Excerpt from "Anti-Inflammatory Drugs: How to Sort Out the Choices"
Mark G. Papich, DVM, DAVCP North Carolina State University Raliegh, NC
Central Veterinary Conference Aug. 23-26, 2003:
Renal toxicity
In the kidney, prostaglandins play an important role to modulate the
tone of blood vessels and regulating salt and water balance. Renal
injury caused by NSAIDs has been described in people, and horses, but
has not been well documented in small animals. Reported cases of
toxicity occurred when high doses were used or when there were other
complicating factors. Renal injury occurs as a result of inhibition of
renal prostaglandin synthesis (Brown, 1989). In animals that have
decreased renal perfusion caused by dehydration, anesthesia, shock, or
pre-existing renal disease, this leads to renal ischemia (Mathews,
1996).
Additional information is needed with regard to the safety of currently
available COX-2 inhibitors on the kidney. Some of the prostaglandins
that play an important role in salt and water regulation and
hemodynamics in the kidney are synthesized by COX-2 enzymes (Rossat et
all 1999). Constitutive COX-2 is found in various sections of the
kidney and administration of drugs that are selective for COX-2, do not
spare the kidney during adverse conditions. Administration of a
specific COX-2 inhibitor to salt-depleted people decreased renal blood
flow, glomerular filtration rate, and electrolyte excretion (Rossat et
al 1999). One of the concerns during the perioperative period is the
renal safety of NSAID in anesthetized animals. Studies published on
carprofen administration to anesthetized healthy dogs showed no adverse
effects on renal function (Ko et al 2000).
*******************************
Excerpt from "Clinical Problem Solving: Putting Clinical Pharmacology
to Work"
Mark G. Papich, DACVCP North Carolina State University Raleigh, NC
Central Veterinary Conference August 23-26 2003
Adult vs Senior/Geriatic Patients
Pets seem to be living longer, and veterinarians are treating more
age-related problems in pets. Veterinary clinics have developed
specific programs in their hospitals for "Senior Pets". There are diets
designed specifically for senior dogs and cats, and even a medication
for the aged dog with cognitive dysfunction (selegiline, Anipryl).
Unfortunately, there is practically nothing available to guide
veterinarians on drug administration to older animals compared to
younger adults. Recommendations published in clinical reviews are based
on extrapolations from studies in people, or the assumption that drug
disposition probably is different in aged animals. Since organ function
declines with age, we presume that drug clearance is affected.
As one ages, there are age-dependent changes in drug distribution that
are a result in a decrease in body water and an increase in the
percentage of body fat. There may be an increase in the volume of
distribution for lipid-soluble drugs and a decrease in distribution for
water-soluble drugs. Unfortunately, there is no available published
information to confirm that these changes in body composttion occur for
veterinary species. >snip<
Disease-Related Differences
Changes in renal function
Age-dependent changes in renal clearance may affect drug clearance
because both glomerular filtration and tubular secretion of drugs
decrease with age (Rowe et al, 1976). >snip<
Changes in Hepatic Function
Like other functions, there are also age-dependent changes in hepatic
clearance. Liver size decreases with age as well as liver blood flow
and microsomal enzyme activity. >snip<
****************************
According to "Minimizing the Risk Factors Associated With the Veterinary
NSAIDs":
One of the most common factors predisposing patients to injury is
surgical anesthesia. Following surgical procedures is one of the four
most common instances that GI injuries occur in dogs.
http://avma.org/onlnews/javma/apr04/040415g.asp
*******************************
GENERAL CONSUMER DRUG CONCERNS
*******************************
Drugs Of Choice: Just Because They're Advertised On TV Doesn't Mean New
Prescription Medications Are Safe
May 17, 2002
LOS ANGELES (The Los Angeles Daily News) -- One person's miracle drug is
another person's poison pill.
For Encino resident Elaine Sherman, Lotronex worked. But the medication,
recalled in 2000 after only 10 months on the market, was fatal to some.
Lotronex, which treats irritable bowel syndrome, was pulled when side
effects forced some patients to have portions of their colons removed.
At least five died.
That didn't deter Sherman from seeking the drug, the only one that had
worked for her in 20 years of visiting gastroenterologists, homeopaths
and nutritionists.
"I tried other countries, and nobody had it but us," Sherman said. "I
called pharmacies in Canada. I had friends check the Internet."
Sherman wasn't alone in her quest. The FDA was swamped with calls from
Lotronex users lobbying for limited access to the drug.
The story of Lotronex captures the complexities that surround the issue
of drug safety, a web formed by the FDA, pharmaceutical companies,
doctors and patients. All have a part to play. The FDA must thoroughly
test a pharmaceutical company's drug, doctors must heed warnings before
prescribing a medication and patients must adequately weigh pros and
cons.
Follow each step, experts say, and it's still a gamble. There's no such
thing as the perfect pill. Reactions to drugs are individual and vary
with gender, race and age.
THE ME-TOO PHENOMENON
A recent study published in the May 1 issue of the Journal of the
American Medical Association shows that the risks posed by new drugs
entering the market may be substantial. The study, led by Dr. Karen
Lasser of Cambridge Hospital and Harvard Medical School, found that one
in five new drugs produced significant side effects that were not
discovered until after FDA approval.
Of 548 drugs approved between 1975 and 1999, 56 -- roughly 10 percent --
later received warnings of serious side effects or were recalled. The
figure rose to 20 percent for drugs approved toward the end of the time
period studied. The study recommended doctors avoid prescribing new
drugs in favor of older established drugs, unless the new drug
represented a breakthrough.
A rebuttal piece by Drs. Robert Temple and Martin Himmel of the FDA
argued the study overstated the dangers. Drug trials involving a few
thousand patients might not reveal all adverse effects -- some of them
rare -- that appear when a drug enters the general population, they
wrote. They also saw no need for doctors to wait before prescribing a
newly approved drug. "It is worth observing that existing therapy does
not always prove to be completely safe and fully satisfactory and that
there is value in having alternatives," they wrote.
Local physicians say the study reinforced their belief in proceeding
with caution when considering new drugs. Patients suffering from a
terminal illness have little to lose. But many drugs introduced to the
market are "me-too drugs," one company's version of an existing product.
"If I had a life-threatening disease, I might take the risk," said Carlo
Michelotti, chief executive officer of the California Pharmacists
Association. "If it's a me-too drug, I wouldn't be anxious to jump on
the bandwagon until it had some history."
STAYING VIGILANT
Dr. Kenneth Murray, a family practitioner in North Hollywood, said he
waits six months to a year before prescribing new nonbreakthrough
medications to his patients. At Providence St. Joseph Medical Center in
Burbank, Murray also serves on a committee that determines which drugs
to stock at the hospital.
"Compared to 20 years ago, pharmaceuticals today are much more powerful
drugs," he said. "The potential to cause harm is enhanced. They really
have tremendous effects on the body."
Doctors say they have a responsibility to prescribe medications properly
and monitor the results. Both doctors and pharmacists also must consider
drug interactions. Even a drug as seemingly benign as aspirin or
ibuprofen can have an adverse effect if taken by the wrong person, said
Dr. Michael Hirt, an internist and director of the Center for
Integrative Medicine at Encino Tarzana Regional Medical Center.
With Lotronex, some doctors didn't pay attention to the patient profile,
said Hirt, who treats Sherman. Lotronex was approved for women with
chronic diarrhea caused by irritable bowel syndrome. But some doctors
prescribed the medication to IBS sufferers with constipation -- a factor
in some but not all of the problem cases, according to the FDA.
The FDA and Lotronex maker GlaxoSmithKline continue to discuss a plan
that would allow the medication to be prescribed in specific
circumstances, said FDA spokesman Jason Brodsky.
"There are two sides to every drug withdrawal," Brodsky said. "Lotronex
is a case in point where the benefits of a drug for some meant a
dramatic improvement in the quality of life. But for others, the product
had serious effects."
Dr. Greg Thompson runs the Los Angeles County-USC Drug Information
Center, which advises health professionals on drugs, including dosages
and side effects. He is critical of efforts to revive Lotronex even
under restricted conditions.
"This isn't cancer," Thompson said. "Irritable bowel syndrome isn't
worth losing your colon over."
Thompson said doctors and pharmacists need to be more vigilant in
reporting adverse reactions to the FDA's MedWatch. The JAMA study
estimated that less than 10 percent of adverse effects are reported to
MedWatch.
Thompson also would like to see a formal last phase added to drug trials
in which physicians are required to report adverse effects for at least
a year after approval.
"In theory, doctors are supposed to do that now," he said. "But it's a
passive participation. We need to be active."
AS SEEN ON TV
The impact of direct marketing by pharmaceutical companies is yet
another piece of the drug-safety puzzle. Doctors say patients often
demand the medications they see advertised, with little knowledge of the
risks.
The JAMA study noted that new drugs are heavily marketed to both doctors
and consumers, which means they may be in wide distribution before
adverse effects are known.
"I don't feel pharmaceutical companies should market to patients," said
Dr. David Wong, an internist who serves on the committee that oversees
pharmaceuticals at Kaiser Permanente in Panorama City. "Good marketing
is what sells these days."
In his North Hollywood practice, Murray has seen the effects of this
marketing. For years, he has known birth control pills can also reduce
acne and, like many doctors, has prescribed them for this off-label use.
The makers of one pill took the unusual and costly step of returning to
the FDA to get approval for this added use. After television commercials
aired for Ortho Tri-Cyclen, many of Murray's female patients asked to
switch to that brand.
"It's brilliant marketing," Murray said. "The company can accurately say
it's the only birth control pill so approved. The truth of the matter is
they all do that."
Doctors, too, if they have success with a particular medication, can be
swept up by hype. So what's a patient who wants to make smart decisions
about medications to do?
The main thing patients can control is how educated they are about the
medications they take, experts said. Patients should have detailed
discussions about benefits and risks with their doctors and pharmacists.
Another thing doctors and patients can do is increase the focus on
wellness. Preventive measures such as nutrition and exercise should be
the first line of defense, Wong said.
"People want the magic pill," he said. "The truth is, everything has a
side effect. There's no free gift."
Copyright 2002 The Los Angeles Daily News. All rights reserved.
nsaids Anti-Inflammatory Drugs: How to Sort Out the Choices
12 posts
• Page 1 of 1
nsaids Anti-Inflammatory Drugs: How to Sort Out the Choices
by malernee » Sat Sep 11, 2004 1:45 pm
- malernee
- Site Admin
- Posts: 462
- Joined: Wed Aug 13, 2003 5:56 pm
nsaids IS THERE A BASIS FOR SELECTION?
by guest » Sun Sep 12, 2004 1:25 pm
NON-STEROIDAL ANTI-INFLAMMATORIES AND CYCLO-OXGENASE : IS THERE A BASIS FOR SELECTION?
Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP, Texas A&M University, College Station, TX
Introduction: NSAID Mechanism of Action
Nonsteroidal antinflammatory drugs (NSAIDs) are generally defined as drugs which target inflammation but are non-steroidal in structure. As a class, nonsteroidal antiinflammatory drugs are defined by their mechanism of action, inhibition of cycloxygenase. Recent advancements in the understanding of the relationship between NSAID pharmacologic effects and differences in their primary target, cyclooxygenase, has offered promise in the reduction of adverse side effects to these drugs. The discussion surrounding this promise requires an appreciation of the normal and abnormal actions of the prostaglandin end products, the ultimate target of NSAIDs, the specific mechanism of action of the NSAIDs and a focus on the cyclooxigenase enzymes.
Cycloxygeanses catalyzes the metabolism of arachidonic acid, a fatty acid released from cell membranes by the action of phospholipase on cell membrane phospholipids. Stimuli such as chemical, mechanical or immune-mediated damage activate phospholipases and the subsequent release of the fatty acid. Conversion of arachidonic acid to prostaglandin endproducts occurs in two steps, at two different sites on the cyclooxygenase enzyme. Arachidonic acid is cyclized and oxidized to the endoperoxide PGG2 at the cyclooxygenase site of the enzyme; this product is then reduced to a second endoperoxide, PGH2 at the peroxidase site of the enzyme. Cycloxygenases are located in virtually all cells except mature red blood cells and PGs are thus ubiquitous throughout the body. Subsequent formation of prostaglandin end products from PGH2 depends on the presence of other enzymes. Prostaglandin end products include prostaglandin-like products thromboxane (TXA2), prostacycline (PGI2) and PGs of the E and F series. The role of PGs is complex but they often balance one another. Their pharmacologic effects are equally complex, and many of their actions result in relaxation (generally PGI and PGE) or contraction of smooth or vascular smooth muscle. Additionally, PGI2 inhibits and TXA2 stimulates platelet aggregation. PGs contribute to all five cardinal signs of inflammation by causing vasodilation and modulating the effects of other inflammatory mediators. Among the prostglandins, PGE 2 is particularly effective as an inflammagen.
PGs are formed in situ and are characterized by half-lives that are short (seconds); thus rersistance of their effects requires persistent formation. Their role in the body could be summarized by describing them as protective, providing for normal homeostatic mechanisms in most tissues. Thus, in all tissues, they are responsible for hemostasis; in the kidneys, for maintenance of renal blood flow in the presence of adverse conditions, in the gastrotintestinal tract, they minimize the adverse effects of hydrochyloric and bile acids, and they mediate all of the cardinal signs of inflammation. In the gastrointestinal tract, protective mechanisms are mediated by prostaglandin of the E series, and include inhibition of hydrochloric acid secretion, and increased bicarbonate and mucus secretion, epithelialization, and mucosal blood flow. Although PGs appear to have a limited role in renal homeostasis under basal conditions, their actions are critical in the presence of hypovolemia or hypotension. PGs of the E series (PGE 2) production in the glomeruli increases during these states. Antagonism of vasoconstrictive mediators such as norepinephrine, angiotensin II and vasopression results in vasodilation and redistribution of renal blood flow from the cortex to the medulla. Direct effects on the rental tubule stimulates sodium and water excretion and secretion of renin from the macula densa (Hart 1987, Rose 1994). The result of these effects is to maintain renal blood flow and urine formation. In contrast to gastrointestinal effeccts, renoprotective effects of PGs become important only during states of hypotension.
Nonsteroidal anti-inflammatory drugs act to block the first step of prostaglandin synthesis by binding to and inhibiting cyclooxygenase conversion of arachidonic acid to PGG2 (Robinson, 1989). This action is both dose and drug dependent. The precise site at which cyclo-oxygenase is inhibited is not known. The planar form which characterizes these drugs is thought to facilitate NSAID binding to cyclooxygenase (Boynton et al. 1988; Higgins, 1985); the NSAID may physically block substrate binding or change conformation such that binding can not occur. Several investigators have shown that some drugs (eg, phenylbutazone and flunixin meglumine) also reduce formation of prostaglandin E2 in inflammatory exudate at therapeutic doses (Lees et al. 1986). The major therapeutic and toxic effects of NSAIDs has been correlated extensively to their ability to inhibit prostaglandin synthesis (Robinson, 1989). Their potency as anti-inflammatory agents relates to their relative potency of inhibition of prostaglandin synthesis (Robinson, 1989) which in turn reflects their interaction with cycloxygenase.
In the early 1990's, cyclooxygenase was recognized to reflect a family of enzymes. At least two forms of cycloxygenase were recognized. An inducible form was discovered following the stimulation of mononuclear phagocytic cells (mouse macrophage and human monocytes) by bacterial lipopolysaacchardes (Masferrer 1990, Fu 1990). COX-2 was initially discovered because of the negative effects of glucocorticoids (eg, dexamethasone) on COX-2 transcription (Crofford 1997). The inducible isoform of the enzyme was named cyclooxygenase 2 to distinguish it from cyclooxygenase I, a constitutive form of the enzyme. The protein structure and enzymatic function of the two enzymes are very similar. Both are integral membrane proteins, but the active site of each sits within the membrane so that it is easily accessed by fatty acid substrates (eg, arachidonic acid). The active site of the enzyme is a channel; the channel appears to be more flexible for COX 2 compared to COX 1, suggesting a wider variety of substrates for this isoform (Crofford 1997). COX 1 is located in the endoplasmic reticulum, while COX 2 is localized to the endoplasmic reticulum and nuclear membrane. The enzymes may use different pools of substrate mobilized in response to different cellular stimuli (Crofford 1997).
