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Tolmetin sodium (TS) is a nonsteroidal anti-inflammatory drug (NSAID) indicated for treatment of musculoskeletal issues. As other NSAID, TS displays a marked side effects on the gastro-intestinal (GI) tract after oral administration. Traditional solid suppositories can cause pain and discomfort for patients, may reach the end of the colon; consequently, the drug can undergo the first-pass effect. TS liquid suppository (TS- LS ) was developed to enhance patient compliance and rectal mucosal safety in high-risk patients receiving highly NSAID therapy. This work was conducted to optimize and evaluate Poloxamer P407/P188-based thermoresponsive TS- LS by using mucoadhesive polymers such as methylcellulose (MC). TS- LS was prepared by cold method and characterized their in vitro physicochemical properties as gelation temperature (GT), gel strength, bioadhesive properties, and in vitro release. The safety of the prepared suppository on rectum, stomach, and liver was evaluated histologically. Pharmacokinetic analyses were performed to compare rectal TS- LS to orally Rhumtol ® capsules. The results showed that the optimized TS- LS ; composed of P407/P188/MC (21/9/0.5% w/w) displayed gelation at rectum temperature ∼32.90 °C, gel strength of 21.35 s and rectal retention force at the administration site of 24.25 × 10 2  dyne/cm 2 . Moreover, TS- LS did not cause any morphological damage to the rectal tissues. Pharmacokinetic parameters of optimized TS- LS formulation revealed 4.6 fold increase in bioavailability as compared to Rhumtol ® capsules. Taken together, the results demonstrated that liquid suppository is a potential and physically safe rectal delivery carrier for improvement rectal bioavailability and in vivo safety of TS.

Acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs have been implicated in drug toxicity. Zomepirac (ZP) is a non-steroidal anti-inflammatory drug that was withdrawn from the market because of anaphylactic reactions and renal injury. We recently established a novel mouse model of ZP-induced kidney injury by increasing zomepirac acyl-glucuronide (ZP-AG) concentration via pretreatment with tri-O-tolyl phosphate, a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine, a glutathione synthesis inhibitor. Although we have shown that ZP-AG is responsible for ZP-induced kidney injury in mice, the exact pathogenic mechanisms of ZP-induced kidney injury have not been investigated yet. In this study, we aimed to investigate the role of immune cells in the pathogenesis of ZP-induced kidney injury, as a representative of AG toxicity. We found that the counts of neutrophils and inflammatory monocytes increased in the blood of mice with ZP-induced kidney injury. However, clodronate liposome- or GdCl 3 -induced monocyte and/or macrophage depletion did not affect blood urea nitrogen and plasma creatinine levels in mice with ZP-induced kidney injury. Neutrophil infiltration into the kidneys was observed in mice with ZP-induced kidney injury, whereas anti-lymphocyte antigen 6 complex, locus G (Ly6G) antibody pretreatment prevented the renal neutrophil infiltration and partially protected against ZP-induced kidney injury. The mRNA expression of neutrophil-infiltrating cytokines and chemokines, interleukin-1α and macrophage inflammatory protein-2α, increased in mice with ZP-induced kidney injury, whereas pretreatment with anti-Ly6G antibody resulted in a marked reduction of their expression. These results suggest that ZP-AG might be involved in kidney injury, partly via induction of neutrophil infiltration. Therefore, this study may provide an important understanding on toxicological role of ZP-AG in vivo that helps to understand toxicity of AG metabolites., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by cotreatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers, such as the glutathione/disulfide glutathione ratio and malondialdehyde levels, were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive. Here, 13 drugs with a carboxylic acid moiety were incubated with human liver microsomes to produce acyl glucuronide conjugates for the determination of acyl glucuronide half-lives by acyl migration and with HepaRG cells to monitor the formation of acyl CoA conjugates, their further conjugate metabolites, and trans-acylation products with glutathione. Additionally, in vitro cytotoxicity and mitochondrial toxicity experiments were performed with HepaRG cells to compare the predictability of toxicity. Clearly, longer acyl glucuronide half-lives were observed for safe drugs compared to drugs that can cause IDT. Correlation between half-lives and toxicity classification increased when "relative half-lives," taking into account the formation of isomeric AG-forms due to acyl migration and eliminating the effect of hydrolysis, were used instead of plain disappearance of the initial 1-O-β-AG-form. Correlation was improved further when a daily dose of the drug was taken into account. CoA and related conjugates were detected primarily for the drugs that have the capability to cause IDT, although some exceptions to this were observed. Cytotoxicity and mitochondrial toxicity did not correlate to drug safety. On the basis of the results, the short relative half-life of the acyl glucuronide (high acyl migration rate), high daily dose and detection of acyl CoA conjugates, or further metabolites derived from acyl CoA together seem to indicate that carboxylic acid-containing drugs have a higher probability to cause drug-induced liver injury (DILI).

