Current Topics (last updated 06/08/00 )
World of Medicine:
- PZI Insulin is "Baaaa-aack"!
- Eli Lilly Discontinues Iletin I Types of Regular, NPH and Lente Insulins!!
- PIVKA...What it is, why we care...
- Erythropoietin (Epogen®) and Hypertension
- Humans and Canine Heartworm
- FIP Update...Acquisition of FIP is via Mutation
- Pheochromocytoma...an overlooked cause of woe
- Degenerative Myelopathy...Misdiagnosis
- Hyperthyroid Diagnosis..an update
- Corneal Ulcers and Acetylcysteine?
- ACVIM 2000...some TidBits
Pentoxifylline (Trental®, Hoechst-Roussel) is a methylxanthine capable of some rather interesting and beneficial effects in veterinary and in human medicine. It acts at the cellular level as an immune modulator and to enhance oxygen availability to tissues, decreases activity of tumor necrosis factor (TNF) alpha ...(which may be an important potential therapeutic factor in some immune-mediated arthropathies), may be beneficial in reducing toxicities secondary to rejection therapy for bone marrow recipients. Phenominologically not understood, pentoxifylline somehow increases RBC deformability and decreases plasma fibrinogen: the resulting effect is improved circulation, especially in cases of vasculitides. Pentoxifylline has significant activity on connective tissue as well, decreasing collagen production and increasing collagenase...thus reducing risks associated with reactive scarring. Recent studies indicate that pentoxifylline may be beneficial in reducing oxidative damage from "hyperreagible" neutrophils...cells with accumulated highly-reactive free radicals that are thought to cause damage to tissue e.g. in septicemia, or other highly inflammatory condition resulting is disproportionate accumulation of inflammatory cell populations. The drug is now being utilized for: idiopathic paronychia, dermatomyositis, erythema multiforme, vasculitis & cutaneous/renal vasculitis of Greyhounds. The text of a recent publication illustrating this phenomenon is provided for you, though in a limited, edited version (VIEW PAPER)
In veterinary medicine, pentoxifylline has been used to successfully treat Dermatomyositis and dermatopathies which result from a putative vasculitis component, such as Ear Margin Dermatosis, vaccine reaction dermatosis. Interestingly a recent report demonstrated that pentoxifylline actually prevents symptoms of contact hypersensitivity in dogs with known allergies to certain plants!
There are many literature references. Some can be found in Capsule Report Dec'96, Vet Dermatol:8: 121, 1997. If desired, I have a long bibliography describing research with this drug, which I can supply via fax or e-mail, if requested.
Ebrel® is a recombinant pharmaceutical classified as a cytokine receptor; this drug is, specifically designed to act as a Tumor Necrosis Factor (TNF) receptor. It is being carefully studied for its ability to reduce or block the activity of (TNF) during the immune-mediated inflammatory cascade which occurs in Rheumatoid Arthritis in humans. In a press release, dated July 17th, 1997, Immunex Corporation describes their controlled study published in the New England Journal of Medicine. They report that 75% of treated (vs 14% of placebo) patients showed significant improvement (measured as at least a 20% reduction in the number of joints that were swollen and tender). Also, 57% of treated patients described at least a 50% reduction of swollen, tender joints! This study was focused on patients that had failed previous standard treatment modalities. The study describes the drug as "safe and well tolerated".
The potential ramnifications of this study and of this type of pharmaceutical approach to immune-mediated inflammatory conditions in veterinary medicine remains to be seen. It is my understanding (" off the record") that studies are already underway...and, so far..".results are very exciting" !
This press release and company publications describing this product, as well as overviews of the molecular physiology of immune-mediated arthritides, and of RA in particular, can be downloaded at the Immunex web site.
Accolate (Zafirlukast) is a leukotriene blocker. Leukotrienes are important inflammatory mediators in the large and small airways; the net result of treatment is, therefore, bronchodilation. In humans the drug is used to treat asthma.This has prompted some veterinarians to try Accolate in their chronic feline asthma patients. They report very good responses; in many instances cats can be weaned off steroids and the various other bronchodilators. Though not approved for cats, veterinarians are using 1/4-1/2 of tab (20mg tab) once to twice daily. Anecdotally, nobody is seeing side effects in cats treated for up to six months. Steroids and bronchodilators are still required with accute flair-ups. Note: there is some experimental work in progress investigating the efficacy of Accolate in dogs with COPD. In a recent issue of Veterinary Forum (1/98) a dose of 1-2mg/kg q12h was suggested.
