FINE-NEEDLE BIOPSY SAMPLE COLLECTION & HANDLING ERRORS
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June 2021
A Peer-Reviewed Journal | cliniciansbrief.com
FINE-NEEDLE BIOPSY
SAMPLE COLLECTION
IN THIS ISSUE
& HANDLING ERRORS
Dermatologic Indications
for Pentoxifylline in Dogs
Suspected Food Allergy
in Dogs: Algorithm
Step-by-Step Euthanasia
Protocols
Case Report: Pelvic Limb
Lameness in a Cat
Differential Diagnoses
for Neutrophilia
Volume 19 Number 4
THE OFFICIAL CLINICAL PRACTICE JOURNAL OF THE WSAVA
June 2021
A Peer-Reviewed Journal | cliniciansbrief.com
Are your patients getting the
canine osteoarthritis (OA)
pain and inflammation
relief they need?
Recommend Galliprant as first-line treatment
FIRST-IN-CLASS non-COX inhibiting NSAID1
MODE OF ACTION TARGETS canine OA pain and inflammation while reducing
the impact on GI, kidney, and liver homeostasis1,2‡
FOR ALL STAGES of OA from the earliest clinical signs*
*Approved for use in dogs older than 9 months of age and greater than 8 pounds.
‡Monitoring is recommended if used long-term. Simple, once-daily chewable tablet
Go to GalliprantVet.com for more information
INDICATION
Galliprant is an NSAID that controls pain and inflammation associated with osteoarthritis in dogs.
IMPORTANT SAFETY INFORMATION
Not for use in humans. For use in dogs only. Keep this and all medications out of reach of children and pets. Store out of reach of dogs and other pets
in a secured location in order to prevent accidental ingestion or overdose. Do not use in dogs that have a hypersensitivity to grapiprant. If Galliprant is
used long term, appropriate monitoring is recommended. Concomitant use of Galliprant with other anti-inflammatory drugs, such as COX-inhibiting
NSAIDs or corticosteroids, should be avoided. Concurrent use with other anti-inflammatory drugs or protein-bound drugs has not been studied. The
safe use of Galliprant has not been evaluated in dogs younger than 9 months of age and less than 8 lbs (3.6 kg), dogs used for breeding, pregnant or
lactating dogs, or dogs with cardiac disease. The most common adverse reactions were vomiting, diarrhea, decreased appetite, and lethargy. For full
prescribing information see Galliprant package insert.
Kirkby Shaw, K, et al. Vet Med Sci. 2016;2:3-9.
1
Rausch-Derra L, et al. Am J Vet Intern Med. 2015;76(10):853-859.
2
Galliprant, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates. ©2021 Elanco or its affiliates. PM-US-21-1577
Adverse Reactions:
In a controlled field study, 285 dogs were evaluated for safety when given either GALLIPRANT
or a vehicle control (tablet minus grapiprant) at a dose of 2 mg/kg (0.9 mg/lb) once daily for
28 days. GALLIPRANT-treated dogs ranged in age from 2 yrs to 16.75 years. The following
adverse reactions were observed:
Table 1. Adverse reactions reported in the field study.
GALLIPRANT Vehicle control
Adverse reaction* (grapiprant tablets) (tablets minus
N = 141 grapiprant)
For oral use in dogs only N = 144
20 mg, 60 mg and 100 mg flavored tablets Vomiting 24 9
A prostaglandin E2 (PGE2) EP4 receptor antagonist; a non-cyclooxygenase inhibiting, Diarrhea, soft stool 17 13
non-steroidal anti-inflammatory drug
Anorexia, inappetence 9 7
Caution:
Lethargy 6 2
Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.
Buccal ulcer 1 0
Description:
GALLIPRANT (grapiprant tablets) is a prostaglandin E2 (PGE2) EP4 receptor antagonist; Immune mediated
hemolytic anemia 1 0
a non-cyclooxygenase (COX) inhibiting, non-steroidal anti-inflammatory drug (NSAID) in the
piprant class. GALLIPRANT is a flavored, oval, biconvex, beige to brown in color, scored tablet *Dogs may have experienced more than one type or occurrence during the study.
debossed with a “G” that contains grapiprant and desiccated pork liver as the flavoring agent. GALLIPRANT was used safely during the field studies with other concurrent therapies,
The molecular weight of grapiprant is 491.61 Daltons. The empirical formula is C26H29N5O3S. including antibiotics, parasiticides and vaccinations.
Grapiprant is N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl] To report suspected adverse drug events and/or to obtain a copy of the Safety Data Sheet
ethyl]amino]carbonyl]-4 methylbenzenesulfonamide. (SDS) or for technical assistance, call 1-888-545-5973.
The structural formula is: For additional information about adverse drug experience reporting for animal drugs,
CH3 contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth
NH
NH O
Information for Dog Owners:
N N
O O
S Owners should be advised of the potential for adverse reactions and be informed of the clinical
CH3 signs associated with drug intolerance. Adverse reactions may include vomiting, diarrhea,
N
H3C
H3C decreased appetite, and decreasing albumin and total protein. Appetite and stools should be
monitored and owners should be advised to consult with their veterinarian if appetite decreases
Indication: or stools become abnormal.
GALLIPRANT (grapiprant tablets) is indicated for the control of pain and inflammation
Clinical Pharmacology:
associated with osteoarthritis in dogs.
Grapiprant is a prostaglandin E2 (PGE2) EP4 receptor antagonist; a non- cyclooxygenase
Dosage and Administration: inhibiting, non-steroidal, anti-inflammatory drug. Grapiprant has a canine EP4 receptor binding
Always provide “Information for Dog Owners” Sheet with prescription. affinity (Ki) of 24 nM.
Use the lowest effective dose for the shortest duration consistent with individual response.