The formation of reactive oxygen species (ROS) could cause cellular damage and eventually lead to apoptosis and necrosis. The ratio between oxidized glutathione and reduced glutathione (GSSG-to-GSH ratio) has been used as an important in vitro and in vivo biomarker of the redox balance in the cell and consequently of cellular oxidative stress. This paper optimizes a LC-MS/MS method for the simultaneous determination of GSH and GSSG. The proposed method is based on the derivatization of reduced GSH using iodoacetic acid (IAA) in order to prevent its rapid oxidation to GSSG during sample preparation. The optimized analytical method was applied to evaluate the effect of different pharmaceutical agents on GSSG-to-GSH ratio in cryopreserved rat and human hepatocytes in culture. Hepatocyte viabilities were also determined at the same time by using the WST-1 assay as a direct measurement of cell mitochondrial respiration. The results obtained demonstrate that cryopreserved rat and human hepatocytes in culture are reliable in vitro models for the evaluation of cellular oxidative stress. In addition, the GSSG-to-GSH ratio measurements could be a biomarker of hepatotoxicity providing similar results to those of cytotoxicity assay., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. However, this group of drugs is associated with serious adverse drug reactions. Previously, we studied the mechanisms underlying toxicity of the NSAID diclofenac using Saccharomycescerevisiae as model system. We identified the involvement of several mitochondrial proteins, a transporter and cytochrome P450 activity in diclofenac toxicity. In this study, we investigated if these processes are also involved in the toxicity of other NSAIDs. We divided the NSAIDs into three classes based on their toxicity mechanisms. Class I consists of diclofenac, indomethacin and ketoprofen. Mitochondrial respiration and reactive oxygen species (ROS) play a major role in the toxicity of this class. Metabolism by cytochrome P450s further increases their toxicity, while ABC-transporters decrease the toxicity. Mitochondria and oxidative metabolism also contribute to toxicity of class II drugs ibuprofen and naproxen, but another cellular target dominates their toxicity. Interestingly, ibuprofen was the only NSAID that was unable to induce upregulation of the multidrug resistance response. The class III NSAIDs sulindac, ketorolac and zomepirac were relatively non-toxic in yeast. In conclusion, we demonstrate the use of yeast to investigate the mechanisms underlying the toxicity of structurally related drugs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Hepatic tryptophan 2,3-dioxygenase (TDO) is one of the rate-limiting enzymes in tryptophan catabolism and plays an important role in regulating the physiological flux of tryptophan into relevant metabolic pathways. In this study, we determined the effect of the non-steroidal anti-inflammatory agents, tolmetin and sulindac, on rat liver TDO activity and the subsequent changes in the hippocampal and striatal neurotransmitter levels. The amount of melatonin produced by the pineal gland was also measured using high performance liquid chromatography (HPLC). Treatment of rats with tolmetin or sulindac (5 mg/kg/bd for 5 days) significantly inhibited liver TDO activity. The results show that whilst tolmetin and sulindac increase serotonin levels in the hippocampus, these agents also significantly reduce dopamine levels in the striatum. Tolmetin, but not sulindac, increased the amount of melatonin produced by the pineal gland. The results of this study suggest that whilst tolmetin and sulindac may be beneficial for patients suffering from depression, these agents also have the potential to induce adverse effects in patients suffering with neurological disorders such as Parkinson's disease.

