by
the administration of the isoxazoline compound. Preferably only one
administration is necessary for microscopic cure.
[0100] The administration of the isoxazoline compound, e.g.
fluralaner is able to reduce the clinical signs of the demodicosis,
and preferably at least one of the dermatological signs, e.g. the
skin lesions, such as erythema, casts, pustules, scales and crusts,
exudation, ulceration and hair loss up to alopecia is reduced
significantly compared to the situation before treatment or without
treatment.
[0101] The administration of the isoxazoline compound, e.g.
fluralaner is able to cure together with a symptomatic therapy
(e.g. antibiotics or antiseptics) the appearance of systemic
symptoms such as generalized lymphadenopathy, lethargy, and
fever.
[0102] The treatment of canine generalized demodicosis in most
cases requires adjunctive therapy. In addition to the effective
miticidal therapy by the isoxazoline compounds according to the
current invention, treatment of concurrent bacterial skin
infection, internal parasites and existing underlying systemic
diseases might be undertaken for successful treatment.
[0103] The isoxazoline compound as described in this application
can be used concurrently with suitable antibiotics in order to
control the secondary bacterial skin infection pyoderma that is
usually associated with generalized demodicosis. Superficial
pyoderma can be treated with oral antibiotics or topical
antibiotics. In certain cases topical treatment with benzoyl
peroxide or chlorhexidine-based shampoos will be useful to control
the bacterial secondary infections.
Example
[0104] Efficacy of orally administered fluralaner (as Bravecto.RTM.
chewable tablets 13.64% fluralaner) compared to topically applied
Advocate.RTM. (10-% imidacloprid/2.5% moxidectin) against
generalized demodicosis in dogs.
Methods
Study Set-Up
[0105] The study was designed as a parallel group, blinded,
randomized, single centre, and positive controlled efficacy study.
Bravecto.RTM. administered as chewable tablets on a single occasion
was the test product and Advocate.RTM., administered three times at
28 day intervals (according to the product label) was included as a
positive control.
[0106] The test system was the individual dog. Dogs with clinical
signs of generalized demodicosis, e.g. erythema, hair loss,
comedones, follicular casts and crusts were enrolled, with consent
from their owners, in the study and were returned to their owners
on completion of the animal phase.
[0107] Dogs included in the study were mostly mongrels and of both
sexes, older than 12 months, weighed between 3.5 and 13.7 kg, and
except for clinical signs of generalized demodicosis, the dogs were
healthy and as far as could be determined the dogs had not been
treated with a glucocorticoid or any product with a miticidal
effect for at least 12 weeks prior to inclusion. Additional
requirements for inclusion were that deep skin scrapings performed
before treatment had to be positive for Demodex spp. mites.
[0108] Sixteen dogs (7 male and 9 female), ranked within sex in
descending order of individual pre-treatment mite counts were
included in the study and allocated to two equal groups. Each dog
was housed individually for the duration of the study in an
indoor/outdoor run, without contact between animals, and was fed
once a day according to the food manufacturer's recommendations.
Potable municipal water was available ad libitum.
[0109] Each dog was acclimatized to the housing and maintenance
conditions for at least 14 days before treatment. As a
precautionary measure all dogs were treated subcutaneously with an
antibiotic (cefovecin), appropriate for the treatment of pyoderma
on Days -14, -1, 13 and 27. Additionally, on Days -14 and 27, deep
skin biopsies were taken from each dog after sedation. The biopsies
indicated that exudative pyoderma was present in two dogs in each
group on Day -14 and that it had cleared by Day 27. Chronic
dermatitis, epidermal acanthosis and hyperkeratosis was present and
unchanged in all dogs on both occasions. No inflammatory cells or
bacteria were observed in the Day 27 biopsies and antimicrobial
therapy was discontinued. Twice during acclimatization (Day -14 and
Day -1) and on Days 27/28, 56 and 84 after treatment each dog was
clinically examined by a veterinarian.
[0110] The dogs were weighed on a calibrated and verified
electronic scale on Days -2, 13, 27, 41, 55, 69 and 84 for dose
calculation for treatment, for the use of sedatives for skin
scrapings and to document the body weight during the study period.
General health observations were performed daily throughout the
complete study period.
