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CSU testing stem-cell treatment on feline chronic kidney disease

Researchers at Colorado State University’s (CSU) James L. Voss Veterinary Teaching Hospital are seeking feline study participants for a novel stem-cell therapy that could repair the damaged organs of cats with chronic kidney disease.

The study involves injecting feline patients with stem cells cultivated from the fat of young, healthy cats, and has shown promise for treating a health problem that affects approximately 50 percent of cats older than 10, CSU said.

Jessica Quimby, DVM, leader of the CSU research, said the current undertaking is designed to further test the efficacy of the treatment now that previous research at the school has established a strong safety profile.

“In our pilot study last year, in which stem cells were injected intravenously, we found stem-cell therapy to be safe, and we saw evidence of improvement among some of the cats enrolled in the trial,” Quimby said in an article published in Phys.org. “In this study, we will further explore stem-cell therapy with the new approach of injecting the cells close to the damaged organs. We hope this proximity could yield even better results.”

According to Quimby, her group’s prior research has demonstrated that the stem-cell treatment could decrease inflammation, promote regeneration of damaged cells, slow loss of protein through urine, and improve kidney function.

Surgery STAT: Use of adult stem cells in clinical orthopedics

Adult stem cells are cells found in various tissues throughout the bodies of both juveniles and adults. By definition, these are undifferentiated cells that can be induced to become any of a number of cell types.

Bone marrow-derived mesenchymal stem cells (BMDMSC) are of particular interest in orthopedics, as cells in this lineage are involved in osteogenic differentiation of cells at the site of bone generation and regeneration. These cells, by virtue of their presence in bone marrow, have easy access to sites of fracture healing. However, only a small fraction (fewer than 0.01 percent) of the cells present in bone marrow are BMDMSC. A bone-marrow aspirate may contain only a few thousand cells — not nearly enough to incite a significant osteogenic effect. For this reason, investigators are expanding these cells in culture to obtain numbers in the millions. This number of cells has been shown to induce bone healing.

 


Photo 1: Dèbridement of fibrous tissue from a delayed union site using a bone curette through a limited approach.

Bone marrow-derived mesenchymal stem cells can be obtained by harvesting bone marrow from a patient and growing that patient’s cells in culture in a laboratory. These are referred to as autogenous cells, or cell autografts. However, this is difficult to do in a clinical setting in which a laboratory is not available for immediate transfer of the marrow sample. There is a large body of experimental data demonstrating the safety and efficacy of BMDMSC from another individual of the same species, referred to as cell allografts. This newer approach will make it easier for clinicians in various practice settings to use these cells, not only for bone healing, but for regeneration of other tissues as well.

 

 


Photo 2: Identification of site of dèbridement and stem cell delivery using a percutaneous approach with fluoroscopic guidance.

Bone marrow-derived mesenchymal stem cells can be grown in a commercial or academic laboratory and used by veterinarians at distant locations by shipping the cells via overnight courier on dry ice.

 

 


Photo 3: Providing access to marrow elements at the site of impaired bone healing by drilling small holes in sclerotic bone.

There are a number of clinical scenarios in which a minimally invasive, biologic approach to tissue regeneration carrying low risks is desirable. These cells can be delivered to virtually any anatomic site via a percutaneous approach. For example, this system can be utilized in any delayed or non-union fracture site, as well as in slowly fusing arthrodesis sites.

 

 


Photo 4: Delivery of stem cells via a limited approach

The delivery site should first be dèbrided (Photo 1) to remove all fibrous tissue that may impede osteogenesis. This dèbridement can be accomplished with a percutaneous approach using fluoroscopic guidance (Photo 2), or a limited open approach. Provide access to the marrow cavity by drilling small holes in any sclerotic bone at the site (using 0.045-inch Kirschner wires, Photo 3). This preparation provides access to the patient’s own stem cells, which may undergo osteogenic differentiation in response to delivery of the allograft BMDMSC. The allograft BMDMSC can be delivered through the same percutaneous or limited open approach (Photo 4), further compromise the vascular supply to the bone and soft tissues.

 

 


Photo 5: Allograft stem cells delivered from an academic or commercial laboratory following expansion in vitro.

The cells (Photo 5) can be delivered in a number of carrier systems designed to retain the cells at the site of interest, to make delivery through a percutaneous approach easy and safe and to augment the osteogenic potential of the cells.

 

 


Photo 6: An example of a mixed carrier system for delivery of stem cells.

Examples of such carrier systems that have been used with success with BMDMSC include: absorbable collagen sponge, absorbable gelatin sponge or powder, autograft cancellous bone, allograft cancellous bone, autograft and/or allograft corticocancellous bone, autologous bone marrow and any combination of these carriers (Photo 6). Radiographs should be taken four weeks status post stem-cell delivery to assess the progress of bone healing. The need for further follow-up will vary depending on the nature of the case, the age of the patient and the robustness of the initial response to stem-cell therapy.