Celosomy is a term used for a group of congenital anomalies characterized by opening of the somatic wall with evisceration. The most common types of celosomy are gastroschisis and omphalocele. They have been associated with maternal age, cigarette smoking, environmental pollution, as well as prenatal exposure to vasoconstrictors and recreational drugs. The aim of this study was to evaluate the effect of prenatal exposure to various selective and non-selective cyclooxygenase-2 (COX-2) inhibitors on the abdominal wall defects in rat. A retrospective statistical analysis was performed on the basis of data collected in our laboratory in the years 1997-2004, during different teratological studies with COX-inhibitors (aspirin, DFU, DuP-697, ibuprofen, paracetamol, piroxicam, propyphenazone, tolmetin). Out of 6744 live born fetuses celosomy was revealed only in four animals exposed to different non-selective COX inhibitors. A single case of gastroschisis was also found in a rat exposed to the selective COX-2 inhibitor. The fetal body weight was significantly lower in COX-exposed group of fetuses when compared with untreated control. It was also significantly decreased in non-malformed fetuses prenatally exposed to COX inhibitors when compared with untreated control. The fetal body weight and length were lower in fetuses born with gastroschisis than with omphalocele. However, when animals with both anomalies were pooled in one group the mean fetal body weight was marginally lower (p = 0.0523) when compared with non-malformed group, while no statistically significant differences were found for fetal length. The pooled statistical analysis done for the concurrent and our own historic data showed that only aspirin statistically increased the risk of abdominal wall defects in rat fetuses. The expected ratio for aspirin is 56.41 per 10,000 offsprings (p < 0.05), which is over 10-times higher than ratio for all non-selective COX inhibitors, including aspirin (6.01/10,000; p < 0.05). No differences were found for selective COX-2 inhibitors. It could be stressed that aspirin, unlike other non-selective and selective COX-2 inhibitors increases the risk of the abdominal wall defects, which are observed more often in growth-retarded fetuses.

Zomepirac [ZP, 5-(chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid] was withdrawn from the market because of unpredictable allergic reactions that may have been caused by ZP-protein adducts formed by reaction of the reactive acyl glucuronide of ZP (ZP-O-G) with endogenous proteins. To test the hypothesis that the reactive ZP acyl coenzyme A thioester (ZP-CoA) was formed and potentially could contribute to formation of ZP-protein adducts, we investigated the acyl CoA-dependent metabolism of ZP in freshly isolated rat hepatocytes (1 mM) and in vivo (100 mg ZP/kg, ip) in rat livers (2 h after dose administration), rat bile (0-4 h), and rat urine (0-24 h). ZP-CoA was detected in freshly isolated hepatocytes and in vivo in rat livers by LC/MS/MS. In addition, the ZP glycine conjugate (ZP-Gly) and ZP taurine conjugates (ZP-Tau) were identified by LC/MS/MS in rat hepatocytes and in vivo in rat livers, rat urine, and rat bile. The identities of ZP-CoA, ZP-Gly, and ZP-Tau were confirmed by comparison of retention times and MS/MS spectra with those of authentic standards. Moreover, the ZP acyl carnitine ester was detected in rat urine and rat bile based upon (i) the chlorine isotope pattern, (ii) MS/MS spectra showing significant ions characteristic for carnitine (m/z 60, 144 and loss of m/z 59) and ZP (m/z 139), and (iii) accurate mass measurements with a mass accuracy of 0.2 ppm. ZP-CoA serves as an obligatory intermediate in the formation of ZP-Gly, ZP-Tau, and ZP carnitine ester, and it is therefore of mechanistic significance that these conjugates were identified. Finally, time-dependent concentration profiles obtained in experiments with rat hepatocytes and in vivo from quantitative analysis of rat livers indicate that ZP-CoA, in addition to ZP-O-G, may contribute to formation of the potentially toxic covalent ZP-protein adducts.

Background: Ibuprofen and tolmetin are popular non-steroidal anti-inflammatory drugs. Previous animal studies taken with single daily doses showed their good prenatal tolerability. However, since both cyclooxygenase (COX) inhibitors have a short half-life, the current report presents drug developmental effects after triple daily doses administration, as they are used in human., Methods: Drugs were separately, orally dosed to pregnant rats triple daily 8 hr apart from day 8 to 21 (GD=1-plug day). The total daily doses were set at 25.5, 255.0, and 600.0 mg/kg for ibuprofen and 25.5, 255.0, and 2550.0 mg/kg for tolmetin. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done., Results: Maternal toxicity and intrauterine growth retardation were found in groups exposed to the highest doses of both drugs. An increase of external variations was reported in groups exposed to the middle and highest dose of ibuprofen and to the highest dose of tolmetin. Skeletal variations were significantly different only in litters treated with the highest doses of the drugs. Pooled statistical analysis showed a higher incidence of midline and ventricular septal (VSD) defect in rat fetuses exposed to COX inhibitors when compared with historical control data. For ibuprofen, the influence on VSD was similar to aspirin., Conclusion: Both COX inhibitors were toxic to dams in the highest doses evaluated, which caused a significantly greater incidence of intrauterine growth retardation and developmental variations., (2004 Wiley-Liss, Inc.)