The measurement of thromboxane B2 synthesis from platelets, which constitutively express COX 1, following blood coagulation is a specific test for COX‑1 activity. In response to endogenous thrombin formation (ie, clot formation) platelet COX‑1 is maximally stimulated to produce thromboxane A2, which is converted to thromboxane B2 (Cryer 1998). The measurement of prostaglandin E2 production from monocytes and macrophages in whole blood following stimulation with lipopolysaccharide is a specific test for COX‑2 activity. Twenty‑four hours after incubation of whole blood with lipopolysaccharide, 95% to 99% of COX activity is COX‑2 and prostaglandin E2 measured 24 hours after lipopolysaccharide stimulation is considered to almost exclusively reflect COX‑2 activity.
Does COX-1 versus COX-2 Selectivity Provide a Rationale Basis for NSAID Selection?
This question might be answered best by providing evidence of selectivity regarding mechanisms of action and toxicity.
Premise 1. Homeostatic PGs are derived primarily from COX-1. Support: Virtually all tissues express COX-1 under basal conditions (Crofford 1997). Subsequent studies revealed constitutive PGs mediated by COX 1 to be largely responsible for basal homeostatic mechanisms, although exceptions exist. Both isoforms of the enzyme are expressed constitutively in the central nervous system and, depending on the species, in selected areas of the kidney. In the gastrointestinal tract, PGE2 mediated by COX-1 is present in all areas of the gastrointestinal tract, and in selected areas, is expressed over 2 fold compared to COX-2 (Kargman 1996, Mizuno1997). In contrast, PGE mediated by COX-2 is induced in the presence of gastrointestinal ulceration or erosions. Indeed, COX-2 appears to be the isoform mediating repair of damaged tissues with expression being greatest within the first 10 days of damage.
COX-2 appears to be responsible for homeostatic mechanisms in selected organs. It is constitutively expressed in the brain and the kidneys. In the brain, expression occurs in selected areas of the spinal cord, where it may be a key mediator of transmission of pain. Expression also increases in response to selected neuronal activity and after seizure activity. Species differences occur in COX-2 expression in the kidney, which occurs in the renal vasculature of the glomeruli, and in the smooth muscle and endothelium of the interlobular vessels. In dogs, COX-2 is constitutively expressed thick ascending loop of Henle and in the macula densa. COX-2 expression is increased by hypovolemia and by angiotensin-converting enzyme inhibitors such as captopril. In the reproductive tract, functions of COX-2 mediated PGs vary, but studies support that absence of COX-2 activity correlates with infertility in females. Conclusion: Although COX-1 PGs largely are responsible for homeostatic actions. COX-2 PGs have important roles in selected tissues (eg, kidney) and an important role in healing. The perioperative use of COX-2 selective drugs should be done cautiously.
Premise 2. Inflammatory PGs are derived primarily from COX-2. In contrast to constitutive PGs, with some exceptions (eg, brain, kidney and reproductive tract) inducible PGs are largely limited to inflammatory responses and are expressed by endothelial and smooth muscle cells, chondrocytes, and inflammatory cells such as macrophages/monocytes, fibroblasts and synovial cells. In addition to bacterial lipopolysaccharide, COX 2 is expressed in response to cytokines (eg, selected interleukins, tumor necrosis factor) and growth factors (eg, platelet-derived, and epidermal). Selected anti-inflammatory mediators may decrease or suppress COX 2 expression (Smith 1998; Masferrer 1996). PGE2 responsible for inflammation is formed primarily by the actions of COX 2 (Seibert 1994). Studies have demonstrated that COX 2 expression increases in inflammatory joint diseases, particularly in synovial endothelial cells, whereas it is essentially non-detectable in normal, non-inflamed tissues. Additionally, studies with selective COX1 or COX 2 inhibitors support COX 2 as the primary enzyme producing inflammation-inducing PGs (Smith 1998). Although the preponderance of evidence supports the roll of COX-2 in mediating inflammation, some evidence exists that COX-2 also decreases the inflammatory response. Interestingly, COX 2 expression is upregulated in selected carcinomas. Increased phenotypic changes in COX 2 has been interpreted in rat intestinal epithelial cells as an increase in tumorigenic potential. Increased COX-2 expression may be a common mechanism by which cellular phenotype is changed allowing unregulated proliferation.
Although COX-2 derived PGs clearly play the dominant role in the generation of inflammation, COX-1 PGs have been found to be upregulated in a number of inflammatory models or syndromes, suggesting that inhibition of COX-1 may be necessary in some inflammatory conditions. Note that NSAIDs are characterized by anti-inflammatory actions other than those mediated by inhibition of PGs (eg, direct inhibition of neutrophil adhesion, uncoupling of oxidative phosphorylation, etc). Finally, although the focus of this discussion is the role of PGs in inflammation, many other mediators are responsible for an inflammatory response. Conclusion: Selective inhibition of COX-2 should only minimally (at most) decrease the efficacy of NSAIDs.
Premise 3. The mechanism of NSAID toxicity is related to inhibition of COX-1 mediated PGS. The NSAIDs are recognized as a class of drugs to be potentially toxic. Among the toxicities, gastrointestinal ulceration is the most common in humans and animals. Although the mechanism of NSAID-induced gastrointestinal toxicity is not clear, NSAIDs as a class inhibit epithelialization and angiogenesis, two actions mediated by COX-1 PGE2 in the gastrointestinal tract (Levi 1990, Hudson 1995). Dogs have been described as being “exquisitively sensitive” to the gastrointestinal effects of NSAIDs and indeed appear to be more sensitive than human beings.
A number of studies have attempted to document the clinical relevance of selective cyclooxygenase inhibition to the severity of NSAID induced gastrointestinal toxicity. Using a human whole blood assay, and a modified human whole blood assay, the effect of 40 NSAIDs on COX-1 and COX-2 concentrations was measured (Warner 1999). Additionally, the effects of specific COX-2 drugs (eg, celecoxib and rofecoxib) were studied. Based on this study, NSAIDs were classified into four groups, depending on the relative potencies (concentration necessary to inhibit 50% or 80% of the respective COX enzyme). Those groups that included NSAIDs relevant to veterinary medicine included: 1. Compounds that fully inhibited both COX 1 and COX 2 (ie, exhibited < 5 fold selectivity for COX 2) included (but were not limited to) in order of least preference for COX 2, fenoprofen, ampyrone, ibuprofen, naproxen, aspirin, indomethacin, ketoprofen, flurbiprofen and ketorolac. Others in this category (not ranked) include carprofen, diclofenac, mefenamic acid, naproxen, and sulindac sulphide. 2. Compounds that inhibited both COX 1 and COX 2 but with preferential activity (5 to 50 fold preference) for COX 2, included celexocib, etodolac, meloxicam and mimesulfide. However, the amount of drug necessary to inhibit 80% of the enzyme was often much greater than the amount necessary to inhibit 50% of the enzymes. Further, the amount of drug necessary to inhibit 80% of the enzyme often overlapped with concentrations that inhibited COX-1. Thus, these compounds have the potential, however, to fully inhibit COX-1 at concentrations that might be considered therapeutic. The third group included compounds (rofecoxib, and experimental drugs) that inhibited COX-2 with only weak activity against COX 1 (greater than 50 fold preference); one of these compounds (rofeoxcib) has recently been approved for use in human medicine as a COX 2 selective drug. The fourth group contained drugs that were weak inhibitors of both COX 1 and COX 2 and included 5-aminosalicylic acid, sodium salicylate, sulfasalazine, toamoxifen, ticlopidine and sulindac.
A subsequent study measured COX-1 and COX-2 activity in whole blood samples collected from human volunteers receiving selected NSIADs. Results revealed marked variability in the inhibitory potency and selectivity of NSAIDs for COX‑1 and COX‑2 activity . Selected NSAIDs (eg, flurbiprofen, ibuprofen, ketoprofen, naproxen, aspirin) were inhibitory to both COX‑1 and COX-2 with poor selectivity for COX-2; others were inhibitory to both COX-1 and COX-2, but with a 5 to 50 fold preference towards COX-2 (todolac, meloxicam, celexocib); or a greater than 50 fold preference for COX-2 (rofecoxib), and finally; some that had minimal effect on either COX-1 or COX-2 (5-aminoslicylic acid, paracemtamol, sulfasalazine). The inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX‑1 inhibitory potency in blood and with COX‑1 selectivity but not with COX‑2 inhibitory potency. However, even those NSAIDs that appeared to be COX‑2 selective had sufficient COX‑1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. Clearly, the risk of gastorintestinal toxicity exists even with relatively COX 2 selective drugs.
The importance of species differences in interpreting these studies is exemplified by a similar study implemented by Ricketts and co-workers (1998) using using canine platelets and endotoxin – stimulated macrophage-like cells. They also studied the effects of various NSAIDs, basing comparison on a COX1:COX2 ratios. The ratios were:; carprofen: 129 for the racemic mixture, 181 for the S isomer and >4.19 for the R isomer; nimesulide: 38; meclofenamic acid: 15.4; tolfenamic acid: 15.0. meloxicam: 2.90; phenylbutazone > 2.64; flunixin meglumine: 0.635; etodolac 0.517; aspirin: < 0.343; ketoprofen: 0.232. These numbers are more aligned with what appears to occur clinically, that is, carprofen and meloxicam as safer drugs compared to aspirin, ketoprofen and meleoxicam. However, this study also suggests that etodolac is less safe than phenylbutazone and even flunixin meglumine, a finding that contrasts with clinical use of these drugs. Despite this incongruency, these two studies, in two different species, offer guidance regarding the selection of NSAIDs to be used in veterinary medicine. Those that have a more favorable COX1:COX2 ratio do appear to be clinically safer in regards to minimizing the risk of NSAID-induced gastrointestinal ulceration. However, as pointed out by comparison of IC50 and IC80 concentrations, selectivity is often lost at higher concentrations, which are likely to occur at therapeutic doses. These two studies also point out the risks of using data that is collected using tissues from species other than the targeted species. Whereas the human data suggests that carprofen is non-selective in humans, the data in dogs notes just the opposite. Clearly these studies indicate that, although selectivity can be used as a basis for NSAID selection, information regarding COX-2 selectivity in one species can not be used as a basis for selectivity in another species.
Conclusion: Although COX-1 mediated actions appear to be responsible for most NSAID GI toxicity, selectivity is lost at higher doses and selectivity apparently can not be extrapolated among species. Tests of selectivity are useful only as screening devices. Finally, clincians need to be aware of other mechanisms of NSAID toxicity not related to PGs (eg, hepatotoxicity).
Evidence of Selective Safety of Currently Available Veterinary COX-1 Protective Drugs
Currently, three veterinary drugs considered to be COX-1 protective (preferred to COX-2 selective since none have been proven to be solely COX-2 selective) are available in the North America: carprofen (US, CA), etodolac (US) and meloxicam (CA). Two sources of data are available for consideration regarding the safety of these drugs. Pre-clinical data generated to support safety during the approval process is available on package inserts. Comparison of these data might offer some discrimination among the products regarding relative safety, although the data reflects overdosing (a situation that is not commonly clinically relevant). For carprofen, dogs received close to 6 times the recommended dose for a year with no evidence (gross or histologic) of GI damage; only mild gross GI damage was evident following two weeks of administration at 10 times the recommended dose. For Etodolac®, at 5.3 times the recommended dose, 6 of 8 animals died with lesions in the gastrointestinal tract from 3 weeks to 9 months after therapy. For meloxicam, at 4 times the dose, no lesions were evident at 4 weeks into therapy. A post-market clinical trial offers insight into safety at doses that more appropriately reflect those likely to be used. Reimer and co workers reported in JVIN (13:742, 1999) that carprofen and etodolac drugs, when compared to a placebo and buffered aspirin (each drug dosed at the recommended label dose; aspirin at 15.6 mg/kg), had a score (based on endoscopic lesions) of 5 compared to a score of 25 for the placebo and aspirin groups when dosed for 28 days. Clearly, this data supports the relative safety of carprofen and etodolac compared to buffered aspirin, suggesting that these are the preferred NSAID products.
Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP, Texas A&M University, College Station, TX
Introduction: NSAID Mechanism of Action
Nonsteroidal antinflammatory drugs (NSAIDs) are generally defined as drugs which target inflammation but are non-steroidal in structure. As a class, nonsteroidal antiinflammatory drugs are defined by their mechanism of action, inhibition of cycloxygenase. Recent advancements in the understanding of the relationship between NSAID pharmacologic effects and differences in their primary target, cyclooxygenase, has offered promise in the reduction of adverse side effects to these drugs. The discussion surrounding this promise requires an appreciation of the normal and abnormal actions of the prostaglandin end products, the ultimate target of NSAIDs, the specific mechanism of action of the NSAIDs and a focus on the cyclooxigenase enzymes.
Cycloxygeanses catalyzes the metabolism of arachidonic acid, a fatty acid released from cell membranes by the action of phospholipase on cell membrane phospholipids. Stimuli such as chemical, mechanical or immune-mediated damage activate phospholipases and the subsequent release of the fatty acid. Conversion of arachidonic acid to prostaglandin endproducts occurs in two steps, at two different sites on the cyclooxygenase enzyme. Arachidonic acid is cyclized and oxidized to the endoperoxide PGG2 at the cyclooxygenase site of the enzyme; this product is then reduced to a second endoperoxide, PGH2 at the peroxidase site of the enzyme. Cycloxygenases are located in virtually all cells except mature red blood cells and PGs are thus ubiquitous throughout the body. Subsequent formation of prostaglandin end products from PGH2 depends on the presence of other enzymes. Prostaglandin end products include prostaglandin-like products thromboxane (TXA2), prostacycline (PGI2) and PGs of the E and F series. The role of PGs is complex but they often balance one another. Their pharmacologic effects are equally complex, and many of their actions result in relaxation (generally PGI and PGE) or contraction of smooth or vascular smooth muscle. Additionally, PGI2 inhibits and TXA2 stimulates platelet aggregation. PGs contribute to all five cardinal signs of inflammation by causing vasodilation and modulating the effects of other inflammatory mediators. Among the prostglandins, PGE 2 is particularly effective as an inflammagen.
PGs are formed in situ and are characterized by half-lives that are short (seconds); thus rersistance of their effects requires persistent formation. Their role in the body could be summarized by describing them as protective, providing for normal homeostatic mechanisms in most tissues. Thus, in all tissues, they are responsible for hemostasis; in the kidneys, for maintenance of renal blood flow in the presence of adverse conditions, in the gastrotintestinal tract, they minimize the adverse effects of hydrochyloric and bile acids, and they mediate all of the cardinal signs of inflammation. In the gastrointestinal tract, protective mechanisms are mediated by prostaglandin of the E series, and include inhibition of hydrochloric acid secretion, and increased bicarbonate and mucus secretion, epithelialization, and mucosal blood flow. Although PGs appear to have a limited role in renal homeostasis under basal conditions, their actions are critical in the presence of hypovolemia or hypotension. PGs of the E series (PGE 2) production in the glomeruli increases during these states. Antagonism of vasoconstrictive mediators such as norepinephrine, angiotensin II and vasopression results in vasodilation and redistribution of renal blood flow from the cortex to the medulla. Direct effects on the rental tubule stimulates sodium and water excretion and secretion of renin from the macula densa (Hart 1987, Rose 1994). The result of these effects is to maintain renal blood flow and urine formation. In contrast to gastrointestinal effeccts, renoprotective effects of PGs become important only during states of hypotension.
Nonsteroidal anti-inflammatory drugs act to block the first step of prostaglandin synthesis by binding to and inhibiting cyclooxygenase conversion of arachidonic acid to PGG2 (Robinson, 1989). This action is both dose and drug dependent. The precise site at which cyclo-oxygenase is inhibited is not known. The planar form which characterizes these drugs is thought to facilitate NSAID binding to cyclooxygenase (Boynton et al. 1988; Higgins, 1985); the NSAID may physically block substrate binding or change conformation such that binding can not occur. Several investigators have shown that some drugs (eg, phenylbutazone and flunixin meglumine) also reduce formation of prostaglandin E2 in inflammatory exudate at therapeutic doses (Lees et al. 1986). The major therapeutic and toxic effects of NSAIDs has been correlated extensively to their ability to inhibit prostaglandin synthesis (Robinson, 1989). Their potency as anti-inflammatory agents relates to their relative potency of inhibition of prostaglandin synthesis (Robinson, 1989) which in turn reflects their interaction with cycloxygenase.