 

Dr. Zachos is an ACVS board-certified surgeon. She is assistant professor of orthopedic surgery at Michigan State University, where she is an attending orthopedic surgeon in the Small Animal Clinic of the Veterinary Teaching Hospital. She also runs a molecular orthopedics laboratory at Michigan State. Her research focus is the development of translational cell-based gene therapy techniques for bone and cartilage regeneration.

Her work has been recognized by the American Academy of Orthopaedic Surgeons, the Orthopaedic Research Society, the Ruth Jackson Orthopaedic Society and the 7th International Conference on Bone Morphogenetic Proteins.

Dr. Smith is a resident in small-animal surgery at the Lois Bates Acheson Teaching Hospital, Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University.

Heartworm preventive resistance is real

 
 
Dr. Wallace Graham said heartworm experts seem to agree genetic change in heartworms is related to resistance to preventive drugs.
 
Dr. Graham is the immediate past president of the American Heartworm Society, and he said that presenters at the organization’s triennial symposium Sept. 8-10 in New Orleans agreed that resistance is real, a more definitive conclusion than was available at the 2010 meeting. But those presenters disagreed over resistance’s causes and contributing factors. 
“Practitioners had believed that they were seeing that for some time, but of course, we can only talk definitively about facts that we have based upon scientific research,” Dr. Graham said. “So, I think some practitioners left the last meeting somewhat unsatisfied, because we were not able to say definitively resistance is possible, whereas now, we were able to do that.” 
Dr. Graham said the symposium’s speakers generally agreed that preventives fail most as a result of failure to properly administer the drugs or test for heartworms, and veterinarians can best serve patients by following the AHS guidelines on heartworm preventive use throughout the year and heartworm testing annually.
 
Dr. Stephen L. Jones, AHS president, said such resistance does not appear to be spreading beyond a small percentage of dogs in the Mississippi Delta, where it likely is most prevalent because of high rates of transmission by mosquitoes, although it could exist elsewhere.
 
Dr. Jones also noted that he has seen only reports of positive tests but no illness among dogs with resistant heartworms. A particularly unlucky dog could have two or three preventive-resistant heartworms, as preventives still protect against most infective larvae that pets encounter. 
When resistant heartworms are suspected in dogs that are receiving preventives, Dr. Jones said it is more important than ever to administer treatment and try to eliminate both adult heartworms and microfilaria. 
Resistance of Dirofilaria immitis to macrocyclic lactone drugs was one of the topics of the symposium, along with developments in diagnostics and epidemiology, heartworm disease management, feline heartworm infection, and clinicians’ observations. 
Since the 2010 meeting, advancement in heartworm research improved understanding of endosymbiont Wolbachia organisms and their connection with heartworms and heartworm disease, the connection between heartworm and feline respiratory disease, and the parasites that produce signs that mimic heartworm-associated respiratory disease in cats, Dr. Graham said.
“It was a jam-packed meeting, and, I think, very well-received by the folks who were in attendance, especially the practitioners,” he said.
Dr. Graham said the veterinary profession needs more knowledge about heartworms and prevention, particularly on how macrocyclic lactones affect heartworms. Since 2010, he said, research has provided a better indication of how preventives work by showing that they seem to modify a heartworm’s ability to hide itself from a host’s immune system.
“It’s impossible to fully understand resistance until we fully understand how the macrocyclic lactones work, and that’s ongoing,” he said.
Dr. Jones said he would like to see further investigation into the pathology of heartworm infection, particularly into why the disease manifests in various clinical signs in dogs, which can have coughing, lung inflammation, or congestive heart failure, or why they can have no clinical signs at all.
The AHS recently approved spending $100,000 on heartworm-related research, which will be in addition to $40,000 available this year through an AHS research fund managed by the Morris Animal Foundation. Dr. Jones said the amount is a substantial investment toward improving understanding of heartworm disease.
Also during the meeting, Dr. Cristiano von Simson of Shawnee, Kan., became AHS vice president, and Dr. Robert W. Stannard of Livermore, Calif., became secretary-treasurer.

Feline Injection-Site Sarcoma

Feline injection-site sarcoma, or FISS, is a controversial topic; however, Dr. Richard Ford presents a comprehensive overview of the history, literature, and current issues associated with FISS. In addition, two very interesting questions are answered: W hat do we still need to learn about FISS and how do we lessen the risk for its development in cats?

Richard B. Ford, DVM, MS, Diplomate ACVIM & ACVPM (Hon)

Figure. Postoperative cat with FISS at FeLV vaccination site. The tumor developed in skin over the left side of the pelvis, indicating an injection site high on the left side. Tumors that develop at this level pose a serious risk for invasion of the ileum if not treated early.