Using current animal models, it is not possible to identify low-molecular-weight compounds (LMWCs) that are likely to be associated with anaphylaxis. It is generally accepted that the ultimate effector mechanism involves drug-induced IgE antibody. The objective of the present study was to determine if diclofenac, zomepirac and glafenine, which are associated with anaphylaxis in humans, have immunostimulating potential in the murine TNP-OVA (trinitrophenyl-ovalbumin) popliteal lymph node assay (PLNA), and more specifically to determine if the immunostimulation caused by these LMWCs results in IgE antibody production. These LMWCs were chosen because both zomepirac and glafenine were removed from the market due to high association with anaphylaxis, and diclofenac, which remains on the market, is frequently associated with anaphylaxis. In addition to conducting a TNP-OVA PLNA, the immunostimulating potential of these compounds was examined in the direct PLNA. When co-administered with TNP-OVA, all three LMWCs caused dose-dependent (0.25, 0.50, 1.00 and 1.25 mg) increases in popliteal lymph node (PLN) weight and cellularity that were observed beginning with the 0.25-mg dose. In addition, beginning with the 0.25-mg dose, all three compounds caused dose-dependent increases in TNP-OVA specific IgM and IgG(1) antibody-forming cells (AFCs). Diclofenac induced an isotype switch and caused a dose-dependent increase in the number of IgE AFCs with no detectable IgG(2a) AFCs and minimal high-dose-only IgG(2b) AFCs. Zomepirac induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50 mg only, and glafenine induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50-1.00 mg. In the direct PLNA, diclofenac caused dose-dependent increases in PLN weight and cellularity that were observed beginning with dose of 0.50 mg, whereas zomepirac failed to increase any PLN parameter and glafenine only increased the PLN weight. These results suggest that diclofenac, zomepirac and glafenine are immunostimulating LMWCs in the TNP-OVA PLNA with the potential to induce IgE antibody against a co-administered hapten-conjugate. Furthermore, these results suggest that the TNP-OVA PLNA offered significant advantages over the direct PLNA. Although it is not realistic to suggest that a single assay, based on a low number of test compounds, can identify all LMWCs with the potential to cause anaphylaxis in humans, these observations do demonstrate the potential utility of the PLNAs in examining LMWC-induced immunomodulation and support further development and investigation of the assays., (Copyright 2002 John Wiley & Sons, Ltd.)

Non-steroidal anti-inflammatory drugs (NSAIDs) cause a range of adverse effects, some of which have been associated with perturbances of lipid metabolic pathways. Previous data demonstrating stereoselective formation of the CoA thioester of R-ibuprofen in particular were suggestive of possible stereoselective effects on lipid metabolism. Our aim was to characterise the relative stereoselectivity of the effects of ibuprofen, flurbiprofen, and ketorolac (0.01-1.0 mM) on both the beta-oxidation of palmitate and oxidative phosphorylation in rat hepatic mitochondria as a means of dissecting prostaglandin related from non-prostaglandin-related events. Beta-oxidation was inhibited stereoselectively by R-ibuprofen (P = 0.015), non-stereoselectively by R- and S-flurbiprofen (P = 0.002 and P = 0.004, respectively), and was essentially unaffected by either enantiomer of ketorolac. At 0.25 mM, inhibition by R-ibuprofen and both flurbiprofen enantiomers was partially reversed by increasing CoA concentrations (0-200 microM). Mitochondrial respiration was moderately inhibited by both enantiomers of ibuprofen and flurbiprofen (P < 0.01), but only by high concentrations (> or = 1 mM) of the enantiomers of ketorolac (P < 0.01). Uncoupling of oxidative phosphorylation measured as stimulation of State 4 respiration contributed to these effects. The data support interactions involving both stereoselective CoA-dependent and non-CoA-dependent mechanisms. The plasma drug concentrations required to achieve these effects are not likely to be attained in the majority of patients, although these concentrations are achievable in the gastrointestinal tract and may contribute to the well-known spectrum of adverse effects in this organ. Some patients do experience systemic adverse events which may be mediated by these mechanisms.