In the early 1990's, cyclooxygenase was recognized to reflect a family of enzymes. At least two forms of cycloxygenase were recognized. An inducible form was discovered following the stimulation of mononuclear phagocytic cells (mouse macrophage and human monocytes) by bacterial lipopolysaacchardes (Masferrer 1990, Fu 1990). COX-2 was initially discovered because of the negative effects of glucocorticoids (eg, dexamethasone) on COX-2 transcription (Crofford 1997). The inducible isoform of the enzyme was named cyclooxygenase 2 to distinguish it from cyclooxygenase I, a constitutive form of the enzyme. The protein structure and enzymatic function of the two enzymes are very similar. Both are integral membrane proteins, but the active site of each sits within the membrane so that it is easily accessed by fatty acid substrates (eg, arachidonic acid). The active site of the enzyme is a channel; the channel appears to be more flexible for COX 2 compared to COX 1, suggesting a wider variety of substrates for this isoform (Crofford 1997). COX 1 is located in the endoplasmic reticulum, while COX 2 is localized to the endoplasmic reticulum and nuclear membrane. The enzymes may use different pools of substrate mobilized in response to different cellular stimuli (Crofford 1997).
The measurement of thromboxane B2 synthesis from platelets, which constitutively express COX 1, following blood coagulation is a specific test for COX‑1 activity. In response to endogenous thrombin formation (ie, clot formation) platelet COX‑1 is maximally stimulated to produce thromboxane A2, which is converted to thromboxane B2 (Cryer 1998). The measurement of prostaglandin E2 production from monocytes and macrophages in whole blood following stimulation with lipopolysaccharide is a specific test for COX‑2 activity. Twenty‑four hours after incubation of whole blood with lipopolysaccharide, 95% to 99% of COX activity is COX‑2 and prostaglandin E2 measured 24 hours after lipopolysaccharide stimulation is considered to almost exclusively reflect COX‑2 activity.
Does COX-1 versus COX-2 Selectivity Provide a Rationale Basis for NSAID Selection?
This question might be answered best by providing evidence of selectivity regarding mechanisms of action and toxicity.
Premise 1. Homeostatic PGs are derived primarily from COX-1. Support: Virtually all tissues express COX-1 under basal conditions (Crofford 1997). Subsequent studies revealed constitutive PGs mediated by COX 1 to be largely responsible for basal homeostatic mechanisms, although exceptions exist. Both isoforms of the enzyme are expressed constitutively in the central nervous system and, depending on the species, in selected areas of the kidney. In the gastrointestinal tract, PGE2 mediated by COX-1 is present in all areas of the gastrointestinal tract, and in selected areas, is expressed over 2 fold compared to COX-2 (Kargman 1996, Mizuno1997). In contrast, PGE mediated by COX-2 is induced in the presence of gastrointestinal ulceration or erosions. Indeed, COX-2 appears to be the isoform mediating repair of damaged tissues with expression being greatest within the first 10 days of damage.
COX-2 appears to be responsible for homeostatic mechanisms in selected organs. It is constitutively expressed in the brain and the kidneys. In the brain, expression occurs in selected areas of the spinal cord, where it may be a key mediator of transmission of pain. Expression also increases in response to selected neuronal activity and after seizure activity. Species differences occur in COX-2 expression in the kidney, which occurs in the renal vasculature of the glomeruli, and in the smooth muscle and endothelium of the interlobular vessels. In dogs, COX-2 is constitutively expressed thick ascending loop of Henle and in the macula densa. COX-2 expression is increased by hypovolemia and by angiotensin-converting enzyme inhibitors such as captopril. In the reproductive tract, functions of COX-2 mediated PGs vary, but studies support that absence of COX-2 activity correlates with infertility in females. Conclusion: Although COX-1 PGs largely are responsible for homeostatic actions. COX-2 PGs have important roles in selected tissues (eg, kidney) and an important role in healing. The perioperative use of COX-2 selective drugs should be done cautiously.
Premise 2. Inflammatory PGs are derived primarily from COX-2. In contrast to constitutive PGs, with some exceptions (eg, brain, kidney and reproductive tract) inducible PGs are largely limited to inflammatory responses and are expressed by endothelial and smooth muscle cells, chondrocytes, and inflammatory cells such as macrophages/monocytes, fibroblasts and synovial cells. In addition to bacterial lipopolysaccharide, COX 2 is expressed in response to cytokines (eg, selected interleukins, tumor necrosis factor) and growth factors (eg, platelet-derived, and epidermal). Selected anti-inflammatory mediators may decrease or suppress COX 2 expression (Smith 1998; Masferrer 1996). PGE2 responsible for inflammation is formed primarily by the actions of COX 2 (Seibert 1994). Studies have demonstrated that COX 2 expression increases in inflammatory joint diseases, particularly in synovial endothelial cells, whereas it is essentially non-detectable in normal, non-inflamed tissues. Additionally, studies with selective COX1 or COX 2 inhibitors support COX 2 as the primary enzyme producing inflammation-inducing PGs (Smith 1998). Although the preponderance of evidence supports the roll of COX-2 in mediating inflammation, some evidence exists that COX-2 also decreases the inflammatory response. Interestingly, COX 2 expression is upregulated in selected carcinomas. Increased phenotypic changes in COX 2 has been interpreted in rat intestinal epithelial cells as an increase in tumorigenic potential. Increased COX-2 expression may be a common mechanism by which cellular phenotype is changed allowing unregulated proliferation.
Although COX-2 derived PGs clearly play the dominant role in the generation of inflammation, COX-1 PGs have been found to be upregulated in a number of inflammatory models or syndromes, suggesting that inhibition of COX-1 may be necessary in some inflammatory conditions. Note that NSAIDs are characterized by anti-inflammatory actions other than those mediated by inhibition of PGs (eg, direct inhibition of neutrophil adhesion, uncoupling of oxidative phosphorylation, etc). Finally, although the focus of this discussion is the role of PGs in inflammation, many other mediators are responsible for an inflammatory response. Conclusion: Selective inhibition of COX-2 should only minimally (at most) decrease the efficacy of NSAIDs.
Premise 3. The mechanism of NSAID toxicity is related to inhibition of COX-1 mediated PGS. The NSAIDs are recognized as a class of drugs to be potentially toxic. Among the toxicities, gastrointestinal ulceration is the most common in humans and animals. Although the mechanism of NSAID-induced gastrointestinal toxicity is not clear, NSAIDs as a class inhibit epithelialization and angiogenesis, two actions mediated by COX-1 PGE2 in the gastrointestinal tract (Levi 1990, Hudson 1995). Dogs have been described as being “exquisitively sensitive” to the gastrointestinal effects of NSAIDs and indeed appear to be more sensitive than human beings.
A number of studies have attempted to document the clinical relevance of selective cyclooxygenase inhibition to the severity of NSAID induced gastrointestinal toxicity. Using a human whole blood assay, and a modified human whole blood assay, the effect of 40 NSAIDs on COX-1 and COX-2 concentrations was measured (Warner 1999). Additionally, the effects of specific COX-2 drugs (eg, celecoxib and rofecoxib) were studied. Based on this study, NSAIDs were classified into four groups, depending on the relative potencies (concentration necessary to inhibit 50% or 80% of the respective COX enzyme). Those groups that included NSAIDs relevant to veterinary medicine included: 1. Compounds that fully inhibited both COX 1 and COX 2 (ie, exhibited < 5 fold selectivity for COX 2) included (but were not limited to) in order of least preference for COX 2, fenoprofen, ampyrone, ibuprofen, naproxen, aspirin, indomethacin, ketoprofen, flurbiprofen and ketorolac. Others in this category (not ranked) include carprofen, diclofenac, mefenamic acid, naproxen, and sulindac sulphide. 2. Compounds that inhibited both COX 1 and COX 2 but with preferential activity (5 to 50 fold preference) for COX 2, included celexocib, etodolac, meloxicam and mimesulfide. However, the amount of drug necessary to inhibit 80% of the enzyme was often much greater than the amount necessary to inhibit 50% of the enzymes. Further, the amount of drug necessary to inhibit 80% of the enzyme often overlapped with concentrations that inhibited COX-1. Thus, these compounds have the potential, however, to fully inhibit COX-1 at concentrations that might be considered therapeutic. The third group included compounds (rofecoxib, and experimental drugs) that inhibited COX-2 with only weak activity against COX 1 (greater than 50 fold preference); one of these compounds (rofeoxcib) has recently been approved for use in human medicine as a COX 2 selective drug. The fourth group contained drugs that were weak inhibitors of both COX 1 and COX 2 and included 5-aminosalicylic acid, sodium salicylate, sulfasalazine, toamoxifen, ticlopidine and sulindac.
A subsequent study measured COX-1 and COX-2 activity in whole blood samples collected from human volunteers receiving selected NSIADs. Results revealed marked variability in the inhibitory potency and selectivity of NSAIDs for COX‑1 and COX‑2 activity . Selected NSAIDs (eg, flurbiprofen, ibuprofen, ketoprofen, naproxen, aspirin) were inhibitory to both COX‑1 and COX-2 with poor selectivity for COX-2; others were inhibitory to both COX-1 and COX-2, but with a 5 to 50 fold preference towards COX-2 (todolac, meloxicam, celexocib); or a greater than 50 fold preference for COX-2 (rofecoxib), and finally; some that had minimal effect on either COX-1 or COX-2 (5-aminoslicylic acid, paracemtamol, sulfasalazine). The inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX‑1 inhibitory potency in blood and with COX‑1 selectivity but not with COX‑2 inhibitory potency. However, even those NSAIDs that appeared to be COX‑2 selective had sufficient COX‑1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. Clearly, the risk of gastorintestinal toxicity exists even with relatively COX 2 selective drugs.
The importance of species differences in interpreting these studies is exemplified by a similar study implemented by Ricketts and co-workers (1998) using using canine platelets and endotoxin – stimulated macrophage-like cells. They also studied the effects of various NSAIDs, basing comparison on a COX1:COX2 ratios. The ratios were:; carprofen: 129 for the racemic mixture, 181 for the S isomer and >4.19 for the R isomer; nimesulide: 38; meclofenamic acid: 15.4; tolfenamic acid: 15.0. meloxicam: 2.90; phenylbutazone > 2.64; flunixin meglumine: 0.635; etodolac 0.517; aspirin: < 0.343; ketoprofen: 0.232. These numbers are more aligned with what appears to occur clinically, that is, carprofen and meloxicam as safer drugs compared to aspirin, ketoprofen and meleoxicam. However, this study also suggests that etodolac is less safe than phenylbutazone and even flunixin meglumine, a finding that contrasts with clinical use of these drugs. Despite this incongruency, these two studies, in two different species, offer guidance regarding the selection of NSAIDs to be used in veterinary medicine. Those that have a more favorable COX1:COX2 ratio do appear to be clinically safer in regards to minimizing the risk of NSAID-induced gastrointestinal ulceration. However, as pointed out by comparison of IC50 and IC80 concentrations, selectivity is often lost at higher concentrations, which are likely to occur at therapeutic doses. These two studies also point out the risks of using data that is collected using tissues from species other than the targeted species. Whereas the human data suggests that carprofen is non-selective in humans, the data in dogs notes just the opposite. Clearly these studies indicate that, although selectivity can be used as a basis for NSAID selection, information regarding COX-2 selectivity in one species can not be used as a basis for selectivity in another species.
Conclusion: Although COX-1 mediated actions appear to be responsible for most NSAID GI toxicity, selectivity is lost at higher doses and selectivity apparently can not be extrapolated among species. Tests of selectivity are useful only as screening devices. Finally, clincians need to be aware of other mechanisms of NSAID toxicity not related to PGs (eg, hepatotoxicity).
Evidence of Selective Safety of Currently Available Veterinary COX-1 Protective Drugs
Currently, three veterinary drugs considered to be COX-1 protective (preferred to COX-2 selective since none have been proven to be solely COX-2 selective) are available in the North America: carprofen (US, CA), etodolac (US) and meloxicam (CA). Two sources of data are available for consideration regarding the safety of these drugs. Pre-clinical data generated to support safety during the approval process is available on package inserts. Comparison of these data might offer some discrimination among the products regarding relative safety, although the data reflects overdosing (a situation that is not commonly clinically relevant). For carprofen, dogs received close to 6 times the recommended dose for a year with no evidence (gross or histologic) of GI damage; only mild gross GI damage was evident following two weeks of administration at 10 times the recommended dose. For Etodolac®, at 5.3 times the recommended dose, 6 of 8 animals died with lesions in the gastrointestinal tract from 3 weeks to 9 months after therapy. For meloxicam, at 4 times the dose, no lesions were evident at 4 weeks into therapy. A post-market clinical trial offers insight into safety at doses that more appropriately reflect those likely to be used. Reimer and co workers reported in JVIN (13:742, 1999) that carprofen and etodolac drugs, when compared to a placebo and buffered aspirin (each drug dosed at the recommended label dose; aspirin at 15.6 mg/kg), had a score (based on endoscopic lesions) of 5 compared to a score of 25 for the placebo and aspirin groups when dosed for 28 days. Clearly, this data supports the relative safety of carprofen and etodolac compared to buffered aspirin, suggesting that these are the preferred NSAID products.
- guest
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Antech News jan 05
by guest » Thu Jan 06, 2005 3:07 pm
January • 2005 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Mechanism of
Action All nonsteroidal anti-inflammatory drugs (NSAIDs) act via a
similar mechanism, which is to inhibit synthesis of prostaglandins (PGs)
via inhibition of the cyclo-oxygenase (COX) enzyme.
Some of the inhibited PGs promote inflammation, while some perform
important body functions.
NSAIDs can either inhibit the inflammatory PGs (via COX-2) or the
important constitutive PGs (via COX-1) or both (non selective). Older
NSAIDs such as ibuprofen, phenylbutazone, naproxen, piroxicam, and
flunixin are nonselective and inhibit both COX-1 and COX-2. Newer NSAIDs
such as the COXIB (celecoxib), carprofen and meloxicam, are mildly COX-2
selective and relatively COX-1 sparing, although this is based on in
vitro studies and it may vary among species. The recently introduced
deracoxib and firocoxib are COX-2 selective drugs, and tepoxalin is a
COX and lipo-oxygenase (LOX) inhibitor.
Types of NSAIDs
COX-2 selective (COXIB) Deracoxib(Deramaxx®), firocoxib (Previcox®).
Mildly COX-2 selective Carprofen (Rimadyl®), meloxicam (Metacam®).
COX and LOX inhibitors Tepoxalin (Zubrin®); this product is not
selective for COX-2, but has some LOX inhibition.
Published Comparisons of NSAIDs No proven advantage has been
established in terms of efficacy or safety, of one over another, but
there are few good studies comparing the different drugs. In a
comparison study of firocoxib and etodolac, no difference in efficacy or
safety was found, whereas studies in the US comparing tepoxalin and
carprofen, and in Europe comparing tepoxalin and meloxicam found that
tepoxalin had a slight trend toward better efficacy and safety. Based on
endoscopic studies, carprofen has been shown to have an advantage over
aspirin in terms of GI toxicosis.
Toxicosis from NSAIDs
GI toxicosis
No proven advantage of COXIBs over mildly COX-2 selective drugs from
controlled studies conducted in dogs or cats.
Need to be wary of studies looking at gastric lesions, as more severe
lesions tend to be located in the proximal small intestine.
FDA has received some reports of GI ulceration associated with deracoxib
administration; mostly involving small intestinal ulcers.
Unsure of predisposing causes of the deracoxib cases but it may be that
pre-existing GI damage results in upregulation of COX-2, which plays a
role in healing of the GI tract.
Animals with low protein may be at increased risk for side effects due
to the highly protein-bound nature of NSAIDs (not an absolute
contraindication, but need to dose these animals carefully and monitor
them closely).
Hepatic toxicosis
Any of the NSAIDS can cause acute, idiosyncratic hepatotoxicosis.
Deracoxib is also a sulfonamide, so it should be used with caution in
breeds predisposed to sulfonamide hypersensitivity (Doberman pinscher,
Samoyed and other white-coated breeds, miniature schnauzer).
It is uncertain whether carprofen causes hepatic toxicosis more often
than other NSAIDs, but it has been associated with liver problems more
than other drugs according to the FDA's adverse event reporting data.
There is no evidence that prior hepatic disease predisposes to
NSAID-induced liver injury. Pre-existing liver enzyme elevation is not a
predictor of hepatic toxicosis from NSAIDs.
Although these drugs are all highly metabolized by the liver for most
drugs, pre-existing liver disease does not seem to affect metabolism
(due to liver function reserve).
Renal toxicosis
COX-1 and COX-2 both play important roles in renal function.
High doses of NSAIDs may cause renal damage (tubular ischemia and
degeneration), although this is seen rarely at therapeutic doses.
Animals with pre-existing renal damage and those with reduced renal
blood flow may be predisposed to renal toxicosis.
Effects on platelet function (COX-1 inhibition)
NSAIDs are capable of inhibiting platelet function and so are not
recommended for patients predisposed to or with pre-exiting hemostatic
disorders (e.g. von Willebrand disease, hemophilia, thrombopathia).
