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Racemic ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+)-KP) are widely used non-steroidal anti-inflammatory drugs (NSAIDs), and commonly detected in the aquatic environment. The present study has evaluated the toxicological effects of RS-KP and S(+)-KP on biotransformation and oxidative stress responses in gills and liver of Atlantic salmon. Fish were exposed for 10 days using different concentrations of RS-KP (1, 10 and 100 μg/L) and S(+)-KP (0.5, 5 and 50 μg/L). Biotransformation and oxidative stress responses were analysed at both transcript and functional levels. In the gills, significant inhibitory effect at transcriptional and enzymatic levels were observed for biotransformation and oxidative stress responses. On the contrary, biotransformation responses were significantly increased at transcriptional and translational levels in the liver, while the associated enzymatic activities did not parallel this trend and were inhibited and further demonstrated by principal component analysis (PCA). Our findings showed that both compounds produced comparable toxicological effects, by producing organ-specific effect differences. RS-KP and S(+)-KP did not bioaccumulate in fish muscle, either due to rapid metabolism or excretion as a result of their hydrophobic properties. Interestingly, the inhibitory effects observed in the gills suggest that these drugs may not undergo first pass metabolism, that might result to downstream differences in toxicological outcomes., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-steroidal anti-inflammatory drugs are drugs with analgesic, antipyretic, and anti-inflammatory effects. This study uses in vitro methods to investigate the potential and unknown genotoxic effects of dexketoprofen trometamol, an active substance in painkillers, on healthy human lymphocytes. In this study, a cytokinesis-block micronucleus cytome assay is used to investigate potential clastogenic, aneugenic activity and to identify chromosome breakages caused by the active drug substance dexketoprofen trometamol; a comet assay is performed to identify the genotoxic damage resulting from DNA single-strand breaks; a real-time reverse transcription polymerase chain reaction panel system is used to evaluate the potential negative effects on the expression of the genes responsible for DNA damage assessment. Dexketoprofen trometamol induces toxic effects in healthy human lymphocytes at concentrations of 750-1000 µg/mL and above, and shows clastogenic, aneugenic activity by inducing micronucleus formations at exposures of 750-500 µg/mL. At concentration intervals of 1000, 500, 250, 100 µg/mL, dexketoprofen trometamol also resulted in DNA damage in the form of strand breaks, as demonstrated by highly significant increases in DNA tail length and density comet parameters when compared to spontaneous values. Human lymphocytes exposed to 750-100 µg/mL dexketoprofen trometamol were found to have significantly increased levels of expression of the XPC, XRCC6, PNKP genes in the DNA damage signaling pathway. It can be concluded that dexketoprofen trometamol may have cytotoxic, cytostatic, genotoxic effects on healthy human lymphocytes in vitro , depending on the concentration and duration of exposure. It is anticipated that this outcome will be supported by advanced studies.

Pharmaceuticals such as racemate ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+)-KP) are highly detectable non-steroidal anti-inflammatory drugs (NSAIDs) in the aquatic environment and therefore are designated as one of the most emerging groups of pollutants that can affect environmental and human health. The potential impact of these pharmaceuticals was assessed for the first time in vitro using a rat hepatocellular carcinoma cell line (H4IIE). Cells were exposed to low and high concentrations of these drugs. Cytotoxicity was determined by MTT reduction assay; CYP1A1 transcriptional and enzymatic levels together with canonical oxidative stress responsive markers (GPx, GR, GST and CAT) were also investigated. Cells exposed to RS-KP and S(+)-KP did not show cytotoxicity effect at the concentrations tested. However, this study highlighted differences between RS-KP and S(+)-KP in most of the evaluated markers, showing compound-, concentration- and time-specific effect patterns which suggest a potential stereo-selective toxicity of these drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To meet the requirements of risk assessment legislature regarding the ecotoxicity of ionizing compounds, the present study attempts to establish easy, robust methods for testing ecotoxicity at various pH levels. An overview is given of the buffering methods found in the literature. This is supplemented by a series of experiments where toxicity and ability to stabilize pH of seven common buffering compounds was tested on Daphnia magna and Pseudokirchneriella subcapitata. We consider a buffer applicable at a given concentration if the pH drift is below 0.2 pH units, and if there are no toxic effects. Twenty-four- and 48-h acute toxicity tests with D. magna were carried on a series of organic buffers with pH monitoring. Based on the experimental results it is possible to give recommendations for buffer concentrations for use in toxicity testing with D. magna at pH levels in the range of pH 6.0-7.8 for 48 h exposure, and pH 6.0-9.5 for 24 h exposure. Forty-eight- and 72-h growth inhibition tests with P. subcapitata were carried out, and recommendations for buffer concentrations at pH 7.5 and 8.0 are made for both 48 and 72 h of exposure., (Copyright © 2012 SETAC.)