To determine the stereospecific pharmacokinetics and gastrointestinal permeability (GI) changes (surrogate measures of toxicity) in the rat following oral administration of S, R, and racemic ketorolac (KT), optically pure enantiomers (S and R 2.5 mg/kg), and racemic KT (5 mg/kg) were administered orally to male Sprague-Dawley rats and plasma samples were collected for 6 h post-dose for pharmacokinetic assessments. KT-induced changes in GI permeability were assessed using sucrose and 51Cr-EDTA as markers of gastroduodenal and distal intestinal permeability, respectively. After the racemate, R-KT was predominant in plasma (AUC S/R, 0.45). No significant differences in pharmacokinetic indices were evident following administration of the racemate as compared with individual enantiomers. In plasma, there was only negligible S-KT after administration of R-KT. After S-KT, on the other hand, AUC of R-KT was found to be 6.7% of that of S-KT. Both permeability markers showed considerable interanimal variability. Gastroduodenal permeability was significantly increased from baseline by the racemate but not by either of the two enantiomers administered alone. Permeability to 51Cr-EDTA was not significantly increased above baseline for any of the treatments. The plasma concentration of R-KT found after administration of S-KT may be from the < 2% chiral impurity which appears magnified due to its slower clearance as compared with its antipode. There is no evidence of a pharmacokinetic interaction between the enantiomers. Since 2.5 mg/kg S-KT is somewhat less toxic on the gastroduodenum than 5 mg/kg racemate, it may be a safer alternative to the latter, at least in the rat model.

We have investigated the effects of intra-articular (i.a.) administration of ketorolac in the rat knee joint. Thirty Sprague-Dawley rats were given 0.25 ml of a standard preparation of ketorolac trometamol (10 mg ml-1) by injection into the right knee joint and 0.25 ml of 0.9% physiological saline solution by injection into the left knee as a control. Ten rats were killed at 24 h, 10 at 48 h and 10 at 5 days after injection. The joints were prepared and sectioned for histological examination. There was significantly more inflammation in those knees that had received i.a. ketorolac at all times of examination, with the most severe changes occurring 5 days after injection. A further group of 10 rats were given 0.25 ml of 10% w/v ethanol in physiological saline (similar to the vehicle for parenteral ketorolac) injected into the knee joint, with a 0.9% saline control injected in the other knee. These rats were then killed at 5 days (as this was the time interval after which we found the maximum inflammatory response in the earlier phase of our study). The joints were prepared and examined histologically. We feel that the absence of inflammatory changes in these joints make it unlikely that ethanol was responsible for the inflammation produced by ketorolac injection.

Unlabelled: Nonsteroidal antiinflammatory drugs (NSAIDs) are useful for the treatment of postoperative pain, but there is continuing concern about adverse effects on renal function. We studied the renal effects of ketorolac in an animal model using Fischer 344 rats undergoing isoflurane anesthesia and laparotomy. Treatment groups--control (C), ketorolac (5 mg x kg(-1) x d(-1)) (K), large-dose ketorolac (15 mg x kg(-1) x d(-1)) (KH), dehydration-ketorolac (5 mg x kg(-1) x d(-1)) (DK), gentamicin (20 mg x kg(-1) x d(-1)) (G), and gentamicin (20 mg x kg(-1) x d(-1)) with ketorolac (5 mg x kg(-1) x d(-1)) (GK)--each comprised 10 animals. Renal function was assessed before laparotomy and after 3 treatment days using concurrent paraaminohippurate and iothalamate clearances, respectively, to estimate renal plasma flow and glomerular filtration rate, and by measuring serum and urine electrolytes, osmolality, urea, and creatinine. A significant increase in serum potassium was found in the GK and DK groups. There were no major changes in renal function in the C, K, KH, and DK groups. Mild renal dysfunction was found in the G group. We found severe and consistent changes in renal function, accompanied by severe, widespread histological changes of acute tubular necrosis, in the GK group. In this postoperative rat model, the combination of ketorolac and gentamicin was deleterious to renal function., Implications: We examined the renal effects of the nonsteroidal antiinflammatory drug ketorolac. Renal function was measured in rats before and after surgery and 3 days' drug administration; the kidneys studied by using microscopy. Only ketorolac plus the antibiotic gentamicin produced marked changes in kidney function and structure.

This article systematically examines government regulation of medicines in the U.K. and the U.S. with specific reference to carcinogenic risk assessment. By taking four non-steroidal anti-inflammatory drugs (NSAIDs) as case studies, it is argued that there have been inconsistencies between regulatory practice and the scientific standards supposed to have been upheld by drug regulatory agencies. Moreover, those inconsistencies are shown to form a trend over time which suggests an erosion and neglect of regulatory rigour during the 1980s. This takes the form of awarding the benefit of the many scientific doubts in carcinogenicity testing to manufacturers rather than to patients.

