Карпрофен для кошек инструкция по применению

General information

The main adverse effects of the NSAID carprofen are cutaneous and hepatic. Photoreactions are being increasingly reported and its chemical similarity to benoxaprofen is worth noting [1,2]. The photosensitivity mechanism is either toxic or allergic. Other cutaneous symptoms, such as burning, pruritus, dermatitis, and skin redness, have also been reported [3]. In trials in the USA, 14% of 1500 patients had slight transient rises in liver function tests, the significance of which is unclear [4]. Headache, dizziness, gastrointestinal discomfort, and dysuria have also been described [3]. Asthma can be precipitated in aspirin-sensitive patients.

Carprofen

Carprofen can provide effective post-surgical pain relief in the dog, cat and rat (Nolan & Reid, 1993b; Slingsby and Waterman-Pearson, 2000; Roughan & Flecknell, 2001), and has also been used in a number of different species with apparent success (Allison et al., 2007; Paull et al., 2007). Both oral and injectable preparations are available. Recent studies have demonstrated efficacy following surgery in mice (Jirkof et al., 2010), but relatively high dose rates were needed to produce significant changes in the Mouse Grimace Scale (MGS)(Matsumiya et al., 2012).

Carprofen

(Rimadyl® and generic)

Carprofen is available throughout the world.

Nonsteroidal Antiinflammatory Drugs.

Ingestion of nonsteroidal antiinflammatory drugs (NSAIDs), such as phenylbutazone, aspirin, carprofen, flunixin meglumine, ibuprofen, and naproxen, has been associated with acute renal failure in small animals, especially dogs. In horses, NSAID toxicosis is usually associated with nonfatal renal papillary necrosis and mucosal ulceration (see the section on Papillary Necrosis). The mechanism of acute renal failure is related to NSAIDs decreasing the synthesis of renal prostaglandins. Because prostaglandins are responsible for maintaining normal renal blood flow, NSAID administration results in afferent arteriolar constriction that decreases renal perfusion, resulting in acute tubular degeneration and medullary papillary necrosis and acute renal failure. The overall incidence of NSAID-induced renal failure in small animals is low and is seen most commonly in animals that ingest excessive amounts of the drug or have a concomitant disorder such as dehydration, congestive heart failure, or chronic renal disease.

7.07.15.1 Carboxylic Acid Derivatives

Despite the moderate in vitro potency of 104 and 105, both compounds showed a robust reduction of Aβ₄₂ levels of 64% and 84%, respectively, when dosed at 10 mg kg^− 1 in APP-YAC transgenic mice, after 7 h p.o. administration. For compound 105, this effect was achieved at a brain concentration of 0.58 μM and a Br:Pl of 0.51. Moreover, 105 demonstrated a dose-dependent lowering of Aβ₄₂ in rats, when dosed orally, at 1, 3, 10, and 30 mg kg^− 1, and with an ED₅₀ = 5 mg kg^− 1, brain EC₅₀ = 1 μM, and plasma EC₅₀ = 3.7 μM. No adverse Notch effects were observed when 105 was tested in a 7-day oral rat safety study, at 250 mg kg^− 1 day^− 1.

10.16.9 Gastrointestinal Toxicoses Associated with Mucosal Metabolism

In Vivo Plasma Protein Binding

The in vivo formation of covalently bound plasma protein adducts by acyl glucuronides has now been demonstrated in humans for a large number of compounds, including beclobric acid [52], clofibric acid [5], carprofen [129], diclofenac [105], diflunisal [7], fenoprofen [124], gemfibrozil [158], ketoprofen [147], probenecid [7], salicylic acid [9], tolmetin [10,139], valproic acid [11], and zomepirac [138], and also to some extent for the acyl glucuronides of flunoxaprofen and benoxaprofen [68] and those of the oxidative metabolites of gemfibrozil [87], where covalent binding was significant for the dicarboxylic acid metabolite (M3) only [159]. Studies with repetitive gemfibrozil dosage in rats showed higher binding for the major gemfibrozil metabolite M3 than for the parent drug [87].