For many of you, when Eli Lilly discontinued manufacture of PZI insulin, considerable worry regarding the management of diabetic cats became the norm. Even today, there is much debate over the appropriate insulin form, duration of action and doses of the many different insulin types...which have grown in numbers of the years as well. **Well..Anthony Laboratories was making PZI insulin (see below). It came as a 40U/ml form that was obtainable through veterinary suppliers but was approved for experimental use only. Thus, you needed to sign some sort of waiver, acknowledging the limited approval for experimental/ compassionate purpose and limited liability of the company. . . **
** Please note that effective immediately (i.e. the first time you read this) Anthony Laboratories has, unfortunately ceased making PZI insulin. Bummer!. However, Blue Ridge Pharmaceuticals is now manufacturing this insulin. This product is the identical formulation that was manufactured by Eli Lilly many years ago! More recent information concerning the efficacy of the Blue Ridge product is discussed in the ACVIM 2000 meeting summary .
Some of the other custom formulated variations of PZI. may or may NOT be similar to the PZI manufactured by Eli Lilly.
In a letter to physcians and veterinarians dated May 15th, 1998, Eli Lilly announced it will phase out all mixed pork-beef insulins (the company's Iletin I line of insulins) The types of insulins affected and popularly used in veterinary medicine are: Regular Iletin I, NPH Iletin I and Lente Iletin I. While a residual supply should be available into 1999, veterinarians are advised to consider alternative (e.g. recombinant- cloned human insulins) medications for their patients that are expected to need long term treatment for diabetes mellitus. You may call the company for additional information at: 888-885-4559.
Sometimes it is necessary to ascertain the bleeding/coagulation status' of animals on an immediate, frequent or ongoing basis. (This usually means NOW...not when the lab gets to it and sends results back the next day.) Examples include presurgical...(e.g.biopsy, neuter or spay, other), suspected platelet, von Willebrandt or liver disorders, vitamin K antagonist intoxication, other suspected or known coagulation factor disorders(s), responses to therapy for DIC, thromboembolism, and vitamin K antagonism or absence. There are relatively easy, in-house tests available for this purpose. One of them will be discussed here as it relates to the measurement of "PIVKA"
PIVKA stands for Proteins Induced by Vitamin K Absence (or Antagonism)1...to be explained below. A test for PIVKA has been likened to running an "amplified PT"...it is more sensitive, and vitamin K-dependent coagulation factor abnormalities can be detected earlier than with a standard PT test. The commercial, in-house test is described below.
.Vitamin K-dependent coagulation factors II, VII, IX & X are produced by the liver. Synthesis of each entails conversion of a specific inactive precursor molecule to the corresponding active factor via a vitamin K-dependent carboxylation step. In the absence (or antagonism) of vitamin K, precursor pools expand and leak into the systemic circulation where they inhibit coagulation. These circulating precursors are the PIVKA protein molecules. In the commercial test, prolongation of coagulation occurs specifically with deficiency of active factors II, VII,& X and/or ...with accumulation of PIVKA (which, in the circulation, can not be converted to the active form).
The test is marketed as Thrombotest® by Nycomed and can be obtained from Accurate Chemical and ScientificCorp., 300 Shames Drive, Westbury, NY 11590 (tel: 1-800-255-9378). You will need a 37o C heating block or water bath, a solution of 3.2 mmol CaCl2 (which you prepare), tri-sodium citrate vacutainer tubes and an accurate glass micropipettor (50µl). A fibrometer may be helpful...especially if routine use of the test is expected.
1.Vitamin K absence or antagonism occurs with intoxication by certain rodenticides, cholestatic liver diseases (decreased absorption of vitamin K from the intestine) or reduced liver function. (Back to Text).
2.For assessing bleeding tendency due to platelet or vWF disorders, the Simplate Device ("Buccal Mucosal Bleeding Time) is available from Animal Blood Bank, Vacaville, CA. (E-mail: Redcell@aol.com). A similar device is availble from Baxter (1-800-234-5227).
3.The ACT test for the intrinsic and common coagulation pathways is simple, can also be done in-house. Results can be highly variable, however, especially in regard to temperature: if incubation is imprecise or approximated (e.g. the "ol' armpit" technique), then control "normal" animal blood should be run concurrently. This test will not be useful for monitoring early exposure to vitamin K antagonists or therapy for it since it does not detect PIVKA and turnover time of measured vitamin-K dependent factors is relatively long. For example, Factor II has a half-life of 2-3 days; factor VII, in contrast, has a half-life of only 4-6 hours.