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

Antinociceptive activity of intracerebroventricularly administered ketorolac tromethamine was evaluated in mice by measuring inhibition of abdominal stretching induced by p-phenylquinone. Ketorolac tromethamine produced dose-dependent antinociception with an ED50 of 7.34 micrograms/mouse (4.97-10.82) and a maximal effect at 30 micrograms. Selective antagonists of opioid receptors were used to determine ketorolac's mechanism of action. The ketorolac tromethamine-induced antinociception was not blocked by the mu- and delta-opioid receptor antagonists, naloxone and ICI-174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu), respectively; however, the kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride significantly blocked this effect. These findings suggest that activation of kappa-opioid receptors appears to play a role in the mechanism of the antinociceptive effect of ketorolac tromethamine. Ketorolac tromethamine may induce the release of endogenous kappa-opioids to produce central nervous system antinociception.

Ketorolac tromethamine is a relatively new non-steroidal anti-inflammatory drug (NSAID), with potent analgesic activity. Similar to other NSAIDs, ketorolac has the potential to impair renal function. To assess the renal hemodynamic impact of the ketorolac in aged lean and obese rats, ketorolac was orally administered to 46-week-old lean and obese Zucker rats for two weeks. Ketorolac was mixed with rat chow in a manner to provide a dose equivalent to 15 mg/kg body weight/day. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured under anesthesia by standard inulin and p-aminohippuric acid clearance method, respectively. Urinary prostaglandin (PG) E2 excretion was measured before and after ketorolac treatment. Ketorolac treatment significantly reduced obese rat GFR (0.47 +/- 0.08 vs 0.78 +/- 0.03 ml/min/g, p < 0.002) and ERPF (1.12 +/- 0.14 vs 2.36 +/- 0.26 ml/min/g, p < 0.001) relative to obese control rats. In comparison, ketorolac did not significantly alter lean rats GFR (0.77 +/- 0.04 vs 0.91 +/- 0.06 ml/min/g) or ERPF (1.92 +/- 0.20 vs 2.48 +/- 0.15 ml/min/g) relative to lean control rats. Chronic ketorolac treatment significantly reduced hematocrit by 20 and 30 percent in lean and obese rats relative to controls, respectively. The renal vascular resistance was significantly increased with ketorolac treatment in obese rats (36 +/- 4 vs 79 +/- 14 mmHg/ml/min, p < 0.001) but not lean rats (28 +/- 3 vs 38 +/- 5 mmHg/ml/min, NS) relative to corresponding controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The local tolerance of ketorolac tromethamine (Toradol, Syntex) was compared with that of four other injectable nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac sodium, piroxicam, ketoprofen, and metamizol magnesium) in the rat paw-lick/muscle irritation assay as described previously. All drugs were tested at concentrations approved for clinical use. After subplantar (footpad) injection, ketorolac produced virtually no pain-on-injection as assessed by the number of paw-lick/lift responses during a 15 min observation period. The other NSAIDs produced slight to moderate paw-lick/lift responses. Redness and swelling at the injection site were less severe for ketorolac than for the other NSAIDs. After intramuscular (i.m.) injection, all of the NSAIDs produced some degree of muscle damage, as assessed histopathologically 24 h after injection. The lesions, consisting primarily of muscle degeneration, were less severe for ketorolac than for the other NSAIDs. Ketorolac and metamizol produced the smallest elevations in serum creatine kinase, as measured 2 h after i.m. dosing, not significantly different from isotonic saline. Overall, ketorolac was better tolerated in the assay than the other injectable NSAIDs, thereby suggesting the possibility of improved local tolerance on clinical use.

In this study the pharmacological evaluation of MED-15, a non-acidic prodrug of tolmetin, is described. After oral administration the new compound shows a marked anti-inflammatory activity similar to that of tolmetin, but with minor ulcerogenic action and lower acute toxicity.

Ketorolac tromethamine is a highly potent member of a class of compounds having both analgesic and antiinflammatory activity. In animal pain models using underlying inflammation, ketorolac markedly inhibited the pain response and increased the pain threshold; it did not exhibit any narcotic or central nervous system depressant effects. It was also active in rat models of acute and chronic inflammation and pyresis. These activities are mediated primarily by potent prostaglandin cyclooxygenase inhibitory activity. Mild central nervous system and cardiovascular effects occurred only at doses far greater than those required for analgesic and antiinflammatory activity. Solutions of ketorolac tromethamine are not irritating. When given intramuscularly to rabbits (0.31-5% solutions), no drug-related irritation or changes in serum creatine phosphokinase were seen. The agent was not irritating when applied to the skin or eyes (less than or equal to 0.5% solutions) of animals.