Today, among the spectrum of vaccine adverse events reported in dogs and cats, feline injection-site sarcoma (FISS) ranks as the most serious. Although it occurs infrequently, the consequences of a malignant tumor developing at a vaccination site are devastating to the patient and owner.

Consider the following facts:

  • Tumors linked to vaccine administration are high-grade sarcomas.
  • Untreated, affected cats will die from complications associated with the tumor.
  • Time from vaccination to tumor development is typically between 3 months and 4 years. A smaller number of tumors develop 5 or more years after vaccine administration.
  • Radical excision (3- to 5-cm margins and 2 muscle planes deep), along with radiation therapy, is recommended for tumors arising in skin over the thorax or abdomen. Limb amputation is recommended for tumors at injection sites on a limb.
  • Despite aggressive surgery, recurrence rates up to 50% are reported.1
  • Local recurrence is common when simple excision of the tumor is attempted; 86% of recurrences develop within 6 months.1
  • Pulmonary metastasis occurs in 21% of cats diagnosed with grade 3 tumors.2

HISTORY OF INJECTION-SITE SARCOMAS
Association with Aluminum
Over 20 years ago, pathologists from the University of Pennsylvania reported an alarming 61% increase in the number of injection-site fibrosarcomas among feline biopsy accessions from 1987 to 1991. This increase was epidemiologically linked to the enactment of a mandatory 1987 rabies vaccination law for pet cats residing in Pennsylvania.3,4

Electron probe microanalysis of tumors identified aluminum (commonly used as an adjuvant in feline vaccines) within macrophages surrounding the sarcomas. The hypothesis was advanced, but not proven, that persistent inflammatory and immunologic reactions to aluminum adjuvants might lead to neoplastic transformation in cats.5

Adjuvants Role in Pathogenesis of FISS
In 1993, an epidemiologic study involving 345 cats with fibrosarcoma provided evidence that vaccination with feline leukemia virus (FeLV) and rabies virus vaccines could lead to tumorigenesis at the injection site, particularly when vaccination was repeatedly administered at the same site.6

At the time the study was conducted, all FeLV and rabies virus vaccines licensed for cats in the U.S. were inactivated, adjuvanted products. This fact raised concerns that chronic inflammation caused by adjuvant-containing vaccines, rather than one particular vaccine brand, played a role in the pathogenesis of these tumors.

Since the early days of vaccine-associated sarcoma (now known as FISS) discovery, several studies have been published that characterize tumor pathology, offer diagnostic recommendations, outline treatment options for affected cats, and assess survival rates.

  • Understanding the pathogenesis of FISS
  • Defining true prevalence
  • Mitigating risk.

A brief chronology of FISS is presented in Table 1.

Table 1. Chronology of Feline Injection-Site Sarcoma
1985 The first FeLV vaccine (inactivated, aluminum adjuvanted) is introduced (Leukocell, Norden Laboratories).
1985 Attenuated rabies virus vaccines sold in the U.S. are replaced with inactivated, adjuvanted rabies virus vaccines.
1987 Pennsylvania mandates administration of rabies virus vaccine to pet cats (at that time, all rabies vaccines sold in the U.S. were inactivated and adjuvanted).
1991 Letter from University of Pennsylvania, Surgical Pathology Laboratory, published in JAVMA cites significant increase in sarcoma occurrence at injection sites in cats, suggesting correlation between rabies vaccination and tumor formation.3
1992 Hypothesis linking tumor development in cats and inflammatory response to aluminum (adjuvant) at vaccine injection sites is advanced, but unproven; aluminum found inside macrophages around injection-site tumors.4
1993 Evidence links (inactivated) FeLV and rabies virus vaccine administration with tumorigenesis.4
1996 AVMA and AAHA jointly sponsor a meeting, leading to formation of the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) to fund and plan research and promote education and awareness.
1997 Vaccination-site guidelines recommend administration of rabies in distal portion of right hindlimb, FeLV in distal portion of left hindlimb, and all other vaccines in right shoulder region.
1999 VAFSTF, in conjunction with Veterinary Cancer Society, recommends “3-2-1 Rule” (see Table 2) regarding diagnosis of suspected sarcomas.
2001 Government report (UK) on vaccine adverse reactions cites FISS were 5× more likely to develop in cats receiving aluminum adjuvanted (FeLV) vaccines than those receiving nonadjuvanted vaccines. (NOTE: The UK is rabies free and dogs/cats are not vaccinated against rabies).7
2004 VAFSTF discontinued; roundtable discussion published, highlighting the controversies surrounding FISS risk management.8
2009 Study published citing changes in characteristics of FISS (392 cases) subsequent to VAFSTF vaccination-site recommendations: FISS decreased at interscapular sites, but more than doubled in pelvic limbs.9
2012 Study cites cats with FISS were significantly less likely to receive recombinant vaccines than inactivated (adjuvanted) vaccines; study also concluded that no vaccine is risk-free.10

ISSUES & CONTROVERSIES
Today, the profession still struggles with ambiguous recommendations and controversy over FISS risk management.

