非甾体抗炎药的研究进展

传统非甾体抗炎药对环氧化酶的选择性较差,副作用明显,临床应用受限.近年来,一些疗效好、副作用低的新型非甾体抗炎药相继问世,应用于临床.本文主要综述了选择性COX-2抑制剂、一氧化氮释放型非甾体抗炎药以及选择性5-LOX/COX-2双重抑制剂三类非甾体抗炎药中的代表药物的研究进展.     

PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology

Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.     

Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs

OBJECTIVES: To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED: PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS: A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.     

Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology.

Uveitis is a common sequela to many ocular diseases. Primary treatment goals for uveitis should be to halt inflammation, prevent or control complications caused by inflammation, relieve pain, and preserve vision.Systemic and topical NSAIDs are essential components of the pharmaceutic armamentarium currently employed in the management of ocular inflammation by general practitioners and veterinary ophthalmologists worldwide. NSAIDs effectively prevent intraoperative miosis; control postoperative pain and inflammation after intraocular procedures, thus optimizing surgical outcome; control symptoms of allergic conjunctivitis;alleviate pain from various causes of uveitis; and circumvent some of the unwanted side effects that occur with corticosteroid treatment. Systemic NSAID therapy is necessary to treat posterior uveitis, because therapeutic concentrations cannot be attained in the retina and choroid with topical administration alone, and is warranted when diseases, such as diabetes mellitus or systemic infection, preclude the use of systemic corticosteroids.Risk factors have been identified with systemic and topical administration of NSAIDs. In general, ophthalmic NSAIDs may be used safely with other ophthalmic pharmaceutics; however, concurrent use of drugs known to affect the corneal epithelium adversely, such as gentamicin, may lead to increased corneal penetration of the NSAID. The concurrent use of NSAIDs with topical corticosteroids in the face of significant preexisting corneal inflammation has been identified as a risk factor in precipitating corneal erosions and melts in people and should be undertaken with caution[8]. Clinicians should remain vigilant in their screening of ophthalmic and systemic complications secondary to drug therapy and educate owners accordingly. If a sudden increase in patient ocular pain (as manifested by an increase in blepharospasm, photophobia, ocular discharge, or rubbing)is noted, owners should be instructed to contact their veterinarian promptly.     

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood

OBJECTIVE: To evaluate cyclooxygenase (COX) selectivity of several nonsteroidal anti-inflammatory drugs (NSAID) in canine blood in vitro. ANIMALS: 11 healthy adult male hound crosses. PROCEDURE: 9 NSAID were studied at 5 concentrations. Thromboxane B2 (TxB2) was assayed as a measure of COX-1 activity in clotted blood. Prostaglandin E2 (PGE2) was assayed as a measure of COX-2 activity in heparinized, lipopolysaccharide (LPS)-stimulated blood. All assays were competitive ELISA tests. Cyclooxygenase selectivity was expressed as a ratio of the concentration of an NSAID that inhibited 50% of the activity (IC50) of COX-1 to the IC50 of COX-2. A separate ratio of the concentration that inhibited 80% of COX activity (IC80) was also determined. A ratio of < 1.0 indicated selectivity for COX-1, whereas a ratio of > 1.0 indicated COX-2 selectivity. RESULTS: Ketoprofen, aspirin, and etodolac were COX-1 selective. Piroxicam, meloxicam, and carprofen had COX-2 selectivity. The IC50 and IC80 values were similar for most NSAID. CONCLUSIONS: This methodology provides repeatable data from individual dogs and is comparable to results of previous in vitro and ex vivo models. Findings are also consistent with those of canine studies performed in vivo, suggesting that this is a viable in vitro assessment of the COX selectivity of NSAID in dogs.     

Use of nonsteroidal anti-inflammatory drugs in food animal practice.