The toxic effects of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) were endoscopically evaluated in several studies conducted between 1975 and 1983 and involving 843 normal volunteers. Anti-inflammatory doses of acetylsalicylic acid (2,400 and 3,900 mg/day) consistently produced significantly more mucosal injury than did any of the newer NSAIDs. Buffering did not reduce the degree of damage. Little or no mucosal injury was seen with placebo, "pro drugs," enteric-coated aspirin, or 1,200 mg/day of ibuprofen (Motrin, Upjohn). However, varying degrees of generally dose-dependent mucosal injury were evident with larger doses of ibuprofen, naproxen, tolmetin sodium, and indomethacin. The amount of mucosal damage after 2,400 mg/day of ibuprofen did not increase when 4,800 mg daily was administered. Duodenal injury corresponded to gastric injury, but it was generally less severe. Short-term studies of one to three days indicated that ibuprofen produced little or no injury when given at a dose of 2,400 mg for one day or 1,600 mg/day for three days. No relation was noted between subjective symptoms and endoscopic findings.

The glycine amide of tolmetin sodium (TGA) functions as a prodrug and was demonstrated to be more potent than the parent compound as an inhibitor of developing and established adjuvant arthritis in the female Lewis rat. In contrast, the glycine amide of indomethacin was less potent than indomethacin. The superiority of TGA relative to tolmetin sodium in alleviating this condition was demonstrated by inhibition of paw swelling and reduction of the degenerative bone changes that are associated with the progression of this chronic animal model of rheumatoid arthritis in humans. These properties were not evident when equimolar mixtures of tolmetin sodium and glycine were administered concurrently. Pharmacokinetic analyses revealed that TGA was absorbed completely and hydrolyzed to tolmetin in the female adjuvant arthritic rat. The combined effects of absorption, distribution and hydrolysis of TGA produced lower peak plasma tolmetin levels than an equivalent dose of tolmetin sodium, but plasma concentrations were sustained for a longer period of time contributing to an apparent increase in potency. Furthermore, TGA displayed a decreased propensity to cause gastrointestinal irritation compared to tolmetin sodium. Several additional amino acid amides of tolmetin were similar to the glycine amide in exhibiting increased potency and reduced gastrointestinal toxicity in comparison to equivalent doses of tolmetin sodium.

Ninety normal volunteers were entered into a double-blind, placebo-controlled study to compare the efficacy of misoprostol (200 micrograms q.i.d.) vs. cimetidine (300 mg q.i.d.) in protecting the gastric and duodenal mucosa from tolmetin-induced (400 mg q.i.d.) injury. After 6 days of treatment, the degree of mucosal injury between treatments was compared by endoscopy, using a predetermined rating scale of 0 (normal mucosa) to 4+ (greater than 25 hemorrhages or erosions or an invasive ulcer). Utilizing a score of less than or equal to 2+ (2-10 hemorrhages or erosions) as a therapeutic success, the overall success rates were 8/30 (26.7%) for placebo, 19/30 (63.3%) for cimetidine, and 27/29 (93.1%) for misoprostol (p less than 0.001). Pairwise comparisons were also significant: misoprostol vs. placebo (p less than 0.001), misoprostol vs. cimetidine (p = 0.006), and cimetidine vs. placebo (p = 0.004). A separate analysis of the gastric scores alone revealed success rates identical to those in the overall evaluation; however, success rates in the duodenum for both misoprostol (29/29) and cimetidine (29/30) were extremely high and did not differ. It is concluded that misoprostol is highly effective and significantly better than cimetidine in protecting the gastric mucosa from tolmetin-induced injury; however, both agents were highly protective in the duodenum.

Ketorolac tromethamine[(+/-)-5(benzoyl)-2,3-dihydro-1N-pyrrolizine-1-carboxylic acid tris hydroxymethylaminomethane salt] is a highly potent member of a new class of compounds having analgesic and anti-inflammatory activity. When given orally in tests involving underlying inflammation it was a potent analgesic, whereas it was inactive in tests for narcotic activity. It was also highly active orally in rat models of acute and chronic inflammation and pyresis. These properties are mediated primarily via the compound's potent prostaglandin cyclooxygenase inhibitory activity. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity. A single 10 mg tablet given orally to human volunteers following surgery provided pain relief equivalent to that provided by 10 mg of morphine given intramuscularly. When given intramuscularly to rabbits (0.25 ml of a 0.31-5% solution) or man (3 ml of a 1-3% solution), no drug-related irritation or changes in creatine phosphokinase were seen. Solutions (less than or equal to 0.5%) applied to the eyes of animals and man were not irritating. When applied topically in rat and rabbit models of ocular inflammation, less than or equal to 0.5% solutions of ketorolac tromethamine inhibited the inflammatory response.