Other Causes of Sarcomas
Most authors agree that vaccines are not exclusively responsible for inducing sarcomas in cats1-3,6,8,10; implicated causes include:

  • Repository corticosteroids
  • Long-acting penicillin
  • Nylon suture left in the skin for extended periods
  • Skin trauma.

These observations support the fact that chronic inflammation, due to a variety of causes, may lead to oncogenesis in some cats.

Roles of Genetics & Adjuvants
All cats do not share equal risk for vaccine-associated tumorigenesis, which supports a role for genetics in determining FISS risk. Several authors suggest that the adjuvants currently present in all inactivated feline vaccines licensed in the U.S. cause chronic inflammation, which may provoke tumor formation in genetically predisposed cats.8

Vaccine Selection Challenges
Recommendations to avoid use of inactivated (adjuvanted) vaccines in cats have been met with resistance from the industry. This is not surprising considering the fact that the majority of rabies vaccines sold and administered in the U.S. are inactivated 1-year and 3-year vaccines.

In addition, in the U.S., there is only 1 nonadjuvanted (recombinant) vaccine each for FeLV and rabies virus (only available as a 1-year vaccine). These vaccines are priced higher per dose than adjuvanted (killed) FeLV and rabies virus vaccines, a factor that influences purchasing decisions.

Vaccine Terms
Adjuvant: Chemical, microbial constituent, or mammalian protein added to an inactivated viral or bacterial vaccine to enhance the immune response to a selected antigen

Attenuated: Vaccine that contains the live virus or bacteria as the immunizing antigen. The virulence of the organism (antigen) is reduced, but is still capable of infecting cells and replicating following inoculation. Attenuated vaccines are not adjuvanted.

Inactivated: Vaccine that contains the killed virus or bacteria as the immunizing antigen. Following inoculation, the antigen is incapable of infecting cells or replicating. All inactivated feline vaccines sold in the U.S. and Canada are adjuvanted.

Recombinant: Vaccine manufactured through gene cloning (plasmid expressed) or by recombining selected DNA from a pathogenic organism with DNA from another virus (viral vectored), leading to the expression, following inoculation, of only essential antigens required to immunize. Recombinant feline vaccines sold in the U.S. and Canada do not contain adjuvant.

WHAT IS STILL UNKNOWN
Prevalence of FISS
Published estimates on the prevalence of FISS vary significantly, depending on the study design, numbers of cats in the study, geographic location of the cats, and the fact that injections other than vaccines are known to induce sarcomas.

Prevalence estimates from 1 in 10,000 cats to as many as 1 in 1000 cats have been cited. Studies reporting risk according to doses of vaccine administered/sold also vary (from 1 to as many as 36 cases per 10,000 doses).11-16

Reliably tracking and reporting prevalence, or the proportion of cats in the population that develop tumors subsequent to vaccination, are critical in learning whether recommendations to reduce or eliminate risk are effective over time. Tracking prevalence of FISS has proven challenging due to several reasons, including: low/inconsistent reporting of FISS, lack of a centralized database, and genetic influence.

Pathogenesis of FISS
Several sophisticated studies have addressed cellular and subcellular changes associated with FISS. Proposed mechanisms tend to center around:

  • Chronic inflammation
  • Up-regulation of platelet-derived growth factor and subsequent proliferation of fibroblasts
  • Mutations in TP53 (so-called “tumor suppressor gene”).
    While there is little agreement on the actual role these factors play in the pathogenesis of FISS, it is agreed that the events leading to tumor formation in cats following vaccine administration involve the complex interaction of:
  • Intrinsic factors, such as individual genetics and nature and degree of inflammatory response following injection
  • Extrinsic factors, such as type of vaccine administered, frequency of administration, and number of vaccines administered at a site.

What isn’t known is how these factors interact in the individual cat, leading to tumorigenesis.

Predicting FISS
Predicting cancer is an important, emerging field in human and veterinary medicine. The ability to detect mutations in the BRCA1 and BRCA2 genes, for example, allows physicians to identify women at significant risk for developing hereditary breast and ovarian cancer.

Mutations in the TP53 gene of some cats with FISS have been detected in studies conducted at the University of Minnesota. Although these studies suggested potential for assessing genetic predisposition for FISS, there is no commercially available test that will reliably predict which cats will develop tumors.

Nonsurgical Treatment Options
If FISS is confirmed, current recommendations consistently cite the role of radical surgery with radiation therapy to prolong survival. It’s the degree of “radical” that obviously impacts the patient’s recovery, postsurgical quality of life, and cost (emotional and financial) to the owner.

Due to the fact that injections other than vaccines can induce tumors in cats, it becomes reasonable to seek nonsurgical treatment and management options to limit the consequences of surgery. At this time, medical treatment of FISS offers limited value to the individual patient, even when combined with radiation therapy.