From these in vivo studies, the extent of protein binding of acyl glucuronides in vivo was found to correlate well with the extent of the exposure of acyl glucuronides, which is measured as the area under the curve (AUC). Increase in plasma glucuronide concentrations leads to higher covalent binding. Increased adduct formation can thus be expected during chronic dosage or with decreased renal clearance of the glucuronide, as in renal failure or resulting from a drug-drug interaction. Indeed, adduct concentrations in elderly patients treated with tolmetin were significantly higher than those in the control group of elderly patients given a single dose [139]. Significant accumulation of protein adducts of tolmetin has also been observed in healthy human volunteers after a 10-day multiple dosing regimen of tolmetin. The bound levels after administration of multiple doses were approximately 10-fold higher than those after a single dose was given to the same subjects [10]. Valproic acid adducts were measurable in the plasma of epileptic patients on chronic drug therapy [11]. Coadministration of probenecid and zomepirac resulted in an increase in the amount of covalent binding and an increase in exposure to zomepirac glucuronide plasma concentrations [160]. Covalent binding of diflunisal and probenecid has been investigated after administration of multiple doses of each drug. After a 6-day regimen in healthy human volunteers of oral diflunisal with concomitant administration of oral probenecid during the last 2 days, measurable covalent binding of both drugs via their acyl glucuronide metabolite has been observed [7]. Dong and Smith [161] showed that the incubation of benoxaprofen, flunoxaprofen, and ibuprofen (500 µM) in sandwich-culture rat hepatocytes resulted in a time-dependent increase in acyl glucuronides for all three profens, with benoxaprofen-acyl glucuronide concentrations higher than flunoxaprofen acyl glucuronide, while ibuprofen-acyl glucuronide was the lowest in concentration. Covalent binding was also shown to increase linearly with acyl glucuronide concentrations. When the acyl glucuronide concentrations were normalized to adduct formation, benoxaprofen-acyl glucuronide proved to be the most reactive, while ibuprofen-acyl glucuronide was the least reactive of the three examined compounds, which is consistent with the relative toxicity of these three drugs in patients.

4 Non-Steroidal Anti-Inflammatory Drugs

Numerous NSAIDs have been advocated for rabbits, but rigorous data are lacking. Some of the agents that have been advocated are aspirin (10 mg/kg SQ), acetaminophen-codeine at 1 ml drug/100 ml water, meloxicam, and carprofen (Lipman et al., 1997; 2008). In an experimental fracture model, both piroxicam and flunixin were shown to reduce limb swelling, but analgesic action was not independently evaluated (More et al., 1989). The cyclooxygenase inhibitor ketorolac tromethamine (Toradol; Roche Laboratories, Nutley, New Jersey) has been evaluated in the rabbit at various doses because of its antithrombotic effect (Shufflebarger et al., 1996; Delaporte-Cerceau et al., 1998). Unfortunately, analgesic activity independent of investigation of these antithrombotic and anti-inflammatory effects appears lacking. In another study using a rabbit model of acute temporomandibular joint inflammation, intraperitoneal and intra-articular administration of 50 μg of ketorolac decreased the generation of the inflammatory mediators, prostaglandin E₂, and bradykinin (Swift et al., 1998). The drug is well absorbed with no untoward effects related to ophthalmic, IM, or intranasal administration (Rooks et al., 1985; Santus et al., 1993). The COX-2 inhibitor meloxicam was evaluated for MAC-altering effects in isoflurane-anesthetized rabbits with or without concurrent butorphanol administration. No independent MAC-altering effects were observed, but meloxicam at 0.3 or 1.5 mg/kg augmented butorphanol-associated MAC reduction (Turner et al., 2006).

Postmarketing drug surveillance (pharmacovigilance)

Postmarketing surveillance of adverse drug reactions occurs in various forms: phase IV clinical trials, spontaneous reporting schemes, intensive monitoring within hospitals (uncommon in veterinary medicine), analysis of health registers (more relevant to human medicine) and prospective studies. ADR reports rarely indicate the need to remove the drug from the market but such reports may lead to changes in dose rate, additional labelling or further clarification of labelling, additional warnings, precautions and contraindications and formulation changes.