Sugars such as trehalose are effectively used by various organisms as protective agents to undergo anhydrobiosis and cryobiosis. The objective of this study was first to establish a method for quantitative delivery of trehalose as a model sugar into oocytes, and then to evaluate its effect on development of mouse zygotes. To this end, a quantitative microinjection technique was developed using volumetric response of microdroplets suspended in dimethylpolysilaxene. To verify accuracy of this technique, both microdroplets and oocytes were microinjected with fluorophore-labeled dextran. Thereafter, injection volumes were calculated from fluorescence intensity, and volumetric responses of both microdroplets and oocytes. Comparison of calculated injection volumes revealed that this technique reflects microinjection into oocytes with pL-accuracy. The next series of experiments focused on toxicity of injection buffers (i.e., 10mM Tris and 15mM Hepes) and trehalose. Microinjection of Hepes and Tris buffer in the presence of 0.1M trehalose resulted in blastocyst rates of 86 and 72%, respectively, without a significant difference when compared to controls (86%). In subsequent experiments, Hepes was used as the injection buffer, and embryonic development of zygotes was studied as a function of intracellular trehalose concentrations. Microinjection of trehalose up to 0.15M resulted in development to blastocyst stage similar to controls (85 and 87%, respectively) while the blastocyst rate was significantly decreased (43%) in the presence of 0.20M intracellular trehalose. When transferred to foster mothers, trehalose-injected zygotes (0.1M) implanted and developed to day 16 fetuses similar to controls, healthy pups were born. The findings of this study suggest that trehalose at effective intracellular concentrations does not impair development of mouse zygotes.

Objective: Gastrointestinal damage and bleeding are the major side effects of non-steroidal anti-inflammatory drugs (NSAID), however the mechanisms of this ulcerogenic action are not fully understood. It has recently been proposed that neutrophil-and oxygen radical-dependent microvascular injuries may be important prime events that lead to mucosal injury. In addition, other factors like bile flow, intact bacterial flora or feeding conditions may contribute to the formation of lesions. Ketoprofen is a NSAID that exists as a pair of R(-) and S (+) enantiomers; like other 2-arylpropionic acids, its anti-inflammatory effects resides almost exclusively in the S (+) isomer. The present study was undertaken to explore the role of oxidative stress in the pathogenesis of intestinal injury induced by oral administration of racemic ketoprofen and its enantiomers given as their water soluble tromethamine salts., Material and Methods: Evaluation of intestinal damage and activities of oxidative stress related enzymes such as myeloperoxidase (MPO), xanthine-oxidase (XO) and superoxide dismutase (SOD) were studied in an experimental animal model using refed rats., Results: After the oral treatment followed by a refeeding period of 24 h, ketoprofen (100, 50, 25 mg/Kg b.w.) dose-dependently caused longitudinal ulcers on the mesenteric side of the middle and lower intestine lumen. The intestinal toxicity caused by S(+)-ketoprofen was significantly lower than the effect observed after racemate and R(-) enantiomer treatments (P <0.001), though the bioinversion of R(-)-ketoprofen to S(+)-enantiomer that occurs in the rat has to be considered. XO activity was unaffected by the studied drugs. Enhanced enteropathy by the racemate and its R (-)-enantiomer was correlated with a significant increase of MPO activity as an index of neutrophil infiltration, and a decrease in SOD activity (p<0.05 Vs control). S(+)-ketoprofen did not significantly change these parameters., Conclusions: These results suggest that reactive oxygen metabolites can contribute significantly to the development of intestinal lesions, and that R(-)-ketoprofen present in racemic preparations can enhance the toxic intestinal effects of S (+)-enantiomer via modification of neutrophil migration and oxidative stress.

The efficacy and tolerability of single doses of dexketoprofen trometamol 12.5 mg, 25 mg, and 50 mg and ketoprofen 50 mg were compared in this double-blind, randomized, placebo-controlled study of 210 patients with moderate to severe pain after removal of one mandibular impacted third molar tooth. Pain intensity and pain relief were monitored for 6 h after administration of medication using visual analogue and verbal rating scales. All four active treatments were significantly more effective than placebo (P < 0.001). Dexketoprofen 25 mg and 50 mg produced an analgesic effect within 30 min of administration and their effect persisted for 6 h. Ketoprofen 50 mg produced a level of analgesia similar to those of the higher doses of dexketoprofen trometamol, but it had a slower onset. The 12.5-mg dose of dexketoprofen trometamol was significantly superior to placebo but produced a lower level and shorter duration of analgesia compared to the other active treatments. There were no significant differences between 25 and 50 mg of dexketoprofen trometamol in any measure of analgesic efficacy. No serious adverse events were observed and there were no significant differences in the incidence of adverse events among treatment groups. These results demonstrate that dexketoprofen trometamol 25 mg is at least as effective as the racemic ketoprofen 50 mg in the treatment of postsurgical dental pain. The more rapid onset of action compared to ketoprofen suggests that dexketoprofen trometamol is more appropriate for treatment of acute pain.