Prostaglandins have a wide variety of physiologic effects. Prostaglandin E2 (PGE2) is a
The dose of GALLIPRANT (grapiprant tablets) is 0.9 mg/lb (2 mg/kg) once daily. prostanoid that exerts its effects via four receptors, EP1, EP2, EP3, and EP4. PGE2 is involved
Only the 20 mg and 60 mg tablets of GALLIPRANT are scored. in mediating inflammatory pain, vasodilation, increasing vascular permeability; as well as
The dosage should be calculated in half tablet increments. gastrointestinal homeostasis, renal function and reproductive functions. The EP4 receptor is
Dogs less than 8 lbs. (3.6 kgs) cannot be accurately dosed. important in mediating pain and inflammation as it is the primary mediator of the PGE2-elicited
Dosing Chart sensitization of sensory neurons1 and PGE2-elicited inflammation.2 Grapiprant blocks
Dose Weight in Weight in 20 mg 60 mg 100 mg PGE2-elicited pain and inflammation by antagonizing the EP4 receptor.
pounds kilograms tablet tablet tablet The EP4 receptor, along with the EP1, EP2 and EP3 receptors, is involved in PGE2 mediated
8-15 3.6-6.8 0.5 effects on gastrointestinal homeostasis and renal function. PGE2 effects mediated solely by the
0.9 mg/lb 15.1-30 6.9-13.6 1 EP4 receptor are stimulation of mucus secretion in the stomach and large intestine, stimulation
(2 mg/kg) 30.1-45 13.7-20.4 0.5 of acid secretion in the stomach, inhibition of small intestine motility and inhibition of cytokine
once daily 45.1-75 20.5-34 1 expression in the large intestine.3 While PGE2 gastroprotective action is mediated by EP1,
75.1-150 34.1-68 1 the healing- promoting action of PGE2 in the stomach is mediated by the EP4 receptor.4 In the
kidney, the PGE2 antinatiuretic effect is mediated by the EP4 receptor.5
The 100 mg tablet is not scored and should not be broken in half.
Breaking the 100 mg tablet in half will not guarantee that half of the active ingredient is EP4 receptors are abundantly expressed in the heart of dogs,6 the clinical relevance of which is
contained within each half of the tablet. For dogs larger than 150 lbs (68 kgs), use a unknown. The EP4 receptor is not involved in generation of pyrexia.
combination of tablet and half tablets to achieve the appropriate dose. Grapiprant is not a potential inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6,
Contraindications: and CYP3A4 mediated metabolism pathways. Grapiprant is a substrate of P-glycoprotein
GALLIPRANT should not be used in dogs that have a hypersensitivity to grapiprant. transport. In vitro metabolism with dog liver microsomes identified two oxidative metabolites,
M3 (hydroxyl) and M5 (N-dealkylation).
Warnings:
Not for use in humans. Keep this and all medications out of reach of children and pets. The pharmacokinetic characterization of grapiprant following oral administration of
Consult a physician in case of accidental ingestion by humans. GALLIPRANT tablets to healthy Beagles is provided in the table below.
For use in dogs only. Store GALLIPRANT out of reach of dogs and other pets in a secured Table 2. Mean (±SD) Plasma Pharmacokinetic Parameters for Grapiprant in Beagles after single
location in order to prevent accidental ingestion or overdose. oral dose of GALLIPRANT tablet formulation
Precautions: Study Study 11 Study 11 Study 22 Study 22
The safe use of GALLIPRANT has not been evaluated in dogs younger than 9 months of 2 mg/kg 2 mg/kg 6 mg/kg 50 mg/kg
age and less than 8 lbs (3.6 kg), dogs used for breeding, or in pregnant or lactating dogs. PK Parameter (n = 10) (n = 10) (n = 8) (n = 8)
Adverse reactions in dogs receiving GALLIPRANT may include vomiting, diarrhea, decreased (Fasted) (Fed) (Fasted) (Fasted)
appetite, mucoid, watery or bloody stools, and decreases in serum albumin and total protein. Tmax3 1.0 1.0 1.0 2.0
If GALLIPRANT is used long term appropriate monitoring is recommended. (hr) (0.5 – 1.03) (0.5 – 8.07) (1.0 – 2.0) (1.0 – 4.0)
Concurrent use with other anti-inflammatory drugs has not been studied. Concomitant Cmax 1210 278 5720 98500
use of GALLIPRANT with other anti-inflammatory drugs, such as COX-inhibiting NSAIDs or (ng/mL) (341) (179) (3220) (13100)
corticosteroids, should be avoided. If additional pain medication is needed after a daily dose AUC(0-inf) 2790 1200 17800 414000
of GALLIPRANT, a non-NSAID/ non-corticosteroid class of analgesic may be necessary. (ng*hr/mL) (982) (523) (5520) (73700)
The concomitant use of protein-bound drugs with GALLIPRANT has not been T1/2 4.60 5.67 5.01 5.21
studied. Commonly used protein-bound drugs include cardiac, anticonvulsant and (hr) (4.19) (3.27) (1.95) (1.66)
behavioral medications. Fed/Fasted Relative
Drug compatibility should be monitored in patients requiring adjunctive therapy. Bioavailability Geometric
0.37 (0.28 – 0.46) NA
Consider appropriate washout times when switching from one anti-inflammatory to another Mean Ratio of AUC
or when switching from corticosteroids or COX-inhibiting NSAIDs to GALLIPRANT use. (90% Confidence Limits)
The use of GALLIPRANT in dogs with cardiac disease has not been studied. 1
Study 1 was a food effect determination study.
It is not known whether dogs with a history of hypersensitivity to sulfonamide drugs will exhibit 2
Study 2 was a PK bridging study conducted using 60 mg GALLIPRANT tablets at 6 mg/kg dose
hypersensitivity to GALLIPRANT. GALLIPRANT is a methylbenzenesulfonamide. and 5 X 100 mg GALLIPRANT tablets at 50 mg/kg dose.
3
Median (Range)
PA101390X_With_Tear_Off W1a
be a he ro
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with C
Guarantee compliance
– Administer the only FDA-approved single-dose
otitis externa treatment and rest your confidence
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Eliminate the stress of at-home treatments
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SAVE THE DAY. Use Claro for your most common Otitis cases. ®
Claro® is indicated for the treatment of otitis externa in dogs associated with susceptible strains of yeast (Malassezia pachydermatis)
and bacteria (Staphylococcus pseudintermedius).
CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian. PRECAUTIONS:
For use in dogs only. Do not use in cats (see POST APPROVAL EXPERIENCE). CLARO® has been associated with
rupture of the tympanic membrane. Reevaluate the dog if hearing loss or signs of vestibular dysfunction are observed
during treatment. Signs of internal ear disease such as head tilt, vestibular signs, ataxia, nystagmus, facial paralysis,
and keratoconjunctivitis sicca have been reported (see POST APPROVAL EXPERIENCE) with the use of CLARO®.
©2021 Elanco or its affiliates. Claro, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates. PM-US-21-1415
See page 2 for product information summary.
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June 2021 cliniciansbrief.com 1
(florfenicol, terbinafine, mometasone furoate)
Otic Solution OUR
AUTHORS
Antibacterial, antifungal, and anti-inflammatory
For Otic Use in Dogs Only
CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a
licensed veterinarian.
DESCRIPTION:
CLARO® contains 16.6 mg/mL florfenicol, 14.8 mg/mL terbinafine (equivalent to
16.6 mg/mL terbinafine hydrochloride) and 2.2 mg/mL mometasone furoate. Inactive
ingredients include purified water, propylene carbonate, propylene glycol, ethyl alcohol,
and polyethylene glycol.
INDICATIONS:
CLARO® is indicated for the treatment of otitis externa in dogs associated with
susceptible strains of yeast (Malassezia pachydermatis) and bacteria (Staphylococcus
pseudintermedius).
DOSAGE AND ADMINISTRATION:
Shake before use. KAITLIN N. BAHLMANN, DVM, is an Hospital in San Diego, California.
CLARO® should be administered by veterinary personnel.
Administer one dose (1 dropperette) per affected ear. The duration of effect should associate veterinarian at Exclusively Her interest is in gastroenterology.
last 30 days.
1.
2.
Clean and dry the external ear canal before administering the product.
Verify the tympanic membrane is intact prior to administration.
Cats Veterinary Hospital in Water- differential diagnosis page 79
3.
4.
Remove single dose dropperette from the package.
While holding the dropperette in an upright position, remove the cap
ford, Michigan, and is pursuing
5.
from the dropperette.
Turn the cap over and push the other end of the cap onto the tip of the board certification in feline practice KATHLEEN COONEY, DVM, MS,
dropperette.
6. Twist the cap to break the seal and then remove cap from the
dropperette.
by the American Board of Veteri- CHPV, CCFP, is the Director of Edu-
7.
8.
Screw the applicator nozzle onto the dropperette.
Insert the tapered tip of the dropperette into the affected external ear canal
nary Practitioners. Dr. Bahlmann cation at the Companion Animal
Euthanasia Training Academy in
and squeeze to instill the entire contents (1 ml) into the affected ear.
9. Gently massage the base of the ear to allow distribution of the solution. earned her DVM from the Univer-
10. Repeat with other ear as prescribed.
Cleaning the ear after dosing may affect product effectiveness. sity of Guelph. She has worked as a Loveland, Colorado, and the Chief
CONTRAINDICATIONS:
Do not use in dogs with known tympanic membrane perforation (see PRECAUTIONS). general practitioner and emergency Medical Officer of Caring Pathways
CLARO® is contraindicated in dogs with known or suspected hypersensitivity to
florfenicol, terbinafine hydrochloride, or mometasone furoate.
WARNINGS:
hospitalist at various clinics across in Denver, Colorado. Dr. Cooney is a
Human Warnings: Not for use in humans. Keep this and all drugs out of reach of
children. In case of accidental ingestion by humans, contact a physician immediately. Canada. Her interests are feline past president of the International
In case of accidental skin contact, wash area thoroughly with water. Avoid contact with
eyes. Humans with known hypersensitivity to florfenicol, terbinafine hydrochloride, or
mometasone furoate should not handle this product.
internal medicine and complex sur- Association for Animal Hospice and
PRECAUTIONS:
Do not administer orally. gical cases. Palliative Care (IAAHPC), where
she designed the Animal Hospice
The use of CLARO® in dogs with perforated tympanic membranes has not been
evaluated. The integrity of the tympanic membrane should be confirmed before case in point page 73
administering the product. Reevaluate the dog if hearing loss or signs of vestibular
dysfunction are observed during treatment. Use of topical otic corticosteroids has been
associated with adrenocortical suppression and iatrogenic hyperadrenocorticism in
and Palliative Care certification
dogs (see ANIMAL SAFETY).
Use with caution in dogs with impaired hepatic function (see ANIMAL SAFETY). STEVEN J. BAILEY, DVM, DABVP program. She has authored 2 books
The safe use of CLARO® in dogs used for breeding purposes, during pregnancy, or in
lactating bitches has not been evaluated. (Feline), is the founder, owner, and and numerous articles and book
ADVERSE REACTIONS:
In a field study conducted in the United States (see EFFECTIVENESS), there were no
directly attributable adverse reactions in 146 dogs administered CLARO®.
medical director of Exclusively Cats chapters. Dr. Cooney has collabo-
To report suspected adverse drug events and/or obtain a copy of the Safety Data Sheet
(SDS) or for technical assistance, contact Bayer HealthCare at 1-800-422-9874. Veterinary Hospital in Waterford, rated in end-of-life training with
For additional information about adverse drug experience reporting for animal drugs, contact
FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth. Michigan. Dr. Bailey’s special inter- AVMA, AAHA, NAVC, IAAHPC,
PHARMACOLOGY:
CLARO® Otic Solution is a fixed combination of three active substances: florfenicol
(antibacterial), terbinafine (antifungal), and mometasone furoate (steroidal
ests include complicated medical Fear Free Program, and Society for
anti-inflammatory). Florfenicol is a bacteriostatic antibiotic which acts by inhibiting
protein synthesis. Terbinafine is an antifungal which selectively inhibits the and surgical cases, as well as Veterinary Medical Ethics. She is a
early synthesis of ergosterol. Mometasone furoate is a glucocorticosteroid with
anti-inflammatory activity.
advanced dentistry. He and his team strong advocate for best practices in
MICROBIOLOGY:
The compatibility and additive effect of each of the components in CLARO® solution
was demonstrated in a component effectiveness and non-interference study. An at Exclusively Cats Veterinary Hos- all aspects of end-of-life care and
in vitro study of organisms collected from clinical cases of otitis externa in dogs
enrolled in the clinical effectiveness study determined that florfenicol and terbinafine
hydrochloride inhibit the growth of bacteria and yeast commonly associated with
pital were the first to identify feline speaks worldwide. Dr. Cooney is
otitis externa in dogs. No consistent synergistic or antagonistic effect of the two
antimicrobials was demonstrated. The addition of mometasone furoate to the knees and teeth syndrome, and working toward board certification
combination did not impair antimicrobial activity to any clinically significant extent.