4.A rather cryptic, semi-scribbled image of the author's version of the coagulation cascade, pointing out the factors germaine to this discussion is available to view.
The author wishes to express a heartfelt appreciation to Drs. David Lewis and Paul Pion in particular and in general, to the consultants and members of VIN who provided invaluable information for the present rather concise overview.
A word of CAUTION: While adding erythropoietin to the treatment regimen of anemic cats in chronic renal failure (CRF) is widely accepted in veterinary medicine, it is extremely important to realize that most of these cats are hypertensive. If hypertension is not adequately controlled prior to treatment with erythropoietin, there is potential for grave consequences! This is because erythropoietin is, itself, hypertensive (though the mechanism is not truly appreciated). Its use is likely to exacerbate uncontrolled hypertension which can be fatal!! .It is strongly recommended that treatment and careful monitoring of systemic blood pressure be introduced early..- certainly before as well as during use of erythropoietin in these animals.
As more information becomes available on this matter I will relay it to you as quickly as I am able...
A recent publication (Infect Med 15: 105-106, 1998) describes a human infested with canine heartworm...a rare but known zoonosis in canine heartworm-endemic regions. Infection is via a bite by an infected mosquito. In humans, there is migration of worms via subcutaneous tissue, muscle sheaths and hematogenous avenues to vessels associated with airways; in the victim described by the current publication, there was involvement of pulmonary parenchymal tissue, as dead and dying worms apparently incited development of a necrotizing pulmonary granuloma. Radiographically, these appear similar to primary neoplastic lesions; diagnosis requires surgical resection...there are no serological tests nor other means for diagnosing canine heartworm in humans at this time.
Symptoms include low-grade chest pain, fever, cough, malaise...any combination of these, or victims may appear assymptomatic. In the latter especially, the problem of distinguishing granulomatous lesions from neoplasia represents a diagnostic dilemna...and surgical resection is generally the only way to rule out the latter.
The following describes the abstract of the report that appeared in the Journal of Clinical Microbiology which demonstrated, proof positive, that FIP viral infection in a given cat is the result of mutation by a its resident feline enteric corona virus (FECV). Indeed, any cat that carries an FECV has the the potential to develop FIP by mutation. Moreover, the data suggest that the mutation rate (FECV-->FIP) is high, since, in the presence of immunosuppresion (i.e. simultaneous FIV infection) and concurrent FECV infection in an otherwise pathogen-free cat population, an alarming number of cats become FIP infected! This begs the question: Is mutation the primary mode of acquiring FIP infection in the cat? Before jumping to any conclusion, consider also that in catteries where corfirmed FIP has been identified, the incidence of FIP is sporadic at worst, suggesting that horizontal transmission is probably NOT an important mode of FIP acquisition/infection. Here is the abstract and reference for you to contemplate, as well as some final comments and thoughts:
J Clin Microbiol 1996 Dec;34(12):3180-4 Poland AM ; Vennema H ; Foley JE ; Pedersen NC Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis 95616, USA.
Two groups of cats were experimentally infected orally with the cat-passaged RM strain of feline enteric coronavirus (FECV-RM). One group of cats (n = 19) had been chronically infected with feline immunodeficiency virus (FIV) for over 6 years, while a second control group (n = 20) consisted of FIV-naive siblings. Fecal virus shedding of FECV occurred in both groups starting on day 3 postinfection, nearly ceased by 4 weeks in FIV-uninfected cats, but remained at high levels in FIV-infected animals. FIV-infected cats shed virus for a longer period of time and at levels 10 to 100 times greater than those for FIV-uninfected cats. The coronavirus antibody response of the FIV-infected cats was delayed and of reduced titer compared with that of the FIV-uninfected animals. Cats in both groups remained asymptomatic for the first two months following FECV-RM infection; however, 8 to 10 weeks postinfection two cats in the FIV-infected group developed feline infectious peritonitis (FIP). The FIP viruses (designated FIPV-UCD9 and -UCD10) isolated from these two cats had almost complete genetic homology to each other and to the infecting FECV-RM. However, unlike FECV-RM, they readily induced FIP when inoculated intraperitoneally into specific-pathogen-free cats. This study confirms that FIPVs are frequently and rapidly arising mutants of FECV. Immunosuppression caused by chronic FIV infection may have enhanced the creation and selection of FIPV mutants by increasing the rate of FECV replication in the bowel and inhibiting the hosts ability to combat the mutant viruses once they occurred. (Author Abstract)
Finally, in a recent discussion of this subject on the Veterinary Information Network (VIN) Dr. Alice Wolf, a boarded and well respected veterinary internal medicine specialist made the following comment:
"It is pretty clear that most cats that develop FIP do so because of a
mutation of a coronavirus they are already carrying, not because they got
exposed to some nasty "FIP virus" from another cat. Generally, in pet cat
households, if one member of the group develops FIP, the others are fine.