Phase IV clinical trials may be conducted by the manufacturer after marketing approval, take place under usual clinical use of the drug and usually do not include a control group. However, it has been demonstrated in human medicine that despite the relatively large size of the cohorts monitored in phase IV studies, spontaneous reporting methods were more likely to detect previously unsuspected ADRs.

Spontaneous ADR reporting schemes can involve reporting of suspected ADRs by practitioners and animal owners through a variety of mechanisms: case reports in the literature, submissions to ADR reporting centers (which may or may not involve regulatory authorities, depending on the country) and reporting directly to the manufacturer. In many countries, manufacturers are now required to report ADRs to appropriate regulatory authorities. Spontaneous reporting schemes are relatively inexpensive and potentially draw data from all patients taking the drug. However, underreporting is a serious disadvantage – it is estimated that more than 95% of ADRs go unreported.

The ADR reporting rate is low within the medical profession and almost certainly even lower within the veterinary profession. Even in countries where ADR reporting is mandatory, the reporting rate by medical practitioners remains low. An analysis of the attitudes of medical practitioners in South Africa to ADR reporting revealed that there were differences in reporting rates between groups within the profession (a larger number of medical specialists reported ADRs compared with general practitioners). Surgical specialists did not report any ADRs during the study (Robins et al 1987). The major reasons identified for failure to report ADRs were: the belief of the medical practitioners that unusual or serious reactions were infrequent; common or trivial ADRs did not warrant reporting; apathy; being too busy to fill in the paperwork. Fear of personal consequences (criticism and medicolegal action) was not deemed to be an important impediment to reporting. The authors concluded somewhat pessimistically that ‘the prognosis is poor (for improved ADR reporting) and it appears that, like all else which passes between doctors and their patients, ADRs will continue to remain largely outside the reach of an external agency’.

Similar studies have not been undertaken within the veterinary profession but there is no reason to assume that the attitudes of veterinarians to ADR reporting are radically better than those of their medical colleagues.

It is clear that the numbers of reports of suspected ADRs are incomplete and highly variable. Furthermore, there is both overascertainment (attribution of an adverse reaction to a drug when in truth it is not related) and underascertainment (failure to recognize that an adverse outcome is in truth an adverse drug reaction). Because of these important factors which influence the numerator and because the total number of times the drug is administered (the denominator) is unknown, it is not possible to calculate accurate rates of adverse reactions and there is no way to determine whether a given number of reports is smaller or larger than would be expected by chance. However, the value of spontaneous reporting programs is in signal detection, permitting hypotheses to be raised that can then be tested: some hypotheses will prove valid and others will not be confirmed. Pharmaco-epidemiology is the new discipline that has arisen to specialize in raising and testing such hypotheses.

Spontaneous reports are also constant reminders of the low frequency but expected adverse drug reactions that may be rarely encountered by individual practitioners – for example, anaphylactic reactions to routine vaccination, vomiting and diarrhea associated with almost any orally administered preparation.

Pain

Pain is a homeostatic mechanism that allows animals to recognize and avoid potential injuries. A painful experience may cause an animal to withdraw from a risky location and may also cause it to avoid that location in the future. Pain is hard to study and quantify because pain is a subjective human characterization of a response to bodily damage. Some scientists and philosophers argue that pain is restricted to humans because the experience of pain suggests self-knowledge or self-awareness of a type that might be restricted to humans. Yet even casual observations of injured mammals and birds suggest a commonality of experience, convincing most animal behaviorists that at least some vertebrates feel pain in the same way as humans do. Going beyond vertebrates, it is also reasonable to suspect some avoidance response to harmful stimuli on the part of most animals. Pain is emphasized here because of its link to the behavioral welfare of animals and the use of behavioral techniques for assessing pain in animals.

Pain can be subdivided into two categories. The first is sharp or immediate pain, which is the instant result of an injury such as a bite, sting, stepping on sharp object, and so on. These stimuli directly activate the nociceptive system and can cause a “reflex” avoidance action that is processed in the spinal cord, well before the signal reaches the brain. The second type of pain is due to inflammation of tissues. Inflammation is a complex immunological response including the dilation of small blood vessels that increases circulation to damaged tissue, but it has the additional adaptation of stimulating the perception of pain.