In a field study (see EFFECTIVENESS), at least 10 isolates from successfully treated
cases were obtained for S. pseudintermedius and M. pachydermatis.
Dr. Bailey has coauthored several in animal welfare.
EFFECTIVENESS:
In a well-controlled, double-masked field study, CLARO® was evaluated against a
articles detailing the condition. procedures pro page 25
vehicle control in 221 dogs with otitis externa. One hundred and forty six dogs were
treated with CLARO® and 75 dogs were treated with the vehicle control. All dogs case in point page 73
were evaluated for safety. Treatment (1 mL) was administered once on Day 0 to the
affected ear(s). Prior to treatment, the ear(s) was cleaned with saline. The dogs were
evaluated on Days 0, 7, 14, and 30. Blood work and urinalysis were obtained on Day 0
ELIZABETH R. DRAKE, DVM,
pre-treatment and Day 30 at study completion. Four clinical signs associated with otitis
externa were evaluated: erythema, exudate, swelling, and ulceration. Success was MARIE CHARTIER, DVM, DACVIM, DACVD, is an associate professor
based on clinical improvement at Day 30. Of the 183 dogs included in the effectiveness
evaluation, 72.5% of dogs administered CLARO® solution were successfully treated,
compared to 11.1% of the dogs in the vehicle-control group (p=0.0001). is a veterinary specialist at BluePearl of small animal dermatology at Uni-
ANIMAL SAFETY:
In a target animal safety study, CLARO® was administered aurally to 12-week-old Beagle Pet Hospital in Charlestown, Massa- versity of Tennessee, where she also
puppies (4 dogs/sex/group) at 0X, 1X, 3X, and 5X the recommended dose once every 2
weeks for a total dosing period of 28 days (3 times the treatment duration). No clinically
relevant treatment-related findings were noted in hearing tests, body weight, weight chusetts, and a member of the Com- completed a dermatology residency.
Dr. Drake earned her DVM from
gain, or food consumption. CLARO® administration was associated with post-treatment
ear wetness or clear aural exudate, increased absolute neutrophil count, decreased
absolute lymphocyte and eosinophil counts, suppression of the adrenal cortical
parative Gastroenterology Society.
response to ACTH-stimulation, decreased adrenal weight and atrophy of the adrenal
cortex, increased liver weight with hepatocellular enlargement/cytoplasmic change, Dr. Chartier earned her DVM from Texas A&M University. Her main
and decreased thymus weight. Other potentially treatment-related effects included mild
changes to AST, total protein, inorganic phosphorus, creatinine, and calcium. Louisiana State University. She area of concentration is the treat-
STORAGE INFORMATION:
Store between 20°C – 25°C (68°F – 77°F), excursions are permitted 15°C – 30°C
(59°F – 86°F).
completed a small animal rotating ment of otitis in companion animals.
HOW SUPPLIED:
CLARO® solution is supplied in a single-use dropperette in a blister. Each dropperette internship in medicine and surgery diagnostic tree page 22
contains one 1 mL dose.
CLARO® is available in cartons of two, ten, or twenty dropperettes. at Angell Animal Medical Center in
Manufactured for
Bayer HealthCare LLC, Animal Health Division Boston, Massachusetts, and a resi-
P.O. Box 390 Shawnee Mission, Kansas 66201 USA.
Bayer, the Bayer Cross and CLARO are registered trademarks of Bayer dency in small animal internal
© 2018 Bayer Continues on page 8
NADA 141-440, Approved by FDA medicine at Veterinary Specialty
LV1802
2 cliniciansbrief.com June 2021
FROM
CLINICIAN’S BRIEF
ON SOCIAL MEDIA
Have you ever diagnosed an
WE axial osteosarcoma in a patient?
ASKED …
Do you dip slides What is the most 42%
into the stain or drip unique vein you Yes
the stain directly have used to gain 58%
onto slides? venous access in No
“We always dip, but it makes a
a patient?
huge mess and usually gets on “I used the dorsal coccygeal vein
shoes and fingers.”—Stephanie B in a huge snapping turtle and
“Dripping is awesome. There is no the cephalic vein in a Galapagos
debris, is less waste, and are no tortoise—it took 6 people and a
more ‘dirty’ and ‘clean’ tubs. 5-gallon bucket to restrain Do you plan on attending
Slides are fine.”—Alexis W him!”—Ericka K in-person continuing
“Dip; I never learned the drip.” “I went in through the tongue education in 2021?
—Chelsey M in a llama. My employer at the
time would not consider the
“We dip but have one set of suggestion of going high up the
slides for both skin and ears
and a separate set for blood
neck.”—Darlene J 15%
“Sublingual in a brown bear” Yes,
smears.”—Ali B but only locally
—Christina L
“I always drip; otherwise, stains
may be contaminated.”—Sarah D “The scrotum in a horse!”