We attempted to determine the extent to which nonsteroidal anti-inflammatory drugs (NSAID) are used in the treatment of food animals, and whether withdrawal times for milk and slaughter are recommended to clients. A survey questionnaire was mailed to a stratified random sample of 2,000 veterinarians whose practices were at least half food animals. A cross-sectional study was used to examine the responses to determine whether differences existed on the basis of a respondent's geographic location, number of years since graduation from veterinary college, and percentage of practice devoted to beef and dairy cattle. The response rate was 71% (1,424/2,000). Of those practitioners responding, 93% (1,325/1,424) reported using NSAID, with approximately 57 (751/1,322), 24 (327/1,322), and 18% (244/1,322) of respondents reporting use more than once a week, once a week, and 1 to 2 times per month, respectively. Dairy practitioners reported more frequent use than did beef practitioners. Use of flunixin meglumine was reported more frequently than the use of aspirin, phenylbutazone, or dipyrone. Approximately 88% (1,146/1,306) of respondents that used NSAID did so in combination with antibiotics. Withdrawal times for milk and meat were made on the basis of guidelines for the antibiotic. When using NSAID alone, recommendations for withdrawal times for milk and meat varied extensively. Overall, practitioners indicated that NSAID were useful and necessary for the treatment of food-producing animals.     

Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species

The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t_1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vd_ss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (t_1/2β) were determined for this selected group of drugs by using the empirically determined function Y=a W^b. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally ‘well behaved’.     

非甾体类抗炎药前处理及检测方法研究进展

非甾体类抗炎药是目前兽医临床中使用最为广泛的一类药物,但此类药物在动物源性食品中的残留对人类的健康造成严重威胁。通过综述国内外非甾体类抗炎药在动物源性食品中的前处理方法和检测方法的研究现状,总结不同前处理方法的优缺点以及多种检测方法的灵敏度和准确性,对非甾体类药物的残留检测发展趋势进行展望,旨在为今后的检测方法开发提供参考。     

Transdermal fentanyl combined with nonsteroidal anti-inflammatory drugs for analgesia in horses

This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 microg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2+/-1.1 ng/mL (mean+/-SD) and a time to peak serum concentration of 26+/-13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P < .05), but lameness scores were not significantly different (P > .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.     

Interspecies allometric meta‐analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species

Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log‐log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross‐species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic.     

Pharmacodynamics and pharmacokinetics of phenylbutazone in calves

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.     

Pharmacodynamics and pharmacokinetics of flunixin in the cat

The non-steroidal anti-inflammatory agent (NSAID) flunixin was administered as single doses both orally and intravenously to six cats at a dose rate of 1.0 mg/kg in a two-part cross-over study. After oral dosing rapid absorption to a mean peak concentration of 2.586 micrograms/ml occurred at a mean time of 1.33 h. Similar mean plasma concentration-time AUC values for oral and intravenous dosing indicated that absorption by the former route was virtually complete. The decline in plasma concentration occurred fairly rapidly with both routes, and elimination half-life was approximately 1.0-1.5 h. The time course of inhibition of serum TXB2 concentration was similar for the two routes of administration, suggesting that similar dosing schedules are likely to be appropriate for evaluation of flunixin in clinical trials.     