RS-37619 showed highly potent analgesic activity when given p.o. in tests utilizing underlying inflammation. It inhibited phenylquinone-induced writhing in the mouse and rat (350 and 180 x aspirin respectively) and the pain induced by flexing the adjuvant-inflamed rat paw (approximately 800 x aspirin). The agent increased the pain threshold of compressed yeast-inflamed rat paws (3-10 x naproxen). RS-37619 did not increase the pain threshold of the non-inflamed paw and was inactive in the mouse hot plate test; therefore it is probably not a centrally acting or morphine-like agent. RS-37619 was also highly active p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (36 x phenylbutazone), cotton pellet-induced granuloma (less than or equal to 1 x indomethacin) and in an 18-day test, prevented the development of adjuvant-induced arthritis (approximately 2 x naproxen). RS-37619 exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. When given p.o., RS-37619 lowered yeast-induced pyrexia (20 x aspirin). Gastrointestinal irritation was seen in the rat with doses greater than or equal to 6.4 mg/kg/day p.o. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity.

Antiinflammatory, analgesic, antipyretic and gastrointestinal ulcerogenic activities of 4-acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole)acetate (AU 8001), a new nonsteroidal antiinflammatory drug, have been investigated and compared with those of tolmetin at equimolar doses in experimental animals. 1. AU 8001 showed inhibitory action on acute and subacute inflammation such as carrageenin hind paw edema and pellet-induced granuloma formation, with an activity similar to that of tolmetin. However, AU 8001 was more active as an antiarthritic agent than tolmetin. AU 8001 had no topical antiinflammatory effect. 2. The analgesic activities of AU 8001 measured by the writhing test and the Randall-Selitto method were comparable to those of tolmetin. Both compounds were ineffective in the hotplate test. 3. AU 8001 also had antipyretic activity but its potency was inferior to tolmetin and acetylsalicylic acid (ASA). 4. AU 8001 elicited almost negligible side effects in the gastrointestinal tract. The ulcerogenic activity of AU 8001, in particular, was extremely weak in relation to tolmetin, indometacin and ASA. 5. AU 8001 caused no appreciable changes in the general behaviour of animals after oral administration.

The comparative gastrointestinal (GI) tolerability of 4'-acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole) acetate (AU-8001), tolmetin and placebo have been studied in rat through a radioactive quantification method with Fe-59 of the GI microbleeding. The drugs were given orally at equimolecular doses of AU-8001 and sodium tolmetin equivalent to 100 mg/kg/day of tolmetin acid. Four days administration of sodium tolmetin induced significant increases of fecal radioactivity (p less than 0.005) whereas no difference was observed between animals treated with equimolecular doses of AU-8001 and control animals. The fecal elimination of radioactivity in the animals treated with sodium tolmetin was also significantly higher than in animals receiving AU-8001 (p less than 0.02).

Tolmetin, a nonsteroidal antiinflammatory drug, is known to induce edema, submucosal hemorrhage, and erosions of the gastrointestinal tract when administered at recommended doses. The purpose of our study was to determine whether misoprostol prevented or reduced the severity of duodenal and gastric mucosal injury induced by tolmetin. Following endoscopic screening, 60 healthy male and female subjects were assigned at random to one of two treatment groups. One group was treated with tolmetin (2000 mg/day, in four divided doses) and misoprostol (200 micrograms four times daily); the other with tolmetin and placebo. Both drugs were administered for six and a quarter days. On the seventh day, 2 hr after the last dose, an endoscopic examination of the gastric and duodenal mucosa was repeated, and the results graded. Subjects with 10 or fewer hemorrhages or erosions were considered treatment successes; those with 11 or more erosions, plus any other lesions, were considered treatment failures. A total of 59 subjects completed the study. One withdrew because of an unsuspected pregnancy. In regard to the gastric mucosa, seven of 29 (24%) placebo subjects were considered treatment successes. In the misoprostol group, 27 of 30 (90%) were treatment successes. This difference is statistically significant at the P less than 0.0001 level. The overall damage to the duodenal mucosa caused by tolmetin is less than that to the gastric mucosa, with the misoprostol-treated subjects having significantly less damage than the placebo subjects (P less than 0.001). Side effects were common in both groups, but almost all were mild, gastrointestinal in origin, and did not require treatment or withdrawal from the study.(ABSTRACT TRUNCATED AT 250 WORDS)