18% 67%
—Lauren G No
Yes,
“Postoccipital sinus in a sea anywhere
turtle”—Erica F
“Palatine vein in a venomous
snake”—Ismar L
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June 2021 cliniciansbrief.com 3
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IN THIS
ISSUE
ON THE COVER
TOP 5
Top 5 Fine-Needle
Biopsy Sample
Collection &
Handling Errors
Isabelle Soga, DVM
candidate
Lisa M. Pohlman, DVM,
MS, DACVP
65
PG
14 TOP 5
Top 5 Dermatologic Indications
for Pentoxifylline in Dogs
Sarah Lewis, DVM, MS
Robert Kennis, DVM, DACVD, MS
22 DIAGNOSTIC TREE
Suspected Food Allergy in Dogs
Elizabeth R. Drake, DVM, DACVD
25 PROCEDURES PRO
Euthanasia Protocols
Kathleen Cooney, DVM, MS, CHPV, CCFP
73 CASE IN POINT
Pelvic Limb Lameness in a Cat
Kaitlin N. Bahlmann, DVM
Steven J. Bailey, DVM, DABVP (Feline)
79 DIFFERENTIAL DIAGNOSIS
Neutrophilia
Marie Chartier, DVM, DACVIM
June 2021 cliniciansbrief.com 5
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June 2021 cliniciansbrief.com 7OUR AUTHORS h CONTINUED FROM PAGE 2
ROBERT KENNIS, DVM, DACVD, SARAH LEWIS, DVM, MS, is a der- veterinary interns, residents, and
MS, is a professor at Auburn Uni- matology resident at Auburn Univer- graduate students. She enjoys pro-
versity. He earned his DVM from sity. She earned her MS and DVM at viding CE in clinical pathology
and completed a residency at Mich- University of Florida and completed through speaking engagements,
igan State University. Dr. Kennis an internship in small animal medi- online courses, and publications.
earned his MS in veterinary immu- cine and surgery at The Ohio State Her research interests include
nology from Texas A&M Univer- University. Dr. Lewis is interested in improvement of clinical pathology
sity. He is the past president of the small animal dermatology, espe- laboratory methods and identifica-
American Academy of Veterinary cially hypersensitivity disorders. tion and characterization of disease
Dermatology and has presented top 5 page 14 in domestic species, particularly in
numerous continuing education shelter animals, as well as pets
seminars at the state, national, and LISA M. POHLMAN, DVM, MS, owned by individuals who cannot
international levels. Dr. Kennis has DACVP, is an associate professor of afford routine veterinary care.
received the Pfizer Distinguished clinical pathology at Kansas State top 5 page 65
Teacher award at both Auburn Uni- University. She earned her DVM
versity and Texas A&M University, from University of Guelph and her ISABELLE SOGA, DVM candidate,
as well as the Texas A&M Associa- MS in clinical pathology from is a senior veterinary student (class
tion of Former Students’ Distin- Auburn University, where she also of 2021) at Kansas State University.
guished Achievement award. His completed a residency. Dr. Pohlman She plans to pursue a small animal
research interests include food serves as the president and medical rotating internship. Her interests
allergy, endocrine alopecia, and director of the Riley County Humane are clinical pathology, internal
feline bacterial infections. Society in Manhattan, Kansas, and medicine, and animal behavior.
top 5 page 14 is an active teacher and mentor of top 5 page 65 n
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02AD-DER21019-0421 24-Hour Technical Support: (866) 933-2472 | www.dechra-us.com | support@dechra.com™ aldosterone release is not fully controlled by ACE inhibitors because angiotensin II is also produced by non-ACE pathways. Therefore, concomitant use of
the aldosterone antagonist spironolactone and the ACE inhibitor benazepril hydrochloride inhibits both ACE and non-ACE pathways.
Pharmacokinetics: Spironolactone is rapidly and extensively metabolized in humans and experimental animals, with species differences in the
metabolism and disposition. Spironolactone is metabolized by microsomal cytochrome P450 enzymes to a primary metabolite, canrenone, and a
(spironolactone and benazepril hydrochloride
secondary metabolite, 7α-thiomethyl-spironolactone (TMS), which are used as markers for spironolactone in dog plasma. Systemic exposure to both
metabolites was comparable when spironolactone was administered alone or in association with benazepril in dogs. Spironolactone absorption is
affected by food and the dose should be administered consistently in fed condition. Spironolactone is mainly excreted as metabolites. After oral
chewable tablets) administration of radiolabeled spironolactone to the dog, 70% of the dose is recovered in feces and 20% in the urine.
After multiple oral doses of 20 mg of spironolactone in association with 2.5 mg of benazepril in dogs (n=18, 9 male and 9 female) for 10 consecutive
Cardiac drug for oral use in dogs only days (steady state), no accumulation was observed.
Approved by FDA under NADA # 141-538 Table 2: Mean Pharmacokinetic Parameters for Canrenone and TMS on Day 10
Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.
Parameters Canrenone (mean ± SD) TMS (mean ± SD)
Description: CARDALIS™ (spironolactone and benazepril hydrochloride chewable tablets) for dogs contains two active ingredients, spironolactone
and benazepril hydrochloride, in a fixed ratio of 8:1 respectively. CARDALIS is supplied as oblong half scored flavored chewable tablets in three sizes: tmax (hour) 4.3 ± 5.2 2.0 ± 2.1
20 mg spironolactone and 2.5 mg benazepril hydrochloride, 40 mg spironolactone and 5 mg benazepril hydrochloride, and 80 mg spironolactone and Cmax (µg/L) 31.6 ± 14.2 175.4 ± 97.7
10 mg benazepril hydrochloride. AUCo-inf (µg•hr/mL) 565.2 ± 247.5 1437.1 ± 762.1
Benazepril belongs to the angiotensin-converting enzyme (ACE) inhibitor class of drugs. Benazepril hydrochloride empirical formula is C24H28N2O5 · t½ (hour) 10.2 ± 3.0 7.7 ± 3.4
HCl and the molecular weight is 460.95. The chemical name is 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]ami-
no]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benazepine-1-acetic acid monohydrochloride and the structural formula is shown below: AUCo-inf = area under the plasma concentration-time curve from time 0 extrapolated to infinity;
0
0H
Cmax = maximum plasma concentration; tmax = time to maximum plasma concentrations;
0 t½ = apparent terminal elimination of half-lifes.