MITIGATING RISK FOR FISS
After over 20 years of causing, diagnosing, and treating injection-site sarcomas in cats, the question that is reasonably asked is: What can a veterinarian do to mitigate the risk for, or limit the consequences of, FISS?

Note that the following succinct review of recommendations has appeared in the literature and been presented at national conferences over the past several years; however, the recommendations have not consistently been subjected to scientific scrutiny and often represent expert opinion rather than results of published studies.

Only administer vaccines when reasonable risk of pathogen exposure is apparent.
There is widespread agreement that limiting the number of vaccines administered to an individual over time may reduce the risk for tumor development. For this reason, veterinarians are strongly encouraged to follow current vaccination guidelines for cats.17

Among adult household cats that have completed the initial vaccination series, core vaccines (feline parvovirus-herpesvirus 1-calicivirus) should be administered at 3-year intervals. Rabies vaccine should be administered according to state or local statutes and at an interval consistent with the product label. Only administer noncore vaccines to cats with realistic exposure risk.

Only administer parenteral vaccines by subcutaneous route.
Intramuscular administration of vaccines does not reduce the risk for FISS. Furthermore, a tumor that develops in skeletal muscle (deep) may be detected later than a tumor that develops in skin (superficial).

Administer vaccines in accordance with current vaccination site recommendations.
Current vaccination site recommendations need to be reassessed. Although most veterinarians seem to follow recommendations published by the VAFSTF in 1996 (rabies, right rear; FeLV, left rear), FISS continue to be diagnosed at the interscapular region.9 Furthermore, it appears that most veterinarians prefer to administer vaccines to cats at sites above the stifle, not below, and over the right shoulder, rather than below the right elbow, as recommended in current feline vaccination guidelines (Figure).

Obviously, the recommendation to inject vaccines at distal limb sites is intended to facilitate complete removal of the tumor and minimize the risk of local recurrence, following amputation of the affected limb.

  • However, tumors can, and have, developed simultaneously in 2 limbs in the same patient.
  • In addition, consistently administering vaccines into distal limb sites results in the administration of subsequent vaccine doses into the same site, which may increase risk for tumor development.
  • Concern has also been expressed over the fact that efficacy of licensed rabies vaccines has never been validated in cats inoculated below the stifle.

Educate clientele about reporting postvaccination lumps.
To promote early diagnosis of FISS, advise owners to:

  • Observe (by touching or petting) their cats for the development of lumps at injection sites and
  • Contact the practice if any lump increases in size or persists beyond 1 month postvaccination.

Manage postvaccination lumps in accordance with the 3-2-1 Rule (Table 2).
When performing a biopsy of an injection-site lump, an incisional rather than excisional biopsy is recommended for at least 2 reasons:

  1. Simply excising a small lump (lumpectomy) may complicate efforts to define the original site in the event sarcoma is diagnosed and the owner delays definitive treatment as the incision heals and hair regrows.
  2. Most postvaccination lumps are benign. However, if the assumption is made that the lump is malignant and no biopsy is performed, the cat undergoes unnecessary surgery and excessive tissue removal for a lesion that would resolve spontaneously.
Table 2. 3-2-1 Rule for Biopsy Diagnosis of Suspected Injection-Site Sarcomas
If a mass meets 1 or more of the following criteria, an incisional (not excisional) biopsy of the mass lesion is recommended.
3: Mass is known to persist for 3 months or longer.
2: Mass is, or becomes, larger than 2 cm in diameter.
1: Mass continues to increase in size 1 month following an injection.

Perform routine thoracic radiographs in cats confirmed to have FISS.
High rates of pulmonary metastases in cats with FISS justify obtaining thoracic radiographs (including left and right lateral views) prior to committing the patient and owner to a definitive treatment protocol.

Avoid the use of adjuvanted (inactivated) vaccines whenever feasible.
Adjuvant is a chemical, microbial constituent, or mammalian protein commonly added to an inactivated (killed) viral or bacterial vaccine to enhance the immune response against a selected pathogen. Adjuvants are known to cause local reactions characterized by inflammation, granulomas and, occasionally, sterile abscess formation.18 Currently, all inactivated (killed) feline vaccines sold in the U.S. and Canada are adjuvanted. Modified-live and recombinant feline vaccines are not.

The hypothesis linking adjuvant-induced chronic inflammation to sarcoma formation has been suggested by several authors beginning in the early 1990s.3-5 Controversy over the role of adjuvant in sarcoma pathogenesis intensified with the publication of a limited number of studies suggesting there was no significant difference in FISS risk posed by adjuvanted versus nonadjuvanted vaccines.10,11,19 No studies have been published that suggest an adjuvanted vaccine is safer than a nonadjuvanted vaccine, with respect to FISS risk.