Treatment
[0111] On Day 0, dogs of one group were treated once orally with
Bravecto.RTM. chewable tablets, based on the dog's individual body
weight, to achieve a minimum dose of 25 mg/kg body weight and an
efficacy over 12 weeks following treatment. The chewable tablet(s)
were administered 20 (.+-.10) minutes after food had been offered
by placement in the back of the oral cavity over the tongue to
initiate swallowing.
[0112] Also on Day 0, commercially available Advocate.RTM. was
administered topically to the other group of dogs (positive
controls) according to the product label. Due to the 28 days
efficacy duration of Advocate.RTM., these dogs were re-treated on
Day 28 and 56. With the dog in a standing position, the coat was
parted until the skin was visible and the Advocate.RTM. was
administered directly onto the skin.
[0113] Both treated groups were observed prior to treatment and
again hourly for four hours after treatment of the last animal, for
possible adverse events. Personnel performing the post-treatment
observations were blinded with respect to the treatment.
Mite Assessments
[0114] Deep skin scrapings (.about.4 cm.sup.2) were made from five
sites on each dog on Days -4, 28, 56 and 84 and were examined under
a stereomicroscope for the presence of Demodex spp. mites. Skin
scrapings of the dogs treated with Advocate.RTM. were performed on
Day 28 and Day 56, before the second or third treatment was
applied, respectively. The same sites and/or sites of new lesions
were scraped at each subsequent examination.
[0115] The clinical signs and the extent of demodectic lesions on
each dog were assessed on the days when skin scrapings were made,
and recorded on a standardised form. The following parameters were
assessed and sketched on a silhouette (left and right hand side)
for each dog: body areas exhibiting erythema; body areas covered by
casts, scales and crusts; body areas with hair loss (1=slight
thinning of hair; 2=conspicuous hair loss; 3=no hair). Colour
photographs illustrating the extent of lesions and their
resolution, were taken of each dog on Day -4 and subsequently at
approximately monthly intervals up to Day 84 after treatment. A
semi-quantitative assessment of hair re-growth was performed,
comparing hair coat before and after the 12 weeks study
duration.
Efficacy Evaluation
[0116] The primary assessment variable in the study was the
decrease in number of mites counted in skin scrapings (immature and
adult live mites combined) following treatment.
[0117] Efficacy was calculated using geometric means with Abbott's
formula:
Efficacy (%)=(Mpre-Mpost)/Mpre.times.100
[0118] where Mpre was the mean number of pre-treatment mite counts,
and Mpost the mean number of post-treatment mite counts.
[0119] Additionally, the groups were compared using an ANOVA (Proc
GLM procedure in SAS) with a treatment effect after a logarithmic
transformation on the mite (count+1) data.
[0120] One dog treated with Advocate.RTM. was removed from the
study on Day 59 due to malignant lymphoma. The results pertaining
to this dog until Day 56, before its exclusion from the study on
Day 59, have been included with those of the other dogs in the
group treated with Advocate.RTM..
Results
[0121] No adverse event considered to be related to oral treatment
with Bravecto.RTM. chewable tablets or topical treatment with
Advocate.RTM. was observed in any dog.
[0122] Treatment with Bravecto.RTM. chewable tablets resulted in a
reduction in the mean mite number present in skin scrapings of
99.8% on Day 28, and of 100% on Days 56 and 84 after treatment. The
treatment with Advocate.RTM. resulted in a reduction in the mean
mite number present in skin scrapings of 98.0% on Day 28, of 96.4%
on Day 56, and of 94.7% on Day 84. Statistically significantly (P
0.05) fewer mites were found on the Bravecto.RTM. treated dogs
compared to Advocate.RTM. treated dogs (Table 1).