Any NSAID with appreciable COX-1 inhibitory function could affect
platelet function (e.g. ketoprofen), although no blinded clinical trials
have confirmed this concern.
Monitoring Dogs on NSAIDs Patients should have a
pre-administration clinical and routine laboratory evaluation. Two weeks
post-initiation of treatment, liver enzymes or bilirubin should be
checked. For long-term therapy, clinical and laboratory evaluation
should be at least yearly, perhaps every 6 months.
Use of NSAIDs in Cats No NSAIDs are registered for cats in the
US, but both meloxicam and ketoprofen are registered for cats in Canada
and Europe, and appear to be relatively safe in cats.
Dose that has been used by some veterinarians (off-label):
Meloxicam, available as injectable and flavored syrup (volume is small
so cats seem to tolerate taste), at 0.1 mg/kg q24h for 2-3 days
initially, then 0.025-0.05 mg/kg 2 -3x per week for longer term use.
Ketoprofen, available in injectable and oral forms, at 2 mg/kg
once; then 1 mg/kg daily.
Carprofen is approved in Europe for cats, but for short-term use
only.
Tramadol hydrochloride (Ultram®) Tramadol has mild analgesic
properties and multiple modes of action, with some opiate effects but it
is not a controlled substance. Pharmacologically, tramadol has an
α2-agonist effect, and antiserotonin and opiate receptor effects,
but the mechanism that contributes to analgesia is unknown. The drug is
inexpensive, and available as the generic product. There are no studies
reported to document its safety and efficacy , although there is a
pharmacokinetic study reported to define its absorption and disposition
in dogs. It tends not to cause vomiting as with opioids. It has been
administered with NSAIDs without any known problems.
Trials have not been done in dogs to establish doses. Based on
pharmacokinetic studies, a dose in dogs of 5mg/kg orally every 6 hrs
will produce plasma concentrations considered to be in the therapeutic
range. Doses have not been established for cats.
Drug Selection For acute pain, such as in perioperative use,
veterinarians have administered injectable NSAIDs with good results.
Drugs used in these instances include ketoprofen, flunixin meglumine,
carprofen, tolfenamic acid (Tolfedine®, available outside the U.S.),
and ketorolac tromethamine (Toradol®). These drugs have been used for
1-2 days to decrease fever and pain from surgery or trauma.
Pre-operative injections of carprofen to dogs were shown to be
beneficial to decrease post-operative pain in dogs after
ovariohysterectomy.
Oral NSAIDs also may be used for acute treatment of myositis,
arthritis, and post-operative pain, or they may be administered
chronically for osteoarthritis. FDA-registered drugs that are
administered in the US to dogs include: carprofen, etodolac, deracoxib,
meloxicam, and tepoxalin. Human drugs that are sometimes used off-label
include aspirin, piroxicam, ketoprofen, and naproxen. For cats, most
experience has been with meloxicam, ketoprofen, and "children's"
aspirin. Outside the US, carprofen, ketoprofen, tolfenamic acid, and
meloxicam are registered for treatment of osteoarthritis in dogs. In
North America and Europe, all these drugs have been administered with
dietary supplements such as glucosamine and chondroitin sulfate.
There are studies available for each drug showing dosage regimens,
and efficacy in comparison to placebo, for the treatment of pain
associated with osteoarthritis. When drugs are compared to one another,
it is difficult to demonstrate differences between these drugs for
reducing pain in animals. Some studies have attempted to show which of
the above drugs is safest. When carprofen, meloxicam, and ketoprofen
were compared in dogs by endoscopic evaluation, there were no
significant adverse effects produced, or differences among the drugs
with respect to gastroduodenal lesions. Aspirin, at least after acute
administration, has been shown to induce mucosal injury, gastritis, and
hemorrhage in dogs. After administration of carprofen, aspirin, and
etodolac at recommended doses to dogs for 28 days, there was
significantly less gastroduodenal lesions from carprofen and etodolac as
compared to aspirin. The effects of carprofen and etodolac were no
different from those of placebo.
Summary There are several choices for treating dogs with
osteoarthritis with NSAIDs. Like people, there may be greater
differences among individuals in their response than there are
differences among the drugs. Some veterinarians have selected aspirin as
an initial drug, because it is inexpensive and familiar to most pet
owners. But, other veterinarians prefer to select an FDA-approved drug
such as the etodolac, carprofen, deracoxib, meloxicam and tepoxalin for
treatment in dogs. Some veterinarians still rely on human drugs used in
an extra-label manner to treat patients refractory to approved animal
drugs. These drugs include piroxicam (Feldene®), naproxen (Aleve®),
and ketoprofen (Orudis®). These have not undergone safety and efficacy
trials in the US. Outside the US, in Canada and Europe, other popular
NSAIDs used in small animals include ketoprofen and tolfenamic acid.
They have a relatively good safety profile and clinical results have
been documented.
For treatment of pain with NSAIDs in cats, none are registered in
the US, and only ketoprofen and meloxicam are approved for use in other
countries and shown to be safe. In the US, ketoprofen is available as a
12.5mg tablet for people, available over-the-counter (Orudis-KT®).
Aspirin is sometimes used in cats, with a "children's aspirin"
administered (81 mg tablet) at a dose of 20 mg/kg every 48 hours.
References: Mathews. Can Vet J 37: 539-545, 1996; MacPhail et al. J
Am Vet Med Assoc 212: 1895-1901, 1998; Reimer et al. J Vet Intern Med
13: 472-477, 1999; Wolfe. New Engl J Med 340: 1888-1899, 1999; Papich.
Vet Clin N. Am (Sm An) 30: 815-837, 2000; Papich. West Vet Conf, 2002.
Submitted by Dr. Mark Papich, NC State Univ, College Vet Med, Raleigh,
NC. Please send comments to the webmaster.
©1997-2004 Antech Diagnostics, Inc.
Site design and maintenance by amesDesign.
Antech News - January 2005
Address:http://www.antechdiagnostics.com/clients/antechNews/2005/jan05_01.htm
Changed:1:43 AM on Tuesday, December 28, 2004
Action All nonsteroidal anti-inflammatory drugs (NSAIDs) act via a
similar mechanism, which is to inhibit synthesis of prostaglandins (PGs)
via inhibition of the cyclo-oxygenase (COX) enzyme.
Some of the inhibited PGs promote inflammation, while some perform
important body functions.
NSAIDs can either inhibit the inflammatory PGs (via COX-2) or the
important constitutive PGs (via COX-1) or both (non selective). Older
NSAIDs such as ibuprofen, phenylbutazone, naproxen, piroxicam, and
flunixin are nonselective and inhibit both COX-1 and COX-2. Newer NSAIDs
such as the COXIB (celecoxib), carprofen and meloxicam, are mildly COX-2
selective and relatively COX-1 sparing, although this is based on in
vitro studies and it may vary among species. The recently introduced
deracoxib and firocoxib are COX-2 selective drugs, and tepoxalin is a
COX and lipo-oxygenase (LOX) inhibitor.
Types of NSAIDs
COX-2 selective (COXIB) Deracoxib(Deramaxx®), firocoxib (Previcox®).
Mildly COX-2 selective Carprofen (Rimadyl®), meloxicam (Metacam®).
COX and LOX inhibitors Tepoxalin (Zubrin®); this product is not
selective for COX-2, but has some LOX inhibition.
Published Comparisons of NSAIDs No proven advantage has been
established in terms of efficacy or safety, of one over another, but
there are few good studies comparing the different drugs. In a
comparison study of firocoxib and etodolac, no difference in efficacy or
safety was found, whereas studies in the US comparing tepoxalin and
carprofen, and in Europe comparing tepoxalin and meloxicam found that
tepoxalin had a slight trend toward better efficacy and safety. Based on
endoscopic studies, carprofen has been shown to have an advantage over
aspirin in terms of GI toxicosis.
Toxicosis from NSAIDs
GI toxicosis
No proven advantage of COXIBs over mildly COX-2 selective drugs from
controlled studies conducted in dogs or cats.
Need to be wary of studies looking at gastric lesions, as more severe
lesions tend to be located in the proximal small intestine.
FDA has received some reports of GI ulceration associated with deracoxib
administration; mostly involving small intestinal ulcers.
Unsure of predisposing causes of the deracoxib cases but it may be that
pre-existing GI damage results in upregulation of COX-2, which plays a
role in healing of the GI tract.
Animals with low protein may be at increased risk for side effects due
to the highly protein-bound nature of NSAIDs (not an absolute
contraindication, but need to dose these animals carefully and monitor
them closely).
Hepatic toxicosis
Any of the NSAIDS can cause acute, idiosyncratic hepatotoxicosis.
Deracoxib is also a sulfonamide, so it should be used with caution in
breeds predisposed to sulfonamide hypersensitivity (Doberman pinscher,
Samoyed and other white-coated breeds, miniature schnauzer).
It is uncertain whether carprofen causes hepatic toxicosis more often
than other NSAIDs, but it has been associated with liver problems more
than other drugs according to the FDA's adverse event reporting data.
There is no evidence that prior hepatic disease predisposes to
NSAID-induced liver injury. Pre-existing liver enzyme elevation is not a
predictor of hepatic toxicosis from NSAIDs.
Although these drugs are all highly metabolized by the liver for most
drugs, pre-existing liver disease does not seem to affect metabolism
(due to liver function reserve).
Renal toxicosis
COX-1 and COX-2 both play important roles in renal function.
High doses of NSAIDs may cause renal damage (tubular ischemia and
degeneration), although this is seen rarely at therapeutic doses.
Animals with pre-existing renal damage and those with reduced renal
blood flow may be predisposed to renal toxicosis.
Effects on platelet function (COX-1 inhibition)
NSAIDs are capable of inhibiting platelet function and so are not
recommended for patients predisposed to or with pre-exiting hemostatic
disorders (e.g. von Willebrand disease, hemophilia, thrombopathia).
Any NSAID with appreciable COX-1 inhibitory function could affect
platelet function (e.g. ketoprofen), although no blinded clinical trials
have confirmed this concern.
Monitoring Dogs on NSAIDs Patients should have a
pre-administration clinical and routine laboratory evaluation. Two weeks
post-initiation of treatment, liver enzymes or bilirubin should be
checked. For long-term therapy, clinical and laboratory evaluation
should be at least yearly, perhaps every 6 months.
Use of NSAIDs in Cats No NSAIDs are registered for cats in the
US, but both meloxicam and ketoprofen are registered for cats in Canada
and Europe, and appear to be relatively safe in cats.
Dose that has been used by some veterinarians (off-label):
Meloxicam, available as injectable and flavored syrup (volume is small
so cats seem to tolerate taste), at 0.1 mg/kg q24h for 2-3 days
initially, then 0.025-0.05 mg/kg 2 -3x per week for longer term use.
Ketoprofen, available in injectable and oral forms, at 2 mg/kg
once; then 1 mg/kg daily.
Carprofen is approved in Europe for cats, but for short-term use
only.
Tramadol hydrochloride (Ultram®) Tramadol has mild analgesic
properties and multiple modes of action, with some opiate effects but it
is not a controlled substance. Pharmacologically, tramadol has an
α2-agonist effect, and antiserotonin and opiate receptor effects,
but the mechanism that contributes to analgesia is unknown. The drug is
inexpensive, and available as the generic product. There are no studies
reported to document its safety and efficacy , although there is a
pharmacokinetic study reported to define its absorption and disposition
in dogs. It tends not to cause vomiting as with opioids. It has been
administered with NSAIDs without any known problems.
Trials have not been done in dogs to establish doses. Based on
pharmacokinetic studies, a dose in dogs of 5mg/kg orally every 6 hrs
will produce plasma concentrations considered to be in the therapeutic
range. Doses have not been established for cats.
Drug Selection For acute pain, such as in perioperative use,
veterinarians have administered injectable NSAIDs with good results.
Drugs used in these instances include ketoprofen, flunixin meglumine,
carprofen, tolfenamic acid (Tolfedine®, available outside the U.S.),
and ketorolac tromethamine (Toradol®). These drugs have been used for
1-2 days to decrease fever and pain from surgery or trauma.
Pre-operative injections of carprofen to dogs were shown to be
beneficial to decrease post-operative pain in dogs after
ovariohysterectomy.
Oral NSAIDs also may be used for acute treatment of myositis,
arthritis, and post-operative pain, or they may be administered
chronically for osteoarthritis. FDA-registered drugs that are
administered in the US to dogs include: carprofen, etodolac, deracoxib,
meloxicam, and tepoxalin. Human drugs that are sometimes used off-label
include aspirin, piroxicam, ketoprofen, and naproxen. For cats, most
experience has been with meloxicam, ketoprofen, and "children's"
aspirin. Outside the US, carprofen, ketoprofen, tolfenamic acid, and
meloxicam are registered for treatment of osteoarthritis in dogs. In
North America and Europe, all these drugs have been administered with
dietary supplements such as glucosamine and chondroitin sulfate.
There are studies available for each drug showing dosage regimens,
and efficacy in comparison to placebo, for the treatment of pain
associated with osteoarthritis. When drugs are compared to one another,
it is difficult to demonstrate differences between these drugs for
reducing pain in animals. Some studies have attempted to show which of
the above drugs is safest. When carprofen, meloxicam, and ketoprofen
were compared in dogs by endoscopic evaluation, there were no
significant adverse effects produced, or differences among the drugs
with respect to gastroduodenal lesions. Aspirin, at least after acute
administration, has been shown to induce mucosal injury, gastritis, and
hemorrhage in dogs. After administration of carprofen, aspirin, and
etodolac at recommended doses to dogs for 28 days, there was
significantly less gastroduodenal lesions from carprofen and etodolac as
compared to aspirin. The effects of carprofen and etodolac were no
different from those of placebo.
Summary There are several choices for treating dogs with
osteoarthritis with NSAIDs. Like people, there may be greater
differences among individuals in their response than there are
differences among the drugs. Some veterinarians have selected aspirin as
an initial drug, because it is inexpensive and familiar to most pet
owners. But, other veterinarians prefer to select an FDA-approved drug
such as the etodolac, carprofen, deracoxib, meloxicam and tepoxalin for
treatment in dogs. Some veterinarians still rely on human drugs used in
an extra-label manner to treat patients refractory to approved animal
drugs. These drugs include piroxicam (Feldene®), naproxen (Aleve®),
and ketoprofen (Orudis®). These have not undergone safety and efficacy
trials in the US. Outside the US, in Canada and Europe, other popular
NSAIDs used in small animals include ketoprofen and tolfenamic acid.
They have a relatively good safety profile and clinical results have
been documented.
For treatment of pain with NSAIDs in cats, none are registered in
the US, and only ketoprofen and meloxicam are approved for use in other
countries and shown to be safe. In the US, ketoprofen is available as a
12.5mg tablet for people, available over-the-counter (Orudis-KT®).
Aspirin is sometimes used in cats, with a "children's aspirin"
administered (81 mg tablet) at a dose of 20 mg/kg every 48 hours.
References: Mathews. Can Vet J 37: 539-545, 1996; MacPhail et al. J
Am Vet Med Assoc 212: 1895-1901, 1998; Reimer et al. J Vet Intern Med
13: 472-477, 1999; Wolfe. New Engl J Med 340: 1888-1899, 1999; Papich.
Vet Clin N. Am (Sm An) 30: 815-837, 2000; Papich. West Vet Conf, 2002.
Submitted by Dr. Mark Papich, NC State Univ, College Vet Med, Raleigh,
NC. Please send comments to the webmaster.
©1997-2004 Antech Diagnostics, Inc.
Site design and maintenance by amesDesign.
Antech News - January 2005
Address:http://www.antechdiagnostics.com/clients/antechNews/2005/jan05_01.htm
Changed:1:43 AM on Tuesday, December 28, 2004
- guest
FDA website search on carprofen Rimadyl heart problems
by malernee » Thu Feb 10, 2005 6:12 pm
use the search feature in the FDA CVM ADE report - I have
done a search on Carprofen using the word "heart" and came up with some
interesting info. I was completely unaware that such a search could be performed.
Learn something new every day:)
Go to:
http://www.fda.gov/cvm/index/ade/ade_web_rpts_AC.pdf
Find Carprofen - Oral - Dogs - and while on that page "click" on the
binocular icon at the top of the page - this will bring up a "search" feature - type
in "heart".
done a search on Carprofen using the word "heart" and came up with some
interesting info. I was completely unaware that such a search could be performed.
Learn something new every day:)
Go to:
http://www.fda.gov/cvm/index/ade/ade_web_rpts_AC.pdf
Find Carprofen - Oral - Dogs - and while on that page "click" on the
binocular icon at the top of the page - this will bring up a "search" feature - type
in "heart".