The controversy surrounding safety of administering nonadjuvanted vaccines over adjuvanted vaccines is likely to continue. The scientific evidence simply isn’t available currently to support unambiguous conclusions. The consequence is that cats will continue to be diagnosed with FISS attributed to routine vaccination.

Despite continuing controversy, the fact—that sarcoma diagnoses in cats became more common as the use of adjuvanted vaccines became more prevalent—remains a critical and undeniable piece of information that highlights a potential role for adjuvant in the pathogenesis of FISS. The recommendation to avoid adjuvanted vaccine in cats whenever feasible is justified.

AAHA = American Animal Hospital Association; AVMA = American Veterinary Medical Association; FeLV = feline leukemia virus; FISS = feline injection-site sarcoma; VAFSTF = Vaccine-Associated Feline Sarcoma Task Force

Why Does My Dog… Make a Beeline for Cat Food?

By Linda Fiorella

There’s a well-known scene in the movie Jaws where Richard Dreyfuss’ character cuts open the belly of a shark and pulls out some unexpected items, including a Louisiana license plate. As some pet owners and all vets know, an X-ray of a pooch’s stomach is also likely to produce some surprising findings.

While some dogs may try to eat pretty much everything, one thing that seems to hold a strong attraction for many dogs across a variety of breeds is cat food.

Dog and cat foods may seem pretty similar on the surface, but there are some important differences. Cats are obligate carnivores, meaning they need to eat meat as their main food source, whereas dogs are omnivores and need a diet with more fiber than a strictly carnivorous diet can provide. Still, there is meat in dog food, too, so why do dogs crave their feline friends’ food so fiercely?

“Since dogs can’t tell us why they love cat food,” says Sharon Crowell-Davis, DVM, DACVB, professor in the College of Veterinary Medicine at the University of Georgia, “and it is pretty consistent amongst most dogs (they just really do love cat food!), I’m going to guess it’s the higher protein content and the effect it has on the flavor.”

Dr. Crowell-Davis even uses cat treats as incentives for some of her canine behavioral patients because the deliciousness galvanizes the pups, just as long as “the dog loves them and the dog’s stomach can handle them, and it helps motivate the dog in learning how to behave the way the owner wants it to,” she says.

But just because something tastes good doesn’t mean we should eat it all the time. Dr. Crowell-Davis compares cat food and dogs to cake and humans. “It’s not necessarily the best thing for our diet, and certainly if we ate nothing but cake, we’d become really sick. But as an occasional treat, it’s not going to hurt us.”

But she points out that with some dogs, even as a rare delicacy, cat food can cause problems because dogs aren’t designed to have such a protein-dense diet. “Some dogs will get an upset stomach — vomiting, diarrhea — from eating cat food, while some other dogs with a tougher stomach can handle cat food,” she says. “If your dog breaks into the bag of cat food, is it going to kill the dog? Absolutely not. But if your dog does vomit or have diarrhea, make sure the dog can’t get [into] the cat food again, because it’s obviously one of those dogs whose GI system reacts badly to cat food.”

Even if your pup is one of those with an iron gut, long term it is not good for a dog to eat primarily cat food, Dr. Crowell-Davis says. It’s not properly balanced for them in terms of the fiber and protein and certain nutrients. Plus, it can be hard on their liver and their kidneys to have so much protein. Even more important, though, is the vice versa — make sure that your kitty is not fed a diet of dog food. “There are two essential ingredients in cat food that are not in dog food,” she says. “Taurine is an amino acid that dogs can manufacture in their own bodies but cats cannot, and also arachidonic acid, which is a fatty acid that cats need.”

For the safety and health of your pet, limit the majority of your pet’s diet to food that has been produced specifically for his or her species.catfood


Virbac issues expanded recall for Iverhart Plus Flavored Chewables

by NEWSTAT

 

Virbac has expanded its voluntary recall of Iverhart Plus Flavored Chewables following its initial recall notice in April 2013. 

According to PetMD, additional specific lots of the heartworm preventive are being recalled because they might not fully protect dogs in the upper third of each weight range.

PetMD cited a letter distributed by Virbac saying that 14 lots of Iverhart Plus Flavored Chewables were below Ivermectin potency levels prior to their expiration. Another 17 lots are being recalled out of caution even though they remain within specification.

Virbac is recalling the following lot numbers for each weight range:

Small dogs (up to 25 pounds)

  • 120092
  • 120397
  • 120398
  • 120798

Medium dogs (26-50 pounds)

  • 120090
  • 120301
  • 120378
  • 120450
  • 121282

Large dogs (51-100 pounds)

  • 120091
  • 120127
  • 120195
  • 120207
  • 120256
  • 120289
  • 120300
  • 120305
  • 120306
  • 120377
  • 120379
  • 120434
  • 120440
  • 120464
  • 120651
  • 120658
  • 120678
  • 120831
  • 121110
  • 121150
  • 121283
  • 121386 

Consumer information

Virbac directs consumers who have questions about the recall to contact Virbac Technical Services at 1-800-338-3659, ext. 3052.