H
N N
HCI
Benazepril hydrochloride is a prodrug which, after absorption from the gastrointestinal tract, is rapidly converted by nonspecific carboxyl esterases,
0 0 mainly in the liver, into its active metabolite benazeprilat. Benazeprilat is itself poorly absorbed from the gastrointestinal tract and the overall
bioavailability of benazeprilat after oral administration is estimated to be less than 7%.
CH3
After multiple oral doses of 2.5 mg of benazepril in association with 20 mg of spironolactone in dogs (n=18, 9 male and 9 female) for 10 consecutive days
Spironolactone, and its active metabolites, act as specific aldosterone antagonists. Spironolactone empirical formula is C24H32O4S and the molecular (steady state), no accumulation was observed. In dogs, benazeprilat is excreted approximately equally by both renal (45%) and hepatic (55%) routes.
weight is 416.57. The chemical name is 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate and the structural
formula is shown below: 0 Table 3: Mean Pharmacokinetic Parameters for Benazeprilat on Day 10
H3C
0
Parameters Benazeprilat (mean ± SD)
CH3 H
tmax (hour) 1.4 ± 0.5
H H
Cmax (µg/L) 23.1 ± 26.6
0 S
AUCo-inf (µg•hr/mL) 146.2 ± 58.8
0 CH3 t½ (hour) 21.4 ± 6.7
Indications: CARDALIS is indicated with concurrent therapy (e.g. furosemide, etc.) for the management of clinical signs of mild, moderate, or severe
Effectiveness: The effectiveness of CARDALIS was evaluated in a well controlled U.S. multi-center, masked, randomized, 360-day field study in
congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI).
client-owned dogs. This study evaluated the effectiveness of CARDALIS in dogs diagnosed with congestive heart failure caused by left-sided AVVI
Dosage and Administration: CARDALIS administration should begin after pulmonary edema is stabilized. CARDALIS should be administered orally once compared to benazepril hydrochloride alone (active control).
daily at a dose of 0.9 mg/lb (2 mg/kg) spironolactone and 0.11 mg/lb (0.25 mg/kg) benazepril hydrochloride, according to dog body weight using a
Dogs ranged from 3 to 19 years of age and 5 to 155 lbs (2.3 to 70.5 kg) at enrollment. The most common breeds were mixed breed, Cavalier King
suitable combination of whole and/or half tablets. All tablet strengths are scored and the calculated dosage according to dog’s weight should be to the
Charles Spaniel, Chihuahua, Shih Tzu, Maltese, Dachshund, and Yorkshire Terrier. Enrolled dogs demonstrated radiographic evidence of congestive heart
nearest half-tablet increment. CARDALIS should be administered with food.
failure prior to enrollment or on Day 0 and exhibited clinical signs associated with left-sided AVVI, including exercise intolerance and/or dyspnea,
Contraindications: Do not administer CARDALIS in conjunction with non-steroidal anti-inflammatory drugs (NSAIDs) in dogs with echocardiographic evidence of left-atrial enlargement, moderate-to-severe mitral regurgitation, and presence of a left-sided cardiac murmur. Dogs
renal insufficiency. Do not administer CARDALIS to dogs with hypoadrenocorticism (Addison’s Disease), hyperkalemia, or hyponatremia. Do not with acquired heart disease other than left-sided AVVI, congenital heart defect, current positive heartworm antigen test, or syncope not related to
administer CARDALIS to animals with known hypersensitivity to ACE inhibitors or spironolactone. heart disease, and dogs intended for breeding or known to be pregnant or lactating, were excluded.
Warnings: Keep CARDALIS in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose. In case of A total of 569 dogs were treated with either CARDALIS (284 dogs) at a dose of 2 mg/kg spironolactone and 0.25 mg/kg benazepril hydrochloride once
accidental overdose, induce vomiting, lavage the stomach (depending on risk assessment), and monitor electrolytes. Symptomatic therapy (e.g. fluid daily or benazepril hydrochloride alone (285 dogs) at a dose of 0.25 mg/kg once daily. Doses were administered with food or within 30 minutes of
therapy) should be provided as medically necessary. CARDALIS is only for use in dogs with clinical evidence of heart failure. feeding. All dogs received concurrent administration of oral furosemide throughout the study (up to 8 mg/kg/day), to manage pulmonary edema.
Human Warnings: Not for use in humans. Keep this and all medications out of the reach of children. Consult a physician in case of ingestion by Digoxin and calcium channel blockers were allowed for control of supraventricular arrhythmias. The use of injectable furosemide was permitted during
humans. the study evaluation period only if used in place of an equivalent oral dose.
Precautions: The safety and effectiveness of concurrent therapy of CARDALIS with pimobendan has not been evaluated. The rate of treatment failure was the primary effectiveness variable used to compare CARDALIS to benazepril hydrochloride alone. Treatment failure
Renal function and serum potassium levels should be evaluated prior to initiating treatment with CARDALIS. Regular monitoring of renal function was defined as cardiac death or euthanasia (including death of unknown cause), recurrence or worsening of pulmonary edema, newly documented
and serum potassium levels is recommended as there may be an increased risk of hyperkalemia. cardiogenic ascites, or clinical signs of congestive heart failure requiring administration of a furosemide dosage higher than 8 mg/kg/day. Failure rates
Dogs undergoing combined treatment with CARDALIS and NSAIDs should be adequately hydrated to avoid renal toxicity. at study Days 30, 90, 180, and 270 were also evaluated as secondary outcomes.
Concomitant use of desoxycorticosterone pivalate (DOCP) with spironolactone may counter the effect of DOCP as DOCP has an opposing mechanism of The rate of failure in the CARDALIS group estimated from the model analysis was statistically different (P = 0.0433) and numerically lower than that of
action to potassium-sparing diuretics like spironolactone. Closely monitor dogs receiving digoxin and spironolactone. Spironolactone decreases digoxin the benazepril hydrochloride alone group, as summarized in Table 4.
elimination and hence raises digoxin plasma concentration. This may result in digoxin toxicity.