- malernee
- Site Admin
- Posts: 462
- Joined: Wed Aug 13, 2003 5:56 pm
COX-2 SELECTIVE NSAID COMMENTS AND CARPROFEN (RIMADYL) HISTO
by guest » Fri Feb 11, 2005 12:38 pm
http://community-2.webtv.net/bjthurman/ ... TIVENSAID/
COX-2 SELECTIVE NSAID COMMENTS AND CARPROFEN (RIMADYL) HISTORY
The human cox-2 inhibitors are, at this time, under the microscope. It has become quite obvious that all is not known about the effects of cox-2 inhibition in humans. This inquiry into the safety of cox-2 specific NSAIDs should be extended to include the cox-2 specific veterinary NSAIDs. Much less is known about the effects of cox-2 inhibition in canines.
The veterinary cox-2 inhibitors include the mildly cox-2 selective carprofen (Rimadyl) and meloxicam (Metacam) as well as the cox-2 selective NSAIDs of the coxib class deracoxib (Deramaxx) and firocoxib (Previcox). (1) Firocoxib is the most cox-2 selective veterinary NSAID approved to date. (2)
All of the concerns about human drug approval, adverse drug events, and monitoring of the safety of cox-2 inhibitors exist and are magnified in veterinary medicine. This is primarily due to differences in pre and post-approval drug clinical trials, in the reporting of ADEs, in diagnostic procedures for pets and humans, in the treatment of illness available for pets and humans and the clients' ability to pay, and the value placed on human life as opposed to the value of the lives of animals. Also, the veterinarian serves a dual role as both physician and pharmacist.
There are considerable differences between pre-approval and post-approval clinical trials for canine NSAIDs and human NSAIDs. Pre-approval clinical trials for veterinary drugs are small, short and use only healthy subjects.
Almost eight years has passed since the first veterinary cox-2 inhibitor was brought to market. We now have at least 4 cox-2 inhibitors. Still, no good information exists as to dog breed differences in metabolism, effects on aged or unhealthy dogs, concomitant drug use, and consequences of long term use. Nevertheless, these drugs are commonly dispensed to dogs of all breeds, all ages, and in varying states of health, often for chronic, daily, long term use.
While it is sometimes the case that problems with human drugs are not identified until the drug is brought to market and used by extremely large numbers of people, this is always the case with veterinary drugs due to their very limited and small trials. According to veterinary clinical pharmacologist Dawn Boothe: "Prelicensing and other experimental studies focus on dose-dependent effects and target a relatively small test population. It is not until a drug is placed in widespread clinical use that we see the idiosyncratic and other more subtle toxicities that are potentially serious." (3)
One of the problems in identifying Vioxx as a possible contributor to heart attack and stroke in humans was that these events commonly occur in the general population. Many cox-2 inhibitor adverse reactions in dogs may be being passed off as common occurrences of old age. Only through huge long-running post-approval clinical trials was the possible connection between Vioxx and heart problems discovered. These types of trials are not conducted with veterinary drugs.
Intensive monitoring within hospitals and analysis of health registers post drug approval is uncommon in veterinary medicine. (24)
There are also differences in the reporting of adverse drug events (ADEs) between veterinary and human drugs. It has been estimated that only about 1/10 of dog adverse reactions to medication are reported as compared to reporting of human adverse reactions. Veterinary clinical pharmacologist Mark Papich states that "the true incidence of adverse drug effects in domestic animals is not known because most are not reported". (17)
In addition, major differences exist in diagnostic procedures for canines and humans. For example, while it is extremely common for physicians to diagnose heart attacks and strokes, it is uncommon for veterinarians to do so. Most veterinarians do not order MRIs or CT scans that are very common diagnostic tools for humans, and many veterinary clients could not pay for them anyway. According to FDA CVM: "Additional limitations in veterinary pharmacovigilance include the cost and availability of diagnostic tests and the lack of comprehensive postmortem information". (21)
Humans survive many cox-2 inhibitor related adverse reactions due to their ability to voice discomfort and to obtain medical treatment which is most often paid for by insurance benefits.
For example, a human can voice stomach discomfort to his physician while a dog obviously cannot, and according to veterinary clinical pharmacologist Dawn Boothe: "Unfortunately, there is no sensitive indicator of gastrointestinal bleeding in dogs and damage may be quite extensive before signs are evident." (16) Therefore even the most common NSAID side effect of gastrointestinal damage is likely to be quite serious in canines. Many dogs who experience gastrointestinal damage, kidney failure, or liver toxicity from cox-2 inhibitors are euthanized because their owners cannot travel, many times out of state, to an advanced veterinary medical care facility for necessary diagnostics, nor pay for extended intensive medical treatment. Additionally, many treatments available to humans are still investigational for pets.
Great value is placed upon human life while animals are still generally legally considered property. Therefore physicians are subject to much liability whenever drugs are used improperly while veterinarians are subject to virtually none.
Finally, while in human medicine there exists the pharmacist to provide drug information and answer specific consumer questions about product use, no such intermediary exists in veterinary medicine.
A brief summary of a few of the highlights of the history of the veterinary cox-2 inhibitor Rimadyl will serve to illustrate most of the above. In short term clinical trials for Rimadyl, the number of reports of adverse reactions were minimal. Most commonly reported were vomiting, lethargy, and appetite change. While an increase in serum activity of ALT was the most frequently reported clinicopathologic change, investigators did not relate any clinical signs to the elevations in ALT. It was reported that clinicopathologic abnormalities and mild adverse effects were the same for the carprofen group and the placebo control group. (4)(5) According to the FDA CVM, based on studies that were submitted for the drug approval process, "the risk of Rimadyl was thought to be negligible". (6).
Rimadyl hit the market in 1997 and was directly advertised to consumers through television commercials (featuring the recovery of old dogs from lameness) as well as full-page magazine ads, print stories, and radio reports. Consequently, it was widely used very quickly. By 1999 the CVM estimated that Rimadyl had been given to 2.5 million dogs. (6)
A brief chronology of select Rimadyl post-approval events 1997 to 2002:
May 1997 - CVM asked Pfizer to change the adverse drug reaction section of the label due to ADE reports received and asked Pfizer to send a "Dear Doctor" letter to veterinarians about Rimadyl's adverse effects. (6)
September 1997 - An extensive adverse reaction section was included in Rimadyl labeling. The existing possibility of a fatal outcome was included. (6)
1998 - 39% (no. 3626) of ALL ADE reports received by FDA CVM involved Rimadyl. About 13% involved death of the dog. (6)
April 28, 1999 - Dog owner Bob Sinclair spoke about Rimadyl and animal drug issues at the FDA Stakeholders meeting in Overland Park, Kansas.
(22) (23)
Spring 1999 - Death was added to the adverse reactions section of the Rimadyl label. (6)
June 24, 1999 - Concerned consumers met with Pfizer officials and were presented with an advance proof print of a new Rimadyl Consumer Information Page. (7)
October 1999 - Jean Townsend of Johns Island, South Carolina brought a class action lawsuit against Pfizer alleging that neither she nor her vet were adequately warned of the possible adverse consequences of Rimadyl use. (8)
December 1, 1999 - The FDA CVM issued a Rimadyl Update. CVM stated that dog owners who had reported ADEs directly to the agency said they were not aware of any potential Rimadyl adverse effects. CVM advised: "As a NSAID with potentially serious side effects, however, the use of Rimadyl should be carefully considered before being incorporated in any therapeutic plan. Moreover, dog owners should have an active role in making that decision." (6)
March 9, 2000 - Another "Dear Doctor" letter was sent by Pfizer to veterinarians. Among other things, this letter informed veterinarians of an Owner Information Sheet to be attached, along with the product insert, to each bottle of Rimadyl Caplets and Rimadyl Chewable Tablets. Veterinarians were also informed that new bottles of Rimadyl would be offered in 2 week, 1 month, and 3 month supplies so that vets would be able to dispense full bottles with the drug information attached. In addition Pfizer stated: "Pfizer, in conjunction with the FDA CVM, encourages veterinarians to provide owners with information about both risks and benefits associated with all potential therapeutic options." (9)
December 13, 2002 - Pfizer was asked by the Division of Surveillance FDA CVM to immediately stop dissemination of certain promotional materials judged to be misleading. (10)
Currently, the Rimadyl label includes the following adverse reactions based on voluntary post-approval drug reporting, listed in decreasing order of frequency by body system:
Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis.
Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, bilirubinuria, hypoalbuminemia.
Approximately one-fourth of hepatic reports were in Labrador Retrievers.
Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation.
Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities including acute tubular necrosis, renal tubular acidosis, glucosuria.
Behavioral: Sedation, lethargy, hyperactivity, restlessness, aggressiveness.
Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis.
Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis.
Immunologic or hypersensitivity: Facial swelling, hives, erythema.
In rare situations, death has been associated with some of the adverse reactions listed above. (11)
This is quite an extensive list for a drug whose risk was thought to be negligible based on pre-approval trials. As of January 3, 2005, the cumulative total of Rimadyl possible ADE reports as posted on the CVM website was 12,919. 2,349 involved death of the dog. (12)
Problems continue to surround the use of Rimadyl and the other veterinary cox-2 inhibitors. A two year review of the consumer messages to the FDA CVM hotline which appeared in JAVMA News on January 15, 2004 revealed the following:
"Frequent comments from pet owners who contact the CVM hotline include these:
* They did not receive a client information sheet when one was available for a drug that was prescribed for their pet.
* The medication they received from their veterinarian was not dispensed in the CVM-approved container but was broken into aliquots that were taken home without the client information sheet or approved label.
* The veterinarian did not conduct or recommend blood testing before and after prescribing the drug, even though baseline testing and/or periodic monitoring was recommended on the label. Common examples include heartworm products and nonsteroidal, anti-inflammatory drugs.
* After reading client information sheets and labels on the Internet about a drug prescribed for their pet, they discovered that their pet may have fallen into a category of animal for which a precaution or contraindication existed."
Article author Dr. Victoria Hampshire of the FDA CVM reminded practitioners that, "Drugs that come with client information sheets are intended to be dispensed in the manufacturer's container, with the sheets accompanying the prescription." (13)
The almost uniform failure of veterinarians to provide the Client Information Sheets for the veterinary cox-2 inhibitors led to the publishing of two additional articles by FDA CVM in 2004 bringing this to the attention of the veterinary community. In a FDA Veterinarian article "Adverse Drug Experience Reports Lead to Label Changes, Other Actions for Safer Animal Drugs", Dr. Thomas Moskal advised veterinarians to communicate risk information for NSAIDs to clients and to be sure that the dog owner receives the Client Information Sheet. (14) In the article "Minimizing the risk factors of the veterinary NSAIDs" which appeared in JAVMA News April 15, 2004 Dr. Moskal stated: "Drug risk information is communicated to veterinary practitioners and to the public through the product labeling...Drugs that come with Client Information Sheets are intended to be dispensed to clients with the Client Information Sheet accompanying the prescription." (15)
Companion animals cannot verbally notify owners when they are experiencing an adverse reaction to a cox-2 inhibitor. The pet owner who sees the dog every day must detect any problems, but can only do so if he or she knows what to watch for.
Veterinarians have failed in their role as physician by failing to obtain informed consent when prescribing NSAIDs, and they have failed in their role as pharmacists by not providing adequate consumer drug information. Dogs have become family members in most households, and are cared for as such. Dog owners should not be left reeling in shock and burdened by extreme guilt when their beloved canine companion suffers or dies from the use of a cox-2 inhibitor, because THEY HAD NO IDEA.
The FDA should not only request, but must enforce, that the FDA recommended and approved Client Information Sheets currently existing for the veterinary NSAIDs be given to pet owners. Pet owners are currently seeking legislation state by state mandating full disclosure of the risks of veterinary drugs such as the cox-2 inhibitors. They should not have to do so. The existing Medication Guide Rule which enforces the providing of FDA prepared Medication Guides for certain human drugs should be amended to include veterinary drugs with FDA mandated and approved Client Information Sheets, or a Veterinary Medication Guide Rule should be implemented.
In addition, the current labels and Client Information Sheets for all of the veterinary NSAIDs should be posted on the FDA website, so that individuals seeking information on the internet do not have to wade through annals of promotional materials at the drug company websites to find FDA approved documents. Currently, the only US information for firocoxib (Previcox) available on the internet at this time is the Freedom of Information Summary (18), which contains a paucity of information. Neither the Previcox label nor the Client Information Sheet may be accessed at the FDA website or elsewhere. A consumer must file a formal, written FOI request and pay a fee to obtain the Previcox label and CIS. (25) Also, consumers should be able to view the causality assessment scores for veterinary NSAID ADE data posted on the FDA CVM website.
Of the cox-2 selective veterinary NSAIDs carprofen (Rimadyl), meloxicam (Metacam), deracoxib (Deramaxx), and firocoxib (Previcox), the most is currently known about carprofen, and therefore I have focused on its history in this discussion. The other three drugs are much less well known because they are much newer drugs.
The coxib Deramaxx, approved August 21, 2002, is thus far responsible for 2400 possible ADEs. 550 involved death of the dog. (12) No data for the coxib Previcox, approved July 21, 2004 (18) has been posted on the FDA CVM website to date. (12) Previcox is the more extreme cox-2 inhibitor. In in vitro canine whole blood assays, Previcox exhibits approximately 380-fold selectivity for cox-2 over cox-1. (2) Deramaxx is similar to Celebrex, while Previcox is similar to Vioxx. (26) (28)
Current evidence suggests that cox-2 is produced constitutively in the brain, spinal cord, kidney, ovary, uterus, placenta, thymus, bone, cartilage, synovia, endothelia, prostrate, and lung. (27)
It is responsible for homeostatic mechanisms in the body and plays an important part in healing. (16) More research is needed regarding the safety of currently available cox-2 inhibitors on the kidney and other organs. According to veterinary clinical pharmacologist Mark Papich: "Some of the prostaglandins that play an important role in salt and water regulation and hemodynamics in the kidney are synthesized by cox-2 enzymes." (19) Prostaglandins mediated by cox-2 are induced when gastrointestinal erosion occurs. Veterinary clinical pharmacologist Dawn Boothe states that "cox-2 appears to be the isoform mediating repair of damaged tissues with expression being greatest within the first 10 days of damage". (16)
A study released January 17, 2005 found that when mice that are genetically prone to hardening of the arteries were treated with a cox-2 inhibitor, their condition worsened. (20) Several studies have linked the human cox-2 inhibitor Vioxx to increased risk of heart attack and stroke. There is concern regarding this with the cox-2 inhibitors Celebrex and Bextra. Indeed, this is the reason the current meetings are taking place. There is no evidence that this is not a concern in dogs, only evidence that such is much less likely to be detected through the voluntary ADE reporting system, for reasons already mentioned in these comments.
In light of the history of carprofen and the current concerns about extreme cox-2 inhibition in humans as well as in animals, one wonders why the extreme cox-2 inhibitor firocoxib (Previcox) was approved as recently as July 2004.
A panel should be convened to discuss the safety of the veterinary NSAIDs and how to improve the current circumstances. This panel should include consumer representatives. Much human suffering is also associated with the sickness and loss of beloved canine companions.
Thank you for considering these comments.
References
(1) Papich, Mark. Nonsteroidal Anti-Inflammatory Drugs. Antech Diagnostics News, January 2005. http://www.antechdiagnostics.com/client ... n05_01.htm.
(2) http://www.emea.eu.int/vetdocs/PDFs/EPA ... 04.en6.pdf
(3) Boothe, Dawn M. Clinical Perspectives on Current and Future Options in Canine NSAID Therapy. Advances No. 3, Pfizer Animal Health - Practical information about the art, science, and research of veterinary medicine. May 2002.
(4) Holtsinger RH, Parker RB, Bealse BS, et al. The therapeutic efficacy of carprofen (Rimadyl) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Traumatol 1995; 5: 140-144.
(5) Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 1995; 206: 807-811.