There is no greater risk to the new cat from the existing household member
than to the existing household member from the new cat. A new cat may be
carrying a coronavirus too."
Finally, I want to thank Dr. Wolf for her intelligent analysis, interpretation and explanantion of these findings..
Pheochromocytoma...an Often Overlooked Syndrome in Dogs and Cats
Pheochromocytoma is a neoplasia associated with medullary chromaffin cells of the adrenal gland. It is quite difficult to diagnose under ideal conditions but nearly impossible to find without a strong index of suspicion. And..veterinarians (this author caught on more than one occasion) can be distracted by clinical and laboratory findings that indicate either another adrenal disease (Cushings?) or a non-adrenal disease. Clinical signs may reflect signs of 1) paroxysmal or sustained excess of serum catecholamines or, in the case of a non-functional masses, 2) signs indicating a space- occupying lesion (that may, for example, invade the caudal vena cava). All too frequently, clinical signs wax and wane....and may be missed! This is a life-threatenting condition, so early recognition is essential!!!
Suspect a pheochromocytoma if:
- Clinical signs of hyperadrenocorticism (many of which can mimic functional pheochromocytomas) do not resolve as expected after appropriate treatment.
- Results of endocrine tests conflict with ultrasound findings. (e.g., you think, "ah..this is a pituitary-dependent hyperadrenocorticism..." based on laboratory tests, but your ultrasound shows only a single, large adrenal gland).
- Systemic hypertension or cardiac arrythmias are present or they develop during anesthesia.
- Hindlimb edema, distension of the abdomen or distension of the caudal superifical cutaneous vessels is present.
A thorough discussion, including specific clinical signs, the diagnosis (not easy) and treatment options for pheochromocytomas can be found in the Clinics of North America, 3/97, pp 359
Degenerative myelopathy has been misdiagnosed all too often, according to the research done at Washington State University and elsewhere. Comparison of numerous myelograms and MRIs has clearly revealed that most of the animals previously diagnosed with degenerative myelopathy, based upon the absence of clear compressive lesions from myelograms, actually had significant disk disease as revealed by MRI. This information was presented at the ACVIM meeting in Chicago June, 1999..
Hyperthyroidism Diagnosis.....an update
Ove the past year or two, a popular laboratory method to aid in or confirm the diagnosis of feline hyperthroidism is the free T4 by equilibrium dialysis. This has an inherent advantage over the standard total T4 (TT4 ) in that the results of the free T4 test were not thought to be influenced by concurrent non-thyroidal illness(es) . However, the most recent findings, presented at the 1999 ACVIM meeting, indicate that this suppositon is NOT true. An elevated free T4 is sometimes seen in the presence of non-thyroidal illness, such as renal disease. Based on studies utilizing thyroid scintillation radiography and comparing results with standard laboratory testing methods, one or more of the following laboratory criterion must be present to pronounce a cat as hyperthyroid:
If the free T4 is elevated BUT the TT4 is in the lower 1/2 of the normal range then the animal is very likely NOT hyperthyroid!
MucomystR (Acetylcysteine) is NOT Appropriate for Corneal Ulcer Treatment
There has been a tradition, over the years, to include acetylcysteine in the "cocktail" formulated for the treatment of corneal ulcers. The origin of this protocol is vague but the important thing to remember is that at least in human studies done perhaps thirty years ago, there was no evidence suggesting that this substance had any merit in the treatment of this problem; indeed, if too much is added to the cocktail, irritation of the cornea resulted. Recent correspondences with several boarded veterinary ophthalmologists by this author suggest that acetylcysteine probably is not beneficial and whether it should be customarily included in the "cocktail" is, at best, a decision made by each veterinarian, realizing, of course, the absence of data.supporting this treatment regimen..
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