Spironolactone and benazepril hydrochloride undergo extensive hepatic biotransformation. Care should be taken when using CARDALIS in dogs with Table 4: Treatment Failure Rates by Treatment Group (Least Square Means)
hepatic dysfunction. Number Percent Treatment 95% Confidence
The safety of CARDALIS has not been evaluated in growing dogs. Spironolactone has an antiandrogenic effect and should be used with caution in Group
of Dogs Failure a,b Interval
P-value
growing dogs. The safety of CARDALIS has not been established in pregnant, lactating or breeding dogs. CARDALIS 216 80.59% 72.57, 86.69%
Adverse Reactions: A U.S. clinical field study comprised of a 360-day treatment period evaluated the safety and effectiveness of CARDALIS 0.0433
Benazepril Hydrochloride 198 88.09% 81.40, 92.59%
compared to benazepril hydrochloride in 569 client-owned dogs with left-sided AVVI. Table 1 summarizes the adverse reactions not directly related to
α = Back-transformed from the logit transformation used in the statistical analysis, which included random
the progression of disease that occurred in greater than 5% of the dogs treated with CARDALIS.
effects associated with study site and the site by treatment interaction.
b = Calculated based on individual animal results.
Table 1: Adverse Reactions Occurring in ≥ 5% of the CARDALIS Treated Dogs
CARDALIS Benazepril Hydrochloride Further, the rate of failure in the CARDALIS group was significantly lower than the group administered benazepril hydrochloride alone at all evaluation
Preferred Term (N = 284) (N = 285) periods past study Day 30. The dogs in the CARDALIS group exhibited a longer median time-to-failure when compared to the control group.
Anorexia 107 (38%) 113 (40%) CARDALIS was safely administered in dogs concurrently receiving furosemide, digoxin, calcium channel blockers, antiparasitics, analgesics/anti-inflam-
Vomiting 70 70 (25%) 25% 51 51 (18%) matories, antibacterials, routine canine vaccines, respiratory treatments, and gastrointestinal treatments.
Lethargy 44 (16%) 41 (14%) Palatability: During the field study, 233 dogs were offered CARDALIS once daily for 14 days. CARDALIS was accepted voluntarily, with or without food,
Diarrhea 43 (15%) 41 (14%) in 87.6% of the 3178 reported doses.
Renal insufficiency 31 (11%) 19 (6.7%) Animal Safety: In a laboratory at safety study, 32 healthy one-year old Beagle dogs (16 males and 16 females) were randomly assigned to an
untreated control group or were dosed orally with CARDALIS once daily for 26 weeks at 0, 1X, 3X, and 5X the maximum recommended daily dose (4
Collapse 16 (5.6%) 12 (4.2%)
mg/kg spironolactone and 0.5 mg/kg benazepril hydrochloride). No dogs were removed and no unscheduled deaths occurred during the study. The
Hepatopathy 16 (5.6%) 8 (2.8%)
dogs dosed with CARDALIS showed no test article-related effects on food or water consumption, body weights, electrocardiographic findings, or blood
Urinary Incontinence 15 (5.3%) 27 (9.5%) pressure. The dogs in the 5X group had lower mean heart rates compared to the other groups at the end of the study.
The following adverse events were seen in fewer than 5% of the study animals, in decreasing order: urine abnormalities, fluid in abdomen, ataxia, Increased mean serum potassium levels were found in dogs in all CARDALIS dose groups but remained within reference range. There was a dose-related
weight loss, digestive tract disorder, hypertension, electrolyte disorder, bronchitis, and hyperactivity. decrease in red cell mass (mean red blood cell count, hematocrit and hemoglobin) but all variables remained within reference ranges. There were
decreases in mean prostate weights in the 3X and 5X groups and signs of slight to marked atrophy of prostate glandular tissue. There was a thickening
Renal insufficiency was reported more frequently in dogs treated with CARDALIS. This finding may be also attributed to the concurrent administration
of the zona glomerulosa of adrenal glands in both male and female in the 3X and 5X treated animals.
of furosemide. The clinical pathology parameters associated with renal function were not statistically different between the treatment groups.
Systemic exposure to the active metabolites of spironolactone (canrenone and 7-α-thiomethyl-spironolactone) and benazepril (benazeprilat) was
The incidence of death, including euthanasia and sudden death, was similar in dogs treated with CARDALIS or benazepril hydrochloride. In most
shown at the three dose levels throughout the study, with no apparent gender effect. Canrenone and benazeprilat exposures were more than dose
cases, death was attributable to the progression of heart disease or the clinical signs associated with congestive heart failure. Deaths of unknown
proportional at steady-state. There was no accumulation with repeated benazeprilat exposures; canrenone accumulation was 30%. Systemic exposure
cause were presumed to be cardiac in nature.
to 7-α-thiomethyl-spironolactone were variable by study day and dose of spironolactone; steady state, dose proportionality, and accumulation could
Serum magnesium and potassium values were significantly higher in the CARDALIS group, although the mean values remained within the reference not be determined.
range and did not change significantly over time. These electrolyte changes are consistent with the potassium-sparing properties of spironolactone.
Storage Information: Store at controlled room temperature, 20° to 25°C (68° to 77°F), in original container. Excursions permitted between 15°C and
One dog treated with CARDALIS was removed from the study at Day 7 because it developed hyperkalemia.
30°C (between 59° and 86°F).
Contact Information: To report suspected adverse events or to request a copy of the Safety Data Sheet (SDS), please call Ceva Animal Health at
How Supplied: CARDALIS chewable tablets for dogs are available in 3 sizes of oblong half scored flavored tablets:
1-800-999-0297. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at
20 mg spironolactone and 2.5 mg benazepril hydrochloride, 40 mg spironolactone and 5 mg benazepril hydrochloride, and
www.fda.gov/reportanimalae.
80 mg spironolactone and 10mg benazepril hydrochloride. Each size is available in 30-count bottles enclosed in color coded packages.