(6) CVM Update. http://www.fda.gov/cvm/index/updates/rimadyl2.html
(7) http://www.escribe.com/pets/doghealth2/m423.html
(8) http://www.hometown.aol.com/sn1154/rim1.html
(9)
http://www.fda.gov/cvm/index/safety/4045.pdf
(10)
http://www.fda.gov/cvm/index/regulatory/w121302pz.pdf
(11) http://www.rimadyl.com/PAHimages/compli ... liance.pdf
(12) http://www.fda.gov/cvm/index/ade/ade_cum.htm
(13) Hampshire, Victoria. Emerging issues regarding informed consent. JAVMA News, 01/15/04. http://www.avma.org/onlnews/javma/jan04/040115f.asp
(14) Moskal, Thomas J. Adverse Drug Experience Reports Lead to Label Changes, Other Actions for Safer Animal Drugs. FDA Veterinarian, March/April 2004. http://www.fda.gov/cvm/index/fdavet/fdavettoc.html
(15) Moskal, Thomas J. Minimizing the risk factors associated with veterinary NSAIDs FDA-CVM offers suggestions based on postmarketing experience. JAVMA News, April 15, 2004. http://avma.org/onlnews/javma/apr04/040415g.asp
(16) Boothe, Dawn. The new nonsteroidal anti-inflammatory drugs. The Central Veterinary Conference, Aug. 2004.
(17) Papich Mark. Adverse drug reactions of clinical significance. The Central Veterinary Conference, Aug. 28-31, 2003.
(18) http://www.fda.gov/cvm/efoi/section2/141-230.pdf
(19) Papich, Mark. Anti-inflammatory drugs: how to sort out the choices. The Central Veterinary Conference, Aug. 28-31, 2003.
(20) http://sfgate.com/cgi-bin/article.cgi?f ... AS4VO1.DTL
(21)
http://www.fda.gov/cvm/index/vmac/CVMFo ... cument.pdf
(22)
http://www.escribe.com/pets/doghealth2/m19225.html
(23)
http://www.fda.gov/ohrms/dockets/docket ... r00003.txt
(24) Maddison, Jill. Adverse Drug Reactions. Ettinger's Textbook of Veterinary Internal Medicine Fifth Edition, Vol. 1. Pennsylvania, Saunders, 2000.
(25) Personal correspondence with Linda Grassie, FDA CVM.
(26)
http://www.terrabase-inc.com/cox-inhibitors.html
(27) Dowling, Patricia. Nonsteroidal Anti-Inflammatory Drugs. The Central Veterinary Conference, Aug. 2004.
(28)
<a href="http://ww
COX-2 SELECTIVE NSAID COMMENTS AND CARPROFEN (RIMADYL) HISTORY
The human cox-2 inhibitors are, at this time, under the microscope. It has become quite obvious that all is not known about the effects of cox-2 inhibition in humans. This inquiry into the safety of cox-2 specific NSAIDs should be extended to include the cox-2 specific veterinary NSAIDs. Much less is known about the effects of cox-2 inhibition in canines.
The veterinary cox-2 inhibitors include the mildly cox-2 selective carprofen (Rimadyl) and meloxicam (Metacam) as well as the cox-2 selective NSAIDs of the coxib class deracoxib (Deramaxx) and firocoxib (Previcox). (1) Firocoxib is the most cox-2 selective veterinary NSAID approved to date. (2)
All of the concerns about human drug approval, adverse drug events, and monitoring of the safety of cox-2 inhibitors exist and are magnified in veterinary medicine. This is primarily due to differences in pre and post-approval drug clinical trials, in the reporting of ADEs, in diagnostic procedures for pets and humans, in the treatment of illness available for pets and humans and the clients' ability to pay, and the value placed on human life as opposed to the value of the lives of animals. Also, the veterinarian serves a dual role as both physician and pharmacist.
There are considerable differences between pre-approval and post-approval clinical trials for canine NSAIDs and human NSAIDs. Pre-approval clinical trials for veterinary drugs are small, short and use only healthy subjects.
Almost eight years has passed since the first veterinary cox-2 inhibitor was brought to market. We now have at least 4 cox-2 inhibitors. Still, no good information exists as to dog breed differences in metabolism, effects on aged or unhealthy dogs, concomitant drug use, and consequences of long term use. Nevertheless, these drugs are commonly dispensed to dogs of all breeds, all ages, and in varying states of health, often for chronic, daily, long term use.
While it is sometimes the case that problems with human drugs are not identified until the drug is brought to market and used by extremely large numbers of people, this is always the case with veterinary drugs due to their very limited and small trials. According to veterinary clinical pharmacologist Dawn Boothe: "Prelicensing and other experimental studies focus on dose-dependent effects and target a relatively small test population. It is not until a drug is placed in widespread clinical use that we see the idiosyncratic and other more subtle toxicities that are potentially serious." (3)
One of the problems in identifying Vioxx as a possible contributor to heart attack and stroke in humans was that these events commonly occur in the general population. Many cox-2 inhibitor adverse reactions in dogs may be being passed off as common occurrences of old age. Only through huge long-running post-approval clinical trials was the possible connection between Vioxx and heart problems discovered. These types of trials are not conducted with veterinary drugs.
Intensive monitoring within hospitals and analysis of health registers post drug approval is uncommon in veterinary medicine. (24)
There are also differences in the reporting of adverse drug events (ADEs) between veterinary and human drugs. It has been estimated that only about 1/10 of dog adverse reactions to medication are reported as compared to reporting of human adverse reactions. Veterinary clinical pharmacologist Mark Papich states that "the true incidence of adverse drug effects in domestic animals is not known because most are not reported". (17)
In addition, major differences exist in diagnostic procedures for canines and humans. For example, while it is extremely common for physicians to diagnose heart attacks and strokes, it is uncommon for veterinarians to do so. Most veterinarians do not order MRIs or CT scans that are very common diagnostic tools for humans, and many veterinary clients could not pay for them anyway. According to FDA CVM: "Additional limitations in veterinary pharmacovigilance include the cost and availability of diagnostic tests and the lack of comprehensive postmortem information". (21)
Humans survive many cox-2 inhibitor related adverse reactions due to their ability to voice discomfort and to obtain medical treatment which is most often paid for by insurance benefits.
For example, a human can voice stomach discomfort to his physician while a dog obviously cannot, and according to veterinary clinical pharmacologist Dawn Boothe: "Unfortunately, there is no sensitive indicator of gastrointestinal bleeding in dogs and damage may be quite extensive before signs are evident." (16) Therefore even the most common NSAID side effect of gastrointestinal damage is likely to be quite serious in canines. Many dogs who experience gastrointestinal damage, kidney failure, or liver toxicity from cox-2 inhibitors are euthanized because their owners cannot travel, many times out of state, to an advanced veterinary medical care facility for necessary diagnostics, nor pay for extended intensive medical treatment. Additionally, many treatments available to humans are still investigational for pets.
Great value is placed upon human life while animals are still generally legally considered property. Therefore physicians are subject to much liability whenever drugs are used improperly while veterinarians are subject to virtually none.
Finally, while in human medicine there exists the pharmacist to provide drug information and answer specific consumer questions about product use, no such intermediary exists in veterinary medicine.
A brief summary of a few of the highlights of the history of the veterinary cox-2 inhibitor Rimadyl will serve to illustrate most of the above. In short term clinical trials for Rimadyl, the number of reports of adverse reactions were minimal. Most commonly reported were vomiting, lethargy, and appetite change. While an increase in serum activity of ALT was the most frequently reported clinicopathologic change, investigators did not relate any clinical signs to the elevations in ALT. It was reported that clinicopathologic abnormalities and mild adverse effects were the same for the carprofen group and the placebo control group. (4)(5) According to the FDA CVM, based on studies that were submitted for the drug approval process, "the risk of Rimadyl was thought to be negligible". (6).
Rimadyl hit the market in 1997 and was directly advertised to consumers through television commercials (featuring the recovery of old dogs from lameness) as well as full-page magazine ads, print stories, and radio reports. Consequently, it was widely used very quickly. By 1999 the CVM estimated that Rimadyl had been given to 2.5 million dogs. (6)
A brief chronology of select Rimadyl post-approval events 1997 to 2002:
May 1997 - CVM asked Pfizer to change the adverse drug reaction section of the label due to ADE reports received and asked Pfizer to send a "Dear Doctor" letter to veterinarians about Rimadyl's adverse effects. (6)
September 1997 - An extensive adverse reaction section was included in Rimadyl labeling. The existing possibility of a fatal outcome was included. (6)
1998 - 39% (no. 3626) of ALL ADE reports received by FDA CVM involved Rimadyl. About 13% involved death of the dog. (6)
April 28, 1999 - Dog owner Bob Sinclair spoke about Rimadyl and animal drug issues at the FDA Stakeholders meeting in Overland Park, Kansas.
(22) (23)
Spring 1999 - Death was added to the adverse reactions section of the Rimadyl label. (6)
June 24, 1999 - Concerned consumers met with Pfizer officials and were presented with an advance proof print of a new Rimadyl Consumer Information Page. (7)
October 1999 - Jean Townsend of Johns Island, South Carolina brought a class action lawsuit against Pfizer alleging that neither she nor her vet were adequately warned of the possible adverse consequences of Rimadyl use. (8)
December 1, 1999 - The FDA CVM issued a Rimadyl Update. CVM stated that dog owners who had reported ADEs directly to the agency said they were not aware of any potential Rimadyl adverse effects. CVM advised: "As a NSAID with potentially serious side effects, however, the use of Rimadyl should be carefully considered before being incorporated in any therapeutic plan. Moreover, dog owners should have an active role in making that decision." (6)
March 9, 2000 - Another "Dear Doctor" letter was sent by Pfizer to veterinarians. Among other things, this letter informed veterinarians of an Owner Information Sheet to be attached, along with the product insert, to each bottle of Rimadyl Caplets and Rimadyl Chewable Tablets. Veterinarians were also informed that new bottles of Rimadyl would be offered in 2 week, 1 month, and 3 month supplies so that vets would be able to dispense full bottles with the drug information attached. In addition Pfizer stated: "Pfizer, in conjunction with the FDA CVM, encourages veterinarians to provide owners with information about both risks and benefits associated with all potential therapeutic options." (9)
December 13, 2002 - Pfizer was asked by the Division of Surveillance FDA CVM to immediately stop dissemination of certain promotional materials judged to be misleading. (10)
Currently, the Rimadyl label includes the following adverse reactions based on voluntary post-approval drug reporting, listed in decreasing order of frequency by body system:
Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis.
Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, bilirubinuria, hypoalbuminemia.
Approximately one-fourth of hepatic reports were in Labrador Retrievers.
Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation.
Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities including acute tubular necrosis, renal tubular acidosis, glucosuria.
Behavioral: Sedation, lethargy, hyperactivity, restlessness, aggressiveness.
Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis.
Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis.
Immunologic or hypersensitivity: Facial swelling, hives, erythema.
In rare situations, death has been associated with some of the adverse reactions listed above. (11)
This is quite an extensive list for a drug whose risk was thought to be negligible based on pre-approval trials. As of January 3, 2005, the cumulative total of Rimadyl possible ADE reports as posted on the CVM website was 12,919. 2,349 involved death of the dog. (12)
Problems continue to surround the use of Rimadyl and the other veterinary cox-2 inhibitors. A two year review of the consumer messages to the FDA CVM hotline which appeared in JAVMA News on January 15, 2004 revealed the following:
"Frequent comments from pet owners who contact the CVM hotline include these:
* They did not receive a client information sheet when one was available for a drug that was prescribed for their pet.
* The medication they received from their veterinarian was not dispensed in the CVM-approved container but was broken into aliquots that were taken home without the client information sheet or approved label.
* The veterinarian did not conduct or recommend blood testing before and after prescribing the drug, even though baseline testing and/or periodic monitoring was recommended on the label. Common examples include heartworm products and nonsteroidal, anti-inflammatory drugs.
* After reading client information sheets and labels on the Internet about a drug prescribed for their pet, they discovered that their pet may have fallen into a category of animal for which a precaution or contraindication existed."
Article author Dr. Victoria Hampshire of the FDA CVM reminded practitioners that, "Drugs that come with client information sheets are intended to be dispensed in the manufacturer's container, with the sheets accompanying the prescription." (13)
The almost uniform failure of veterinarians to provide the Client Information Sheets for the veterinary cox-2 inhibitors led to the publishing of two additional articles by FDA CVM in 2004 bringing this to the attention of the veterinary community. In a FDA Veterinarian article "Adverse Drug Experience Reports Lead to Label Changes, Other Actions for Safer Animal Drugs", Dr. Thomas Moskal advised veterinarians to communicate risk information for NSAIDs to clients and to be sure that the dog owner receives the Client Information Sheet. (14) In the article "Minimizing the risk factors of the veterinary NSAIDs" which appeared in JAVMA News April 15, 2004 Dr. Moskal stated: "Drug risk information is communicated to veterinary practitioners and to the public through the product labeling...Drugs that come with Client Information Sheets are intended to be dispensed to clients with the Client Information Sheet accompanying the prescription." (15)
Companion animals cannot verbally notify owners when they are experiencing an adverse reaction to a cox-2 inhibitor. The pet owner who sees the dog every day must detect any problems, but can only do so if he or she knows what to watch for.
Veterinarians have failed in their role as physician by failing to obtain informed consent when prescribing NSAIDs, and they have failed in their role as pharmacists by not providing adequate consumer drug information. Dogs have become family members in most households, and are cared for as such. Dog owners should not be left reeling in shock and burdened by extreme guilt when their beloved canine companion suffers or dies from the use of a cox-2 inhibitor, because THEY HAD NO IDEA.
The FDA should not only request, but must enforce, that the FDA recommended and approved Client Information Sheets currently existing for the veterinary NSAIDs be given to pet owners. Pet owners are currently seeking legislation state by state mandating full disclosure of the risks of veterinary drugs such as the cox-2 inhibitors. They should not have to do so. The existing Medication Guide Rule which enforces the providing of FDA prepared Medication Guides for certain human drugs should be amended to include veterinary drugs with FDA mandated and approved Client Information Sheets, or a Veterinary Medication Guide Rule should be implemented.
In addition, the current labels and Client Information Sheets for all of the veterinary NSAIDs should be posted on the FDA website, so that individuals seeking information on the internet do not have to wade through annals of promotional materials at the drug company websites to find FDA approved documents. Currently, the only US information for firocoxib (Previcox) available on the internet at this time is the Freedom of Information Summary (18), which contains a paucity of information. Neither the Previcox label nor the Client Information Sheet may be accessed at the FDA website or elsewhere. A consumer must file a formal, written FOI request and pay a fee to obtain the Previcox label and CIS. (25) Also, consumers should be able to view the causality assessment scores for veterinary NSAID ADE data posted on the FDA CVM website.
Of the cox-2 selective veterinary NSAIDs carprofen (Rimadyl), meloxicam (Metacam), deracoxib (Deramaxx), and firocoxib (Previcox), the most is currently known about carprofen, and therefore I have focused on its history in this discussion. The other three drugs are much less well known because they are much newer drugs.
The coxib Deramaxx, approved August 21, 2002, is thus far responsible for 2400 possible ADEs. 550 involved death of the dog. (12) No data for the coxib Previcox, approved July 21, 2004 (18) has been posted on the FDA CVM website to date. (12) Previcox is the more extreme cox-2 inhibitor. In in vitro canine whole blood assays, Previcox exhibits approximately 380-fold selectivity for cox-2 over cox-1. (2) Deramaxx is similar to Celebrex, while Previcox is similar to Vioxx. (26) (28)
Current evidence suggests that cox-2 is produced constitutively in the brain, spinal cord, kidney, ovary, uterus, placenta, thymus, bone, cartilage, synovia, endothelia, prostrate, and lung. (27)
It is responsible for homeostatic mechanisms in the body and plays an important part in healing. (16) More research is needed regarding the safety of currently available cox-2 inhibitors on the kidney and other organs. According to veterinary clinical pharmacologist Mark Papich: "Some of the prostaglandins that play an important role in salt and water regulation and hemodynamics in the kidney are synthesized by cox-2 enzymes." (19) Prostaglandins mediated by cox-2 are induced when gastrointestinal erosion occurs. Veterinary clinical pharmacologist Dawn Boothe states that "cox-2 appears to be the isoform mediating repair of damaged tissues with expression being greatest within the first 10 days of damage". (16)
A study released January 17, 2005 found that when mice that are genetically prone to hardening of the arteries were treated with a cox-2 inhibitor, their condition worsened. (20) Several studies have linked the human cox-2 inhibitor Vioxx to increased risk of heart attack and stroke. There is concern regarding this with the cox-2 inhibitors Celebrex and Bextra. Indeed, this is the reason the current meetings are taking place. There is no evidence that this is not a concern in dogs, only evidence that such is much less likely to be detected through the voluntary ADE reporting system, for reasons already mentioned in these comments.
In light of the history of carprofen and the current concerns about extreme cox-2 inhibition in humans as well as in animals, one wonders why the extreme cox-2 inhibitor firocoxib (Previcox) was approved as recently as July 2004.
A panel should be convened to discuss the safety of the veterinary NSAIDs and how to improve the current circumstances. This panel should include consumer representatives. Much human suffering is also associated with the sickness and loss of beloved canine companions.