TABLE-US-00003 TABLE 1 Geometric mean reductions in Demodex spp.
mite counts of dogs treated once orally with Bravecto .RTM. or
topically on three occasions at 28 day intervals with Advocate
.RTM. Study Days Study groups Bravecto .RTM. Advocate .RTM. p-value
-4 Mean.sup.a mite counts (n) 447.0 509.4/478.6.sup.b Na.sup.c
Count range (n) 41-1740 79-2724 28 Mean.sup.a mite counts (n) 0.8
10.0 Count range (n) 0-14 0-496 Efficacy (%) 99.8 98.0 0.0917 56
Mean.sup.a mite counts (n) 0.0 18.5 Count range (n) Na.sup.c 0-115
Efficacy (%) 100.0 96.4 <0.0001 84 Mean.sup.a mite counts (n)
0.0 25.6 Count range (n) Na.sup.c 0-286 Efficacy (%) 100.0 94.7
0.0020 .sup.aGeometric mean .sup.bMite counts calculated without
one dog, which was euthanized on Day 59 .sup.cNot applicable
[0123] The prevalence of erythematosus patches on the dogs treated
once orally with Bravecto.RTM. chewable tablets was reduced from
62.5% of the dogs on Day -4 prior to treatment to 12.5% of the dogs
12 weeks following initiation of treatment.
[0124] The prevalence of crusts, casts or scales was reduced from
100% prior to treatment to 12.5% 12 weeks following initiation of
treatment.
[0125] In comparison, the prevalence of erythematosus patches on
dogs treated three times at a 28 days interval with Advocate.RTM.
was reduced from 87.5% to 0% and the prevalence of crusts, casts
and scales was reduced from 100% to 42.9% (Table 2).
TABLE-US-00004 TABLE 2 Reduction in the prevalence of dermatologic
changes in dogs with generalized demodicosis after treatment with
either Bravecto .RTM. or Advocate .RTM. Clinical Symptom Day -4 Day
28 Day 56 Day 84 Bravecto .RTM.: prevalence of lesions on days
before and after treatment.sup.a (number of dogs/number of dogs per
group) Erythematous 62.5% (5/8) 37.5% (3/8) 12.5% (1/8) 12.5% (1/8)
patches Crusts, casts or 100% (8/8) 62.5% (5/8) 62.5% (5/8) 12.5%
(1/8) scales Advocate .RTM.: prevalence of lesions on days before
and after initial treatment.sup.b (number of dogs/number of dogs
per group) Erythematous 87.5% (7/8) 50% (4/8) 0% (0/8) 0%
(0/7).sup.c patches Crusts, casts or 100% (8/8) 100% (8/8) 37.5%
(3/8) 42.9% (3/7).sup.c scales .sup.aDogs were treated once orally
on Day 0 .sup.bDogs were treated topically on Day 0, on Day 28 and
again on Day 56. Skin assessments were performed before treatment.
.sup.cMite counts calculated without one dog, which was euthanized
on Day 59.
[0126] Hair re-growth compared to the proportion of the body area
covered by hair prior to treatment is summarized in Table 3. By
Days 56 and 84 after initiation of treatment, hair re-growth on the
majority of dogs in both groups exceeded the hair-coat of the dogs
by 90% compared with the pre-treatment assessment.
TABLE-US-00005 TABLE 3 Hair re-growth on dogs with generalized
demodectic mange after treatment with Bravecto .RTM. or Advocate
.RTM. Hair re-growth score: frequency of occurrence Bravecto
.RTM..sup.a Advocate .RTM..sup.b (number of dogs/number of dogs
(number of dogs/number of dogs Study per group) per group) day 1
(0-50%) 2 (50-90%) 3 (>90%) 1 (0-50%) 2 (50-90%) 3 (>90%) 28
3/8 1/8 4/8 6/8 1/8 1/8 56 0/8 1/8 7/8 0/8 1/8 7/8 84 0/8 1/8 7/8
0/7.sup.c 1/7.sup.c 6/7.sup.c .sup.aDogs were treated once orally
on Day 0 .sup.bDogs were treated topically on Day 0, on Day 28 and
again on Day 56. Skin assessments were performed before treatment.
.sup.cMite counts calculated without one dog, which was euthanized
on Day 59.
[0127] The body weight of every dog increased similarly in both
groups during the study period.
CONCLUSIONS
[0128] Single oral administration of Bravecto.RTM. (13.64%
fluralaner) chewable tablets is highly effective against
generalized demodicosis, with no mites detectable at 56 and 84 days
following treatment. In comparison, Advocate.RTM. (10%
imidacloprid/2.5% moxidectin) administered three times at 28 day
intervals, is also highly effective against generalized
demodicosis, but most dogs still harboured mites at all assessment
time points. Both treatments resulted in a marked reduction of skin
lesions and increase of hair-growth 12 weeks after the initial
treatment.
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