Clinical Pharmacology:
Mechanism of Action: The main pharmacological target of spironolactone and benazepril is the renin-angiotensin-aldosterone system (RAAS) at CARDALIS™ trademark is the property of Ceva Santé Animale S.A.
different levels in the cascade. Spironolactone and its active metabolites (including 7-α-thiomethyl-spironolactone and canrenone) act as specific Made in Germany
antagonists of aldosterone (regardless of the source) by binding competitively to mineralocorticoid receptors located in the kidneys, heart and blood C36510O 08-A1-v1
vessels. Manufactured for:
Benazepril hydrochloride is a prodrug hydrolyzed in vivo into its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective inhibitor Ceva Animal Health, LLC, 8735 Rosehill Road
of angiotensin-converting enzyme (ACE), thus preventing the conversion of inactive angiotensin I to active angiotensin II. This prevents deleterious Lenexa, KS 66215
effects of vasoconstriction and aldosterone release, including sodium and water retention, and vascular and myocardial remodeling. However, Rev 0.3 (JAN 2020)Spironolactone + Benazepril HCI
There is a new
couple in town
Spironolactone is the essential
addition to an ACE inhibitor
The only FDA approved combination drug for the
management of congestive heart failure (CHF) in dogs.
Improved patient acceptance solves owner compliance challenges.
CARDALIS™ chewable tablets provide half of the ACVIM quad-therapy recommendation
for congestive heart failure.*
Chewable tablets Once a day With meal Flavored**
for dogs
*In 2019, the ACVIM published new guidelines recommending a quadruple therapy approach for the treatment of CHF in dogs.
The safety and efficacy of CARDALIS™ has not been investigated with pimobendan.
**Non-allergenic beef flavoring ©2021 Ceva Animal Health, LLC.
See page
See legal 10 for
on page X product information summary. CARDALIS™ trademark is the property of Ceva Santé Animale S.A.The end is near.
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© 2021 Antech Diagnostics, Inc. AM-902-17-01 05-21TOP 5 TOP 5 DERMATOLOGIC INDICATIONS FOR PENTOXIFYLLINE IN DOGS Sarah Lewis, DVM, MS Robert Kennis, DVM, DACVD, MS Auburn University
PA
entoxifylline
ntemortem
is a methylxanthine
diagnosis of deriva-
tive that pancreatic
inhibits phosphodiesterase
disease is a to
raise intracellular
challenge.cyclic
Histopathol-
adenosine
monophosphate
ogy remains
levels
the
1
; this
goldcan have many
standard of
global effects, including
diagnosis improved
for pancreatic circulation
neopla-
and reduced inflammation.
sia and pancreatitis.1 Pentoxifylline
Pancreatic
inhibitsbiopsy
RBC deformability, microvascular
provides a definitive diag- con-
striction, andof
nosis thrombus formation
pancreatitis, ; decreases
assuming
1
a
proinflammatory cytokine
representative production,
sample is neutro-
phil degranulation,
obtained. Annatural
open orkiller cell activity,
laparo-
leukocyte adhesion,
scopic chemotaxis,
approach and adherence
can be made to
to keratinocytes ; and stimulates fibroblasts to
collect samples.
1-3
produce collagenase and promote wound heal-
ing.1,2 Cytokines inhibited by pentoxifylline
include tumor necrosis factor-a, interferon-g,
interleukin-1 (IL-1), IL-6, IL-8, and IL-10.1
September 2015 cliniciansbrief.com 15TOP 5 h DERMATOLOGY h PEER REVIEWED
Pentoxifylline (10-30 mg/kg PO every 8 to 12
TOP 5 DERMATOLOGIC INDICATIONS hours) has a reported elimination half-life of 24
FOR PENTOXIFYLLINE to 404 minutes that supports 8-hour administra-
tion.4-6 In dogs, oral bioavailability is variable and
1. Cutaneous Vasculitis reported to be 15% to 50%.5,6 Pentoxifylline is
2. Canine Familial Dermatomyositis available as a 400-mg extended-release tablet and
is commonly halved or quartered to achieve the
3. Other Ischemic Dermatopathies
intended dosage.5,6 No controlled studies have
4. Allergic Contact Dermatitis directly investigated the pharmacokinetic effects of
breaking the extended-release tablet. Pentoxifylline
5. Atopic Dermatitis
is generally well-tolerated in dogs, and GI upset is
the most commonly reported adverse effect.5,6
Anecdotal reported use in veterinary medicine is
vast; however, peer-reviewed studies evaluating its
efficacy for the treatment of specific diseases are
limited and generally retrospective. Based on anec-
dotal evidence in human and veterinary medicine,
there is believed to be a lag in onset to clinical effect
that may last several months.6-8 Previously, con-
cerns about cost limited the use of pentoxifylline in
veterinary medicine, but affordable generic formu-
lations are now available.
Following are 5 common uses of pentoxifylline in
veterinary dermatology according to the authors.
1
dF
IGURE 1 Multifocal to coalescing erythematous macules on the ventral
abdomen of a dog with cutaneous vasculitis. Because the lesion does not
blanch on diascopy, it is likely due to vasculitis or hemorrhage. Image Cutaneous Vasculitis
courtesy of Amelia White, Auburn University Cutaneous vasculitis refers to inflammation
of the blood vessels in the skin (Figure 1)
that results in altered blood flow and isch-
emic necrosis of the skin (Figure 2).9 The condition
may be idiopathic or caused by adverse drug reac-
tion, infection, insect bite, or neoplasia.8 Treatment
should address the underlying cause and repair tis-
sue damage.9 Pentoxifylline is an ideal treatment
(regardless of cause) because of its effect on perfu-
sion and inflammation.
Because pentoxifylline has a potential delayed
onset of effect, it is often combined with other
drugs (eg, glucocorticoids).9 In a retrospective
study,10 9 of 19 dogs with vasculitis were treated
with pentoxifylline (10-20 mg/kg PO every 12
dF
IGURE 2 Full-thickness dermal necrosis on the hock of a patient with a
hours) alone (1 dog) or in combination (8 dogs)
neutrophilic necrotizing vasculitis suspected to be secondary to a spider
bite. Pentoxifylline (25 mg/kg PO every 12 hours) and open wound manage- with prednisone (1.5-3 mg/kg/day) with variable
ment were provided. Image courtesy of Karly Hicks, Auburn University success. Six dogs had complete resolution, 2 had
16 cliniciansbrief.com June 2021You can also read