Thank you for considering these comments.
References
(1) Papich, Mark. Nonsteroidal Anti-Inflammatory Drugs. Antech Diagnostics News, January 2005. http://www.antechdiagnostics.com/client ... n05_01.htm.
(2) http://www.emea.eu.int/vetdocs/PDFs/EPA ... 04.en6.pdf
(3) Boothe, Dawn M. Clinical Perspectives on Current and Future Options in Canine NSAID Therapy. Advances No. 3, Pfizer Animal Health - Practical information about the art, science, and research of veterinary medicine. May 2002.
(4) Holtsinger RH, Parker RB, Bealse BS, et al. The therapeutic efficacy of carprofen (Rimadyl) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Traumatol 1995; 5: 140-144.
(5) Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 1995; 206: 807-811.
(6) CVM Update. http://www.fda.gov/cvm/index/updates/rimadyl2.html
(7) http://www.escribe.com/pets/doghealth2/m423.html
(8) http://www.hometown.aol.com/sn1154/rim1.html
(9)
http://www.fda.gov/cvm/index/safety/4045.pdf
(10)
http://www.fda.gov/cvm/index/regulatory/w121302pz.pdf
(11) http://www.rimadyl.com/PAHimages/compli ... liance.pdf
(12) http://www.fda.gov/cvm/index/ade/ade_cum.htm
(13) Hampshire, Victoria. Emerging issues regarding informed consent. JAVMA News, 01/15/04. http://www.avma.org/onlnews/javma/jan04/040115f.asp
(14) Moskal, Thomas J. Adverse Drug Experience Reports Lead to Label Changes, Other Actions for Safer Animal Drugs. FDA Veterinarian, March/April 2004. http://www.fda.gov/cvm/index/fdavet/fdavettoc.html
(15) Moskal, Thomas J. Minimizing the risk factors associated with veterinary NSAIDs FDA-CVM offers suggestions based on postmarketing experience. JAVMA News, April 15, 2004. http://avma.org/onlnews/javma/apr04/040415g.asp
(16) Boothe, Dawn. The new nonsteroidal anti-inflammatory drugs. The Central Veterinary Conference, Aug. 2004.
(17) Papich Mark. Adverse drug reactions of clinical significance. The Central Veterinary Conference, Aug. 28-31, 2003.
(18) http://www.fda.gov/cvm/efoi/section2/141-230.pdf
(19) Papich, Mark. Anti-inflammatory drugs: how to sort out the choices. The Central Veterinary Conference, Aug. 28-31, 2003.
(20) http://sfgate.com/cgi-bin/article.cgi?f ... AS4VO1.DTL
(21)
http://www.fda.gov/cvm/index/vmac/CVMFo ... cument.pdf
(22)
http://www.escribe.com/pets/doghealth2/m19225.html
(23)
http://www.fda.gov/ohrms/dockets/docket ... r00003.txt
(24) Maddison, Jill. Adverse Drug Reactions. Ettinger's Textbook of Veterinary Internal Medicine Fifth Edition, Vol. 1. Pennsylvania, Saunders, 2000.
(25) Personal correspondence with Linda Grassie, FDA CVM.
(26)
http://www.terrabase-inc.com/cox-inhibitors.html
(27) Dowling, Patricia. Nonsteroidal Anti-Inflammatory Drugs. The Central Veterinary Conference, Aug. 2004.
(28)
<a href="http://ww
- guest
Nonsteroidal anti-inflammatory drug enteropathy in rats
by malernee » Sat Feb 26, 2005 7:24 pm
January 1997 • Volume 112 • Number 1
Nonsteroidal anti-inflammatory drug enteropathy in rats: Role of permeability, bacteria, and enterohepatic circulation
Abstract TOP
BACKGROUND & AIMS: The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains poorly understood. The aim of this study was to examine the relative importance of the three suggested components of the pathogenesis of NSAID enteropathy, namely, epithelial permeability, enteric bacterial numbers, and enterohepatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage.
METHODS: Rats were given diclofenac or nitrofenac at 12-hour intervals. Epithelial permeability to [51Cr]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs. Serum levels and biliary excretion of the two drugs were determined by high-performance liquid chromatography.
RESULTS: Diclofenac caused a progressive increase in epithelial permeability, marked increases in enteric gram-negative bacterial numbers, and frank intestinal ulceration. Nitrofenac caused similar changes in intestinal permeability after a single dose but no further increase with repeated administration. Moreover, nitrofenac had no effect on enteric bacterial numbers and did not cause frank ulceration. Unlike diclofenac, nitrofenac did not undergo extensive enterohepatic recirculation. Two other NSAIDs that do not undergo enterohepatic recirculation (nabumetone and aspirin) also did not modify enteric bacterial numbers or cause intestinal ulceration.
CONCLUSIONS: Enterohepatic recirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostaglandin synthesis is relatively unimportant.
(Gastroenterology 1997 Jan;112(1):109-17)
Publishing and Reprint Information TOP
Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.
Articles with References to this Article TOP
This article is referenced by these articles:
Chemotherapy- and radiotherapy-induced intestinal damage is regulated by intestinal trefoil factor
Gastroenterology
March 2004 • Volume 126 • Number 3
P.L. Beck*, J.F. Wong*, Y. Li*, S. Swaminathan*, R.J. Xavier‡, K.L. Devaney‡, Daniel K. Podolsky‡* ABSTRACT
FULL TEXT
Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation
Gastroenterology
July 2003 • Volume 125 • Number 1
Ossama A. Hatoum*, David G. Binion*, Mary F. Otterson‡, David D. Gutterman** ABSTRACT
FULL TEXT
Multiple mechanisms in indomethacin-induced impairment of hepatic cytochrome P450 enzymes in rats
Gastroenterology
March 2002 • Volume 122 • Number 3
Yasuhiro Masubuchi, Emi Masuda, Toshiharu Horie ABSTRACT
FULL TEXT
Drug enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats
Gastroenterology
December 2000 • Volume 119 • Number 6
Chessley R. Atchison*, A. Brian West‡, Arun Balakumaran*, Sally J. Hargus§, Lance R. Pohl||, Davis H. Daiker*, Judith F. Aronson*, Walter E. Hoffmann¶, Bryan K. Shipp#, Mary Treinen–Moslen* ABSTRACT
FULL TEXT
Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice
Gastroenterology
September 2000 • Volume 119 • Number 3
Paul L. Beck*,‡, Ramnik Xavier*,‡,§, Naifang Lu§, Nanthakumar N. Nanda*,‡, Mary Dinauer¶, Daniel K. Podolsky*,‡, Brian Seed§,‡ ABSTRACT
FULL TEXT
Antibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice
Gastroenterology
June 2000 • Volume 118 • Number 6
Karen L. Madsen*, Jason S. Doyle‡, Michele M. Tavernini*, Lawrence D. Jewell‡, Robert P. Rennie§, Richard N. Fedorak* ABSTRACT
FULL TEXT
Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats
Gastroenterology
December 1998 • Volume 115 • Number 6
Sven Seitz, Urs A. Boelsterli ABSTRACT
FULL TEXT
Nonsteroidal anti-inflammatory drug enteropathy in rats: Role of permeability, bacteria, and enterohepatic circulation
Abstract TOP
BACKGROUND & AIMS: The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains poorly understood. The aim of this study was to examine the relative importance of the three suggested components of the pathogenesis of NSAID enteropathy, namely, epithelial permeability, enteric bacterial numbers, and enterohepatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage.
METHODS: Rats were given diclofenac or nitrofenac at 12-hour intervals. Epithelial permeability to [51Cr]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs. Serum levels and biliary excretion of the two drugs were determined by high-performance liquid chromatography.
RESULTS: Diclofenac caused a progressive increase in epithelial permeability, marked increases in enteric gram-negative bacterial numbers, and frank intestinal ulceration. Nitrofenac caused similar changes in intestinal permeability after a single dose but no further increase with repeated administration. Moreover, nitrofenac had no effect on enteric bacterial numbers and did not cause frank ulceration. Unlike diclofenac, nitrofenac did not undergo extensive enterohepatic recirculation. Two other NSAIDs that do not undergo enterohepatic recirculation (nabumetone and aspirin) also did not modify enteric bacterial numbers or cause intestinal ulceration.
CONCLUSIONS: Enterohepatic recirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostaglandin synthesis is relatively unimportant.
(Gastroenterology 1997 Jan;112(1):109-17)
Publishing and Reprint Information TOP
Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.
Articles with References to this Article TOP
This article is referenced by these articles:
Chemotherapy- and radiotherapy-induced intestinal damage is regulated by intestinal trefoil factor
Gastroenterology
March 2004 • Volume 126 • Number 3
P.L. Beck*, J.F. Wong*, Y. Li*, S. Swaminathan*, R.J. Xavier‡, K.L. Devaney‡, Daniel K. Podolsky‡* ABSTRACT
FULL TEXT
Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation
Gastroenterology
July 2003 • Volume 125 • Number 1
Ossama A. Hatoum*, David G. Binion*, Mary F. Otterson‡, David D. Gutterman** ABSTRACT
FULL TEXT
Multiple mechanisms in indomethacin-induced impairment of hepatic cytochrome P450 enzymes in rats
Gastroenterology
March 2002 • Volume 122 • Number 3
Yasuhiro Masubuchi, Emi Masuda, Toshiharu Horie ABSTRACT
FULL TEXT
Drug enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats
Gastroenterology
December 2000 • Volume 119 • Number 6
Chessley R. Atchison*, A. Brian West‡, Arun Balakumaran*, Sally J. Hargus§, Lance R. Pohl||, Davis H. Daiker*, Judith F. Aronson*, Walter E. Hoffmann¶, Bryan K. Shipp#, Mary Treinen–Moslen* ABSTRACT
FULL TEXT
Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice
Gastroenterology
September 2000 • Volume 119 • Number 3
Paul L. Beck*,‡, Ramnik Xavier*,‡,§, Naifang Lu§, Nanthakumar N. Nanda*,‡, Mary Dinauer¶, Daniel K. Podolsky*,‡, Brian Seed§,‡ ABSTRACT
FULL TEXT
Antibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice
Gastroenterology
June 2000 • Volume 118 • Number 6
Karen L. Madsen*, Jason S. Doyle‡, Michele M. Tavernini*, Lawrence D. Jewell‡, Robert P. Rennie§, Richard N. Fedorak* ABSTRACT
FULL TEXT
Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats
Gastroenterology
December 1998 • Volume 115 • Number 6
Sven Seitz, Urs A. Boelsterli ABSTRACT
FULL TEXT
- malernee
- Site Admin
- Posts: 462
- Joined: Wed Aug 13, 2003 5:56 pm
Effect of carprofen on hemostatic variables in dogs.
by malernee » Sat Feb 26, 2005 7:26 pm
Am J Vet Res. 2001 Oct;62(10):1642-6. Related Articles, Links
Effect of carprofen on hemostatic variables in dogs.
Hickford FH, Barr SC, Erb HN.
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
OBJECTIVE: To evaluate the effect of carprofen on hemostatic variables in clinically normal dogs. ANIMALS: 12 clinically normal Labrador Retrievers. PROCEDURE: 10 dogs (6 females, 4 males) received carprofen (2.2 mg/kg of body weight, PO, q 12 h) for 5 days. Two dogs (untreated control group; 1 female, 1 male) did not receive carprofen. Hemostatic variables (platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen, platelet aggregation, and bleeding time) were assessed for all dogs prior to treatment, on day 5 of treatment, and 2 and 7 days after discontinuation of the drug (days 7 and 12). Serum biochemical variables and Hct were assessed prior to treatment and on days 5 and 12. RESULTS: In dogs receiving carprofen, platelet aggregation was significantly decreased, and onset of aggregation was significantly delayed on days 5, 7, and 12, compared with pretreatment values. Activated partial thromboplastin time was significantly increased on days 5, 7, and 12 over pretreatment values in treated dogs, but values remained within reference ranges. Significant differences were not detected in buccal mucosal bleeding time, other serum biochemical and hemostatic variables, or Hct, compared with pretreatment values and the internal control group. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of carprofen for 5 days causes minor but not clinically important alterations in hemostatic and serum biochemical variables in clinically normal Labrador Retrievers. Carprofen is commonly used to treat osteoarthritis and chronic pain in dogs, but prior to this study, its effect on platelet aggregation and hemostatic variables was unknown.
Effect of carprofen on hemostatic variables in dogs.
Hickford FH, Barr SC, Erb HN.
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
OBJECTIVE: To evaluate the effect of carprofen on hemostatic variables in clinically normal dogs. ANIMALS: 12 clinically normal Labrador Retrievers. PROCEDURE: 10 dogs (6 females, 4 males) received carprofen (2.2 mg/kg of body weight, PO, q 12 h) for 5 days. Two dogs (untreated control group; 1 female, 1 male) did not receive carprofen. Hemostatic variables (platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen, platelet aggregation, and bleeding time) were assessed for all dogs prior to treatment, on day 5 of treatment, and 2 and 7 days after discontinuation of the drug (days 7 and 12). Serum biochemical variables and Hct were assessed prior to treatment and on days 5 and 12. RESULTS: In dogs receiving carprofen, platelet aggregation was significantly decreased, and onset of aggregation was significantly delayed on days 5, 7, and 12, compared with pretreatment values. Activated partial thromboplastin time was significantly increased on days 5, 7, and 12 over pretreatment values in treated dogs, but values remained within reference ranges. Significant differences were not detected in buccal mucosal bleeding time, other serum biochemical and hemostatic variables, or Hct, compared with pretreatment values and the internal control group. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of carprofen for 5 days causes minor but not clinically important alterations in hemostatic and serum biochemical variables in clinically normal Labrador Retrievers. Carprofen is commonly used to treat osteoarthritis and chronic pain in dogs, but prior to this study, its effect on platelet aggregation and hemostatic variables was unknown.
- malernee
- Site Admin
- Posts: 462
- Joined: Wed Aug 13, 2003 5:56 pm
Dermaxx™ (deracoxib) 25 mg tablets, recall
by guest » Sat Aug 13, 2005 7:10 pm
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINE - CLASS III
_______________________________
PRODUCT
a) Dermaxx™ (deracoxib) 25 mg tablets,
A coxib-class NSAID *For Use in Dogs Only*.
The product is packed in plastic screw top
bottles containing 30 and 90 tablets each.
Recall # V-091-5;
b) Deramaxx (deracoxib) 100 mg tablets,
A coxib-class NSAID *For Use in Dogs Only*.
The product is packed in plastic screw top
bottles containing 90 tablets. Recall # V-092-5
CODE
a) Lot numbers SPT3C001, SPT3C208, SPN3C213 and SPT3C029;
b) Lot number SPN3C166
RECALLING FIRM/MANUFACTURER
Recalling Firm: Novartis Animal Health US, Inc, Greensboro, NC, by telephone and fax on June 15, 2005, and follow up letter on June 28, 2005.
Manufacturer: Pfizer Pharmaceuticals Llc formally Gd Searle Llc, Caguas, PR. Firm initiated recall is ongoing.
REASON
Product does not meet the finished product assay specifications.
VOLUME OF PRODUCT IN COMMERCE
a) Unknown;
b) 4530 bottles
DISTRIBUTION
CA. GA, and HI
_______________________________
PRODUCT
a) Dermaxx™ (deracoxib) 25 mg tablets,
A coxib-class NSAID *For Use in Dogs Only*.
The product is packed in plastic screw top
bottles containing 30 and 90 tablets each.
Recall # V-091-5;
b) Deramaxx (deracoxib) 100 mg tablets,
A coxib-class NSAID *For Use in Dogs Only*.
The product is packed in plastic screw top
bottles containing 90 tablets. Recall # V-092-5
CODE
a) Lot numbers SPT3C001, SPT3C208, SPN3C213 and SPT3C029;
b) Lot number SPN3C166
RECALLING FIRM/MANUFACTURER
Recalling Firm: Novartis Animal Health US, Inc, Greensboro, NC, by telephone and fax on June 15, 2005, and follow up letter on June 28, 2005.
Manufacturer: Pfizer Pharmaceuticals Llc formally Gd Searle Llc, Caguas, PR. Firm initiated recall is ongoing.
REASON
Product does not meet the finished product assay specifications.
VOLUME OF PRODUCT IN COMMERCE
a) Unknown;
b) 4530 bottles
DISTRIBUTION
CA. GA, and HI
- guest
do cox 2 drugs effect bone healing ?
by guest » Mon Sep 12, 2005 1:19 pm
In the Journal of the American Academy of Orthopaedic Surgeons, two
researchers from the University of North Carolina School of Medicine (UNC) reviewed
several studies that examined the use of NSAIDs as analgesics for patients
recovering from fractures.