Heartworm drug resistance: It’s real

Christy Corp-Minamiji, DVM
For The VIN News Service

In the world of canine heartworm disease research, reluctance to use the R word has evaporated. Leading authorities in pet parasites now concur that resistance to the class of drugs used in heartworm preventive drugs is real.  
 
“We now have proof there is resistance to the macrocyclic lactone (ML) class,” said Dr. Byron Blagburn, an Auburn University parasitologist who did much of the research on strains of heartworm found in the Mississippi Delta, where loss of efficacy to preventive drugs was first suspected. “It’s accepted by the entire industry now,” Blagburn said.

This recognition has placed the industry in uncertain territory. While the entire ML class is implicated in the resistance data, variations in product formulation and ingredient combinations may mean some products work better than others.

In an interview with the VIN News Service, Blagburn was careful to distinguish between drug class and drug product. “All preventives contain at least one macrocyclic lactone and at least one product (containing each ingredient in the class) failed. It does seem to involve all major drugs in that category,” he said, “but not all products are equal.”

The question of whether drug-resistant strains of heartworm are emerging in the United States has been scrutinized for years. Until now, however, experts have been careful to avoid using the so-called R word, “resistant,” to describe the strains that appear not to respond as expected to macrocyclic lactones.

Blagburn credits the evolution in understanding of heartworm susceptibility and identification of the resistant strains to “an inter-collegiate, inter-laboratory, collaborative process.”

The consensus is embodied in a recent update by the Companion Animal Parasite Council (CAPC) of its heartworm prevention guidelines. The new text on the CAPC website states: “Recent work has shown that there are isolates of heartworms that are capable of developing to adults in dogs receiving routine prophylaxis with any of the available macrocyclic lactones.”

In short, a dog faithfully given heartworm-prevention medication may still become infested with the parasitic worm Dirofilaria immitis, which inhabits the arteries of the lungs and sometimes a portion of the heart, causing serious and potentially fatal disease.

Convincing evidence of resistance was presented by multiple researchers at a meeting of the American Association of Veterinary Parasitologists in Chicago last month, according to CAPC President-elect Dr. Susan Little, a veterinary parasitologist at Oklahoma State University. Although research has focused on heartworm isolates from the South and Southeast, the CAPC notes that “At this time, the geographic extent of these resistant heartworms is not known.”

The macrocyclic lactone class of drugs in question comprises avermectin drugs (ivermectin and selamectin) and milbemycins (milbemycin oxime and moxidectin). These drugs are found in all commercial heartworm preventives, including: Heartgard (ivermectin), Tri-Heart Plus (ivermectin), Sentinel (milbemycin oxime), Revolution (selamectin), Advantage Multi (moxidectin), ProHeart6 (moxidectin), and Trifexis (milbemycin oxime).

The resistance finding begs the question: Is there any point to using the products?

Absolutely, say Blagburn and Little. Both state that the preventive products still work very well. There may be breaks in prevention with certain products in certain areas, but to the expert mind, this state of affairs only increases the need for year-round preventive action and annual testing for heartworm disease.

“To make a presumption that because resistance exists, the products should be discontinued is absolutely ludicrous,” Blagburn said.

While increased use of a drug usually is implicated in speeding the development of resistance in target parasites or pathogens, the canine heartworm may be different. With the heartworm, a number of factors work against the propagation of resistant genetics, according to Blagburn. The factors include:

  • Refugia. The population of heartworms not exposed to the drugs — heartworms living in wild canids such as wolves, foxes and coyotes, and in untreated domestic dogs — helps to dilute the heartworm gene pool, keeping the resistant genes from predominating.
  • Life cycle. Heartworms go through multiple larval stages, taking a relatively long time to reach reproductive maturity. The longer it takes a species to reach reproductive age, the slower the genetic change in its population.
  • Involvement of an insect vector. Heartworms are transmitted from host to host via the bites of infected mosquitoes, a fact that acts as a speed bump to genetic turnover.

   
While the spread of resistant genes is inevitable, Blagburn said, drug resistance is likely to spread geographically more slowly than has been the case with related worms, such as gastrointestinal parasites.

The recent heartworm research is notable not only for the multi-institute approach, but because the investigation into reports of product failure was spearheaded by the manufacturer of one of the products in question. In communication with the VIN News Service, Dr. Jason Drake of Novartis Animal Health explained the genesis of the studies:

“In recent years, the U.S. Food and Drug Administration (FDA) has seen an increase in reports of lack of efficacy in all approved heartworm preventive therapies – reports that were from manufacturers and veterinarians,” Drake said. “After listening to the concerns of veterinarians in the Mississippi River Valley, Novartis Animal Health decided to invest in understanding this problem and, if resistance was confirmed, to work with veterinarians to help contain the spread of resistance.”  