Pharmacodynamics and pharmacokinetics of miloxicam in the horse

The novel non-steroidal anti-inflammatory drug (NSAID) miloxicam was administered intravenously to six New Forest ponies at a dosage rate of 0.6 mg/kg in a two-part cross-over study. In each part, three horses received miloxicam and three were given a placebo preparation. The actions of miloxicam, compared to placebo, were assessed in a carrageenan-sponge model of acute inflammation. The rise in skin temperature over the site of the acute inflammatory reaction was less in treated ponies, but differences were not statistically significant. Concentrations of the enzymes acid phosphatase (AP) and lysozyme in inflammatory exudates harvested at 4, 8, 12 and 24 h were not significantly different in drug-treated animals compared with those receiving placebo. Concentrations of protein and lactate dehydrogenase (LDH) in exudate and exudate leucocyte numbers were significantly reduced in drug-treated horses when data for all sampling times were pooled. The differences were not significant, however, at each sampling time. Exudate concentrations of the eicosanoids, bicyclic-PGE2, 6-keto-PGF1 alpha and TXB2, were reduced significantly by miloxicam at most sampling times, and serum TXB2 was also significantly reduced at 4 and 8 h but not at 12 and 24 h after drug administration. These pharmacodynamic findings correlated with the pharmacokinetic properties of miloxicam. The plasma concentration-time curve was defined by a three-compartment open model in one pony and by a two-compartment model in five ponies. Mean values for pharmacokinetic parameters for the five ponies were: t1/2 alpha 0.40 h; t1/2 beta 2.70 h; Vd area 0.158 l/kg; ClB 41.87 ml/kg/h. Exudate concentrations of miloxicam were initially similar to and eventually greater than concentrations in plasma, and this may explain the more prolonged inhibition of eicosanoid synthesis in exudate than in serum. These findings demonstrate the value of relating, in a single experimental study, drug action on a range of variables to drug fate in the body.     

Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep

OBJECTIVE: To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(-) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling. ANIMALS: 8 female Dorset crossbred sheep. PROCEDURE: A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP [3 mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg, IV),and R(-) KTP (1.5 mg/kg, IV). RESULTS: Both KTP enantiomers had elimination half-life and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(-) KTP Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP, but not R(-) KTP, also significantly inhibited PGE2 synthesis in exudate for 12 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.     

Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs

OBJECTIVE: To assess cyclooxygenase (COX) expression and prostanoid concentrations in pyloric and duodenal mucosae of dogs after administration of nonsteroidal anti-inflammatory drugs (NSAIDs). ANIMALS: 8 healthy dogs. PROCEDURES: Each dog received carprofen (4.4 mg/kg, q 24 h), deracoxib (2 mg/kg, q 24 h), aspirin (10 mg/kg, q 12 h), and placebo (1 dog treat, q 24 h) orally for 3 days (4-week interval between treatments). Before study commencement (baseline) and on day 3 of each treatment, pyloric and duodenal mucosal appearance was assessed endoscopically and biopsy specimens were obtained for histologic examination. Cyclooxygenase-1 and COX-2 protein expressions were assessed via western blotting, and prostanoid concentrations were measured via ELISAs. An ANOVA was used to analyze data. RESULTS: Treatments had no effect on mucosal appearance and ulceration was not evident histologically. In pyloric and duodenal mucosae, COX-1 expression was unaffected by treatments. Cyclooxygenase-2 expression remained unchanged in pyloric mucosa; in duodenal mucosa, aspirin significantly increased COX-2 expression, compared with effects of deracoxib and carprofen. At baseline, total prostaglandin and thromboxane B2 concentrations in pyloric mucosa were significantly greater than those in duodenal mucosa. Aspirin significantly decreased both prostanoid concentrations in both mucosal tissues, compared with other treatments. In pyloric mucosa, carprofen administration significantly decreased total prostaglandin and thromboxane B2 concentrations, compared with deracoxib administration. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, prostanoid synthesis was greater in pyloric mucosa than it was in duodenal mucosa. Nonselective NSAIDs significantly decreased prostanoid concentrations in these mucosae, compared with the effects of a selective COX-2 NSAID.     

基于非线性混合效应模型分析兽药药代动力学研究进展

利用数学建模分析兽药药代动力学历来已久。兽药药代动力学中应用数学建模和模拟分析可简化和加快兽药研发进程。非线性混合效应模型分析方法是兽药药代动力学建模和模拟的主要方法之一,该方法对临床合理用药、新药研发及评审更高效具有很大意义,同时阐明一些传统药动学无法回答的问题。本文综述了非线性混合效应模型在分析兽药药代动力学主要原理及应用进展,以期望非线性混合效应模型分析方法在我国新兽药研发与评审中应用提供积极有益的参考。