One of the studies - as reported in the Journal of Bone Joint Surgery (2000)
- compared the recovery of nearly 100 patients who had fractured a femur
(the long bone that runs from the hip to the knee). The fractures of 32 subjects
healed improperly and were classified as "nonunion," while fractures
repaired correctly in a control group of 67 subjects.
The researchers found a significant association between the use of NSAIDs
and the nonunion of fractures. More than 60 percent of the nonunion group
reported regular NSAID use compared to only 13 percent in the control group. Among
the subjects who used NSAIDs, the average healing time was a full two months
longer than among those who used no NSAIDs at all.
Based on this and other similar studies, the UNC researchers concluded that
during the healing of fractures, NSAIDs should be avoided. They also noted
that COX-2 inhibitors not only have an adverse effect on bone healing, but may
also impair the healing of ligaments.
In the Journal of the American Academy of Orthopaedic Surgeons, two
researchers from the University of North Carolina School of Medicine (UNC) reviewed
several studies that examined the use of NSAIDs as analgesics for patients
recovering from fractures.
One of the studies - as reported in the Journal of Bone Joint Surgery (2000)
- compared the recovery of nearly 100 patients who had fractured a femur
(the long bone that runs from the hip to the knee). The fractures of 32 subjects
healed improperly and were classified as "nonunion," while fractures
repaired correctly in a control group of 67 subjects.
The researchers found a significant association between the use of NSAIDs
and the nonunion of fractures. More than 60 percent of the nonunion group
reported regular NSAID use compared to only 13 percent in the control group. Among
the subjects who used NSAIDs, the average healing time was a full two months
longer than among those who used no NSAIDs at all.
Based on this and other similar studies, the UNC researchers concluded that
during the healing of fractures, NSAIDs should be avoided. They also noted
that COX-2 inhibitors not only have an adverse effect on bone healing, but may
also impair the healing of ligaments.
This is interesting. I continue to be amazed at how much information concerning animals we can get by reviewing human publications. Her is another.
Pharmacol Res. 2004 Aug;50(2):151-6. Related Articles, Links
Is there an inhibitory effect of COX-2 inhibitors on bone healing?
Seidenberg AB, An YH.
Orthopaedic Research Laboratories, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 708, Charleston, SC, USA.
The use of the new selective cyclooxygenase-2 (COX-2) inhibitors (such as celecoxib and rofecoxib) for the treatment of pain and inflammation caused by fractures, cementless total joint replacements, soft tissue healing to bone, and spinal fusion surgeries has been controversial due to the convincing data collected from nonspecific NSAIDs such as indomethacin and naproxen regarding their inhibitory effects on bone healing and the similar effects of COX-2 specific NSAIDs in animal models. Is there a significant inhibitory effect of COX-2 inhibitors on bone healing in humans? To answer this question, we reviewed existing scientific evidence (based mainly on a MedLine search) of the potential effects of COX-2 inhibitors on bone healing. The literature shows that COX-2 inhibitors do have inhibitory effects on bone healing in animal models, but the effects of COX-2 inhibitors on similar processes in humans remain largely unknown. Copyright 2004 Elsevier Ltd.
Publication Types:
Review
Review, Tutorial
researchers from the University of North Carolina School of Medicine (UNC) reviewed
several studies that examined the use of NSAIDs as analgesics for patients
recovering from fractures.
One of the studies - as reported in the Journal of Bone Joint Surgery (2000)
- compared the recovery of nearly 100 patients who had fractured a femur
(the long bone that runs from the hip to the knee). The fractures of 32 subjects
healed improperly and were classified as "nonunion," while fractures
repaired correctly in a control group of 67 subjects.
The researchers found a significant association between the use of NSAIDs
and the nonunion of fractures. More than 60 percent of the nonunion group
reported regular NSAID use compared to only 13 percent in the control group. Among
the subjects who used NSAIDs, the average healing time was a full two months
longer than among those who used no NSAIDs at all.
Based on this and other similar studies, the UNC researchers concluded that
during the healing of fractures, NSAIDs should be avoided. They also noted
that COX-2 inhibitors not only have an adverse effect on bone healing, but may
also impair the healing of ligaments.
In the Journal of the American Academy of Orthopaedic Surgeons, two
researchers from the University of North Carolina School of Medicine (UNC) reviewed
several studies that examined the use of NSAIDs as analgesics for patients
recovering from fractures.
One of the studies - as reported in the Journal of Bone Joint Surgery (2000)
- compared the recovery of nearly 100 patients who had fractured a femur
(the long bone that runs from the hip to the knee). The fractures of 32 subjects
healed improperly and were classified as "nonunion," while fractures
repaired correctly in a control group of 67 subjects.
The researchers found a significant association between the use of NSAIDs
and the nonunion of fractures. More than 60 percent of the nonunion group
reported regular NSAID use compared to only 13 percent in the control group. Among
the subjects who used NSAIDs, the average healing time was a full two months
longer than among those who used no NSAIDs at all.
Based on this and other similar studies, the UNC researchers concluded that
during the healing of fractures, NSAIDs should be avoided. They also noted
that COX-2 inhibitors not only have an adverse effect on bone healing, but may
also impair the healing of ligaments.
This is interesting. I continue to be amazed at how much information concerning animals we can get by reviewing human publications. Her is another.
Pharmacol Res. 2004 Aug;50(2):151-6. Related Articles, Links
Is there an inhibitory effect of COX-2 inhibitors on bone healing?
Seidenberg AB, An YH.
Orthopaedic Research Laboratories, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 708, Charleston, SC, USA.
The use of the new selective cyclooxygenase-2 (COX-2) inhibitors (such as celecoxib and rofecoxib) for the treatment of pain and inflammation caused by fractures, cementless total joint replacements, soft tissue healing to bone, and spinal fusion surgeries has been controversial due to the convincing data collected from nonspecific NSAIDs such as indomethacin and naproxen regarding their inhibitory effects on bone healing and the similar effects of COX-2 specific NSAIDs in animal models. Is there a significant inhibitory effect of COX-2 inhibitors on bone healing in humans? To answer this question, we reviewed existing scientific evidence (based mainly on a MedLine search) of the potential effects of COX-2 inhibitors on bone healing. The literature shows that COX-2 inhibitors do have inhibitory effects on bone healing in animal models, but the effects of COX-2 inhibitors on similar processes in humans remain largely unknown. Copyright 2004 Elsevier Ltd.
Publication Types:
Review
Review, Tutorial
- guest
Re: COX-2 SELECTIVE NSAID COMMENTS AND CARPROFEN (RIMADYL) H
by brankalei@yahoo.com » Tue Jan 31, 2006 8:05 pm
- brankalei@yahoo.com
NSAIDs cause direct injury to the gastrointestinal tract
by malernee » Tue Jun 20, 2006 1:09 pm
Role of Nonsteroidal Anti-Inflammatory Drugs in Gastrointestinal Tract Injury and Repair
J Am Vet Med Assoc 222[7]:946-951 Apr 1'03 Topics in Drug Therapy 70 Refs
* Julia Tomlinson, BVSc, MS, DACVS, and Anthony Blikslager, DVM, PhD, DACVS
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606 [* address correspondence]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice for a variety of conditions including arthritis and colic in horses. However, it has been documented that NSAIDs cause direct injury to the gastrointestinal tract. This group of drugs has also been shown to inhibit healing of injured tissue in the gastrointestinal tract, suggesting caution should be used when treating animals with gastrointestinal disease. Nonsteroidal anti-inflammatory drugs cause injury to gastrointestinal mucosa in 2 ways: direct topical injury and inhibition of prostaglandin synthesis. Although NSAIDs are thought to interfere with mucosal protective mechanisms, such as optimal mucosal blood flow and mucus and bicarbonate secretion, the exact pathways of NSAID-induced injury have not been fully elucidated. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin production by acting on the cyclooxygenase (COX) enzyme. This enzyme converts arachidonic acid to prostaglandins. The enzyme has several iso-forms, including the "housekeeping" COX-1 and the inducible enzyme COX-2. The latter is upregulated by a variety of inflammatory stimuli, including bacterial lipopolysaccharide, and is constitutively expressed in select tissues (e.g., kidney). Nonsteroidal anti-inflammatory drugs that inhibit both COX isoforms inhibit the production of housekeeping prostaglandins and may render the gastrointestinal tract more susceptible to injury. Thus, the development of drugs that selectively inhibit inducible COX-2 has been hailed as the answer to preventing NSAID-induced gastrointestinal injury while inhibiting inflammation and providing analgesia; however, recent research has revealed a more complex picture.
______
Br J Surg. 2004 Dec;91(12):1613-8. Related Articles, Links
Comment in:
Br J Surg. 2005 Mar;92(3):378.
Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity.
Cahill RA, Sheehan KM, Scanlon RW, Murray FE, Kay EW, Redmond HP.
Department of Academic Surgery, Cork University Hospital, National University of Ireland (Cork), Cork, Ireland.
BACKGROUND: Selective inhibitors of inducible cyclo-oxygenase (COX-2) are of potential benefit in the perioperative period for both their analgesic and, perhaps, antineoplastic actions. However, their effects on laparotomy and intestinal wound healing are unknown. METHODS: Forty adult Sprague-Dawley rats underwent laparotomy, descending colonic transection and handsewn reanastomosis. The animals were randomized to receive either a selective COX-2 inhibitor (rofecoxib, 10 mg/kg) or an equal volume of water by gavage before operation and then daily after surgery. Animals were killed after 3 or 7 days, and their wounds were evaluated by means of tensiometry (skin and colonic wounds) and bursting pressure measurement (colonic anastomoses). In addition, haematoxylin and eosin-stained intestinal sections were examined and scored by a blinded independent observer. RESULTS: Five animals that received rofecoxib had anastomotic leaks by day 7 compared with none in the control group (P = 0.048). Intact colonic suture lines were also significantly weaker in this group (tensile strength at day 3, P = 0.043; bursting pressure on days 3 and 7, both P = 0.019). Skin wound strengths were similar in the two groups at both time points. CONCLUSION: Although beneficial in the treatment of pathological inflammation, selective COX-2 inhibitors may adversely affect colonic anastomotic healing. Copyright 2004 British Journal of Surgery Society Ltd.
________________
Br J Surg. 2006 Apr;93(4):489-97. Related Articles, Links
Selective cyclo-oxygenase 2 inhibition affects ileal but not colonic anastomotic healing in the early postoperative period.
de Hingh IH, van Goor H, de Man BM, Lomme RM, Bleichrodt RP, Hendriks T.
Department of Surgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
BACKGROUND: Selective cyclo-oxygenase 2 (COX-2) inhibitors are increasingly prescribed in the perioperative period. Recent recognition of a possible role for COX-2 in wound healing has raised concerns about the safety of their use in surgical practice. Therefore, the influence of celecoxib, a selective COX-2 inhibitor, on early anastomotic healing was investigated. METHODS: Celecoxib, in doses of 15, 50 or 200 mg per kg per day, was given daily from the day before operation onwards to male Wistar rats that received both ileal and colonic anastomoses. Anastomotic strength was assessed by measuring the breaking strength and bursting pressure on the third day after operation. A second group received a dose of 50 mg per kg per day and a colonic anastomosis only, and healing was assessed on the third and fifth day after surgery. RESULTS: Expression of COX-2 protein was upregulated in the anastomotic area. Administration of celecoxib, at all doses tested, resulted in a significantly higher ileal dehiscence rate than in control rats (P = 0.002). In contrast, colonic anastomoses healed normally within the same animals. The latter was confirmed in rats with colonic anastomoses only. CONCLUSION: In this model, administration of the COX-2 inhibitor celecoxib affected ileal but not colonic anastomotic healing in the early postoperative period.
J Am Vet Med Assoc 222[7]:946-951 Apr 1'03 Topics in Drug Therapy 70 Refs
* Julia Tomlinson, BVSc, MS, DACVS, and Anthony Blikslager, DVM, PhD, DACVS
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606 [* address correspondence]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice for a variety of conditions including arthritis and colic in horses. However, it has been documented that NSAIDs cause direct injury to the gastrointestinal tract. This group of drugs has also been shown to inhibit healing of injured tissue in the gastrointestinal tract, suggesting caution should be used when treating animals with gastrointestinal disease. Nonsteroidal anti-inflammatory drugs cause injury to gastrointestinal mucosa in 2 ways: direct topical injury and inhibition of prostaglandin synthesis. Although NSAIDs are thought to interfere with mucosal protective mechanisms, such as optimal mucosal blood flow and mucus and bicarbonate secretion, the exact pathways of NSAID-induced injury have not been fully elucidated. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin production by acting on the cyclooxygenase (COX) enzyme. This enzyme converts arachidonic acid to prostaglandins. The enzyme has several iso-forms, including the "housekeeping" COX-1 and the inducible enzyme COX-2. The latter is upregulated by a variety of inflammatory stimuli, including bacterial lipopolysaccharide, and is constitutively expressed in select tissues (e.g., kidney). Nonsteroidal anti-inflammatory drugs that inhibit both COX isoforms inhibit the production of housekeeping prostaglandins and may render the gastrointestinal tract more susceptible to injury. Thus, the development of drugs that selectively inhibit inducible COX-2 has been hailed as the answer to preventing NSAID-induced gastrointestinal injury while inhibiting inflammation and providing analgesia; however, recent research has revealed a more complex picture.
______
Br J Surg. 2004 Dec;91(12):1613-8. Related Articles, Links
Comment in:
Br J Surg. 2005 Mar;92(3):378.
Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity.
Cahill RA, Sheehan KM, Scanlon RW, Murray FE, Kay EW, Redmond HP.
Department of Academic Surgery, Cork University Hospital, National University of Ireland (Cork), Cork, Ireland.
BACKGROUND: Selective inhibitors of inducible cyclo-oxygenase (COX-2) are of potential benefit in the perioperative period for both their analgesic and, perhaps, antineoplastic actions. However, their effects on laparotomy and intestinal wound healing are unknown. METHODS: Forty adult Sprague-Dawley rats underwent laparotomy, descending colonic transection and handsewn reanastomosis. The animals were randomized to receive either a selective COX-2 inhibitor (rofecoxib, 10 mg/kg) or an equal volume of water by gavage before operation and then daily after surgery. Animals were killed after 3 or 7 days, and their wounds were evaluated by means of tensiometry (skin and colonic wounds) and bursting pressure measurement (colonic anastomoses). In addition, haematoxylin and eosin-stained intestinal sections were examined and scored by a blinded independent observer. RESULTS: Five animals that received rofecoxib had anastomotic leaks by day 7 compared with none in the control group (P = 0.048). Intact colonic suture lines were also significantly weaker in this group (tensile strength at day 3, P = 0.043; bursting pressure on days 3 and 7, both P = 0.019). Skin wound strengths were similar in the two groups at both time points. CONCLUSION: Although beneficial in the treatment of pathological inflammation, selective COX-2 inhibitors may adversely affect colonic anastomotic healing. Copyright 2004 British Journal of Surgery Society Ltd.
________________
Br J Surg. 2006 Apr;93(4):489-97. Related Articles, Links
Selective cyclo-oxygenase 2 inhibition affects ileal but not colonic anastomotic healing in the early postoperative period.
de Hingh IH, van Goor H, de Man BM, Lomme RM, Bleichrodt RP, Hendriks T.
Department of Surgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
BACKGROUND: Selective cyclo-oxygenase 2 (COX-2) inhibitors are increasingly prescribed in the perioperative period. Recent recognition of a possible role for COX-2 in wound healing has raised concerns about the safety of their use in surgical practice. Therefore, the influence of celecoxib, a selective COX-2 inhibitor, on early anastomotic healing was investigated. METHODS: Celecoxib, in doses of 15, 50 or 200 mg per kg per day, was given daily from the day before operation onwards to male Wistar rats that received both ileal and colonic anastomoses. Anastomotic strength was assessed by measuring the breaking strength and bursting pressure on the third day after operation. A second group received a dose of 50 mg per kg per day and a colonic anastomosis only, and healing was assessed on the third and fifth day after surgery. RESULTS: Expression of COX-2 protein was upregulated in the anastomotic area. Administration of celecoxib, at all doses tested, resulted in a significantly higher ileal dehiscence rate than in control rats (P = 0.002). In contrast, colonic anastomoses healed normally within the same animals. The latter was confirmed in rats with colonic anastomoses only. CONCLUSION: In this model, administration of the COX-2 inhibitor celecoxib affected ileal but not colonic anastomotic healing in the early postoperative period.
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