He highlighted data demonstrating that the entire drug class is affected. “Regardless of which product was used, whether it was oral, topical or injected, protection against some Dirofilaria immitis isolates from the Mississippi River Valley was less than 100 percent for all active ingredients included in the ML class,” he said.

While the entire class of drugs appears vulnerable to resistance, not every product has shown reduced efficacy.

Bayer Animal Health, maker of Advantage Multi, a topical drug that contains moxidectin, said by email to the VIN News Service that while research has shown a failure of injectable moxidectin to protect all dogs in a challenge study, the company is unaware of any published data showing a similar failure of moxidectin product applied to the skin.

Little, the parasitologist and CAPC president-elect, confirmed this. She explained: “The CAPC statement refers to all active ingredients because of the injectable moxidectin data, which have been presented in detail. Topical moxidectin is thought to result in higher plasma levels than injectable moxidectin, so there are likely differences in performance. But right now, we don’t fully understand what those differences may be.”   

Another pharmaceutical company, Merial, maker of Heartgard Plus, expressed support for the updated CAPC guidelines but downplayed resistance concerns. “Presently, there is no evidence that reduced susceptibility to macrocyclic lactones is a widespread phenomenon in the D. immitis population or will ever become one,” the company stated by email to the VIN News Service. “Further work will be needed to determine the extent to which the existence of resistant isolates will be a concern.”

In the meantime, how concerned should dog owners be about whether their dog’s heartworm preventive is effective?

Little advises that dog owners should not panic, but make sure they pay attention to maintaining a good heartworm prevention program, working in conjunction with their veterinarian. “Compliance is more important than ever before,” she said.

“What worries me,” Little continued, “is when I hear people say, “Oh, heartworm preventives — I hear those don’t work anymore.” She stressed that preventive products still work quite well for their intended function – preventing heartworm disease.

“Not every third-stage larva is resistant,” she said, referring to the infective stage in the heartworm life cycle. “It’s not uniform throughout the population, and the number of worms is correlated with the severity of disease.”

Little went on to say that because “disease severity is linked, in part, to the number of worms present in a dog,” if one or two worms escape a preventive rather than the 25 to 30 worms that may infest an un-medicated dog, “that may be a success in terms of disease prevention.”

Little pointed out that the heartworm preventive products have always been marketed as heartworm disease preventives. “And they still are. They’re just not, in some areas, complete heartworm infection preventives.”

The CAPC guidelines emphasize the need for year-round use of heartworm preventives in uninfected dogs and annual antigen testing.   

One method of treating heartworm disease, using preventive products over a long period to kill adult worms, has been fingered as a suspect in the development of resistant heartworms.

A passage in the CAPC guidelines written in capital letters practically shouts the importance of using approved “adulticide” products to treat heartworm infected dogs rather than the “slow-kill” method of using macrocyclic lactone preventives to gradually treat an adult heartworm infection.

According to the American Heartworm Society, this method can take up to two years of continuous administration to clear an infection entirely.

The need to abandon the slow-kill approach was reiterated in no uncertain terms by Blagburn. He said: “We have good data to convey to veterinarians that using anything other than the available adulticide to eliminate heartworm infections can be risky. We need to avoid slow-kill in every situation if at all possible.”

The problem with using the slow-kill technique to kill adult heartworms, experts say, is this: If there are microfilariae in the infected dog that are resistant to the macrocyclic lactone drug used, those parasites will be transmitted to mosquitoes, potentially finding their way to a new dog in which to reproduce, increasing the risk to all dogs in the area.

Little repeated the prohibition against the slow-kill technique even more strongly, calling the method irresponsible given what we now know. “If we select for resistance, even in an individual dog, we put every animal in the area at risk. We just can’t do slow-kill anymore,” she said.

That’s not to blame those who used the technique previously, she added. “We didn’t know. We thought it was OK. We were trying to do in some situations what we thought was best for the dog. But it’s no longer a viable option.”

Little and Blagburn stressed that if a veterinarian believes that the slow-kill approach truly is medically indicated, the dog first must be free of circulating microfilariae. Only dogs without microfilariae should be maintained on preventives long-term, they said.

Given the preponderance of evidence of resistance presented at the veterinary parasitology meeting last month, Little said the CAPC board had no difficulty concluding that resistance is an issue.

“When we saw the data, it was confirmation,” she said. “It was very compelling because it was multiple laboratories finding the same evidence. We have very strong evidence that there has been a shift in preventive efficacy in laboratory studies that corresponds with what veterinarians have been telling us from the field.

“There are some veterinarians who are now rightfully saying, ‘I told you so,’ ” she commented with a smile, but added, “We needed the lab confirmation.”
Heartworm Cycle

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