Dexketoprofen, the active enantiomer of the racemic compound ketoprofen, is a new nonsteroidal antiinflammatory drug (NSAID) of the arylpropionate family. The efficacy and safety of dexketoprofen trometamol were compared with the equivalent enantiomeric dose of ketoprofen in a multicenter, randomized, double-blind 3-week trial of adult outpatients with pain due to osteoarthritis of the knee. After a washout period of 7-15 days, patients were randomly assigned to receive either dexketoprofen trometamol 25 mg tid (N = 89) or ketoprofen 50 mg tid (N = 94). Of the 183 patients enrolled, two were lost to follow-up. At the end of treatment (3 weeks), the main efficacy outcome measures were significantly better in the dexketoprofen trometamol group than in the ketoprofen group. In addition, overall physician assessment indicated that 75% of the dexketoprofen group had improved compared with 50% of the ketoprofen patients. There were fewer adverse events in the dexketoprofen treatment group, but the difference did not reach statistical significance. These results demonstrate that dexketoprofen trometamol 25 mg tid is more effective than ketoprofen 50 mg tid in short-term symptomatic treatment of knee osteoarthritis and suggest that the tolerability of dexketoprofen trometamol is more favorable than ketoprofen. Therefore, the substitution of dexketoprofen for racemic ketoprofen may be advantageous in clinical practice.

Recent reports have disagreed on whether the bioavailability of S(+)-ketoprofen is affected by the presence of R(-)-ketoprofen. To examine this directly, we designed a randomized crossover study in beagle dogs. [14C]-S(+)-ketoprofen trometamol and R(-)-ketoprofen trometamol were administered in the following percentage ratios: A, 99:1; B, 95:5; C, 90:10; D, 70:30; E, 50:50. Treatments were administered as a single oral dose of 1 mg/kg tromnetamol salt. Each of eight dogs received all five combinations in random order with a 1-week wash-out period between doses. Blood samples were taken before drug administration and at regular intervals for 240 min after dosing. A progressive increase in the plasma concentration of [14C]-S(+)-ketoprofen was observed on going from treatment E (lowest dose of Senantiomer) to treatments containing the highest doses of [14C]-S(+)-ketoprofen. When the pharmacokinetic calculations were normalized to the dose of [14C]-S(+)-ketoprofen, we found no statistically significant differences among the normalized AUC and Cmax values of the five treatments. Therefore, S(+)-ketoprofen absorption was linear and was not influenced by the presence of R(-)-ketoprofen. Furthermore, there were no significant differences in tmax values among treatments, indicating that the rate of S(+)-ketoprofen absorption was also unaffected by the presence of R(-)-ketoprofen.

This randomized three-way, crossover pharmacokinetic study was performed to determine whether food or an antacid alters the bioavailability of dexketoprofen trometamol. A total of 24 healthy volunteers received three single 25 mg doses of dexketoprofen trometamol administered either in fasting condition, after an antacid (Maalox), or after a high-fat breakfast. Each volunteer received the three treatments in a randomized order, with a 7-day washout period between treatments. Blood samples were taken at regular intervals up to 24 h after dose. Plasma dexketoprofen concentrotions were determined by HPLC and the main outcome measures were area under curve of concentration vs. time (AUC0-infinity), maximal plasma concentration (Cmax), and time to reach maximal concentration (t(max)). Administration of an antacid 10 min before dexketoprofen trometamol had no clinically relevant effect on any of the pharmacokinetic parameters. Food did not alter the extent of absorption of dexketoprofen trometamol, but t(max) was significantly increased and C(max). significantly decreased compared with the fasting state. In conclusion, we can state that neither antacid nor food has a significant effect on the overall bioavailability of dexketoprofen trometamol.

We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.

The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg in 18 healthy volunteers. In the second study, the pharmacokinetics and tolerability of oral dexketoprofen trometamol in tablet form were evaluated after either a single 25 mg dose (24 volunteers) or a repeated dose of 25 mg twice daily for 7 days (12 volunteers). The absorption of dexketoprofen from dexketoprofen trometamol capsules was bioequivalent to that of ketoprofen. On the other hand, the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen. Dexketoprofen trometamol showed the most rapid absorption rate, with highest Cmax and shortest t(max) values, whereas dexketoprofen free acid had the slowest absorption rate, and ketoprofen had an intermediate absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred. Dexketoprofen trometamol was well tolerated, with no clinically relevant adverse events reported.

A total of 125 outpatients with moderate to severe pain after surgical removal of one impacted third molar were randomly assigned to receive dexketoprofen trometamol 12.5 or 25 mg or dipyrone 575 mg. For first-dose assessments, patients rated their pain intensity and its relief at regular intervals. From 60 min post dose to the end of the 6-h observation period, both doses of dexketoprofen trometamol had higher pain relief scores than dipyrone: Between 3 and 6 h the differences were statistically significant. In addition, peak measures (PIDmax and PARmax) were statistically superior after both doses of dexketoprofen trometamol compared to dipyrone. The overall efficacy assessed at the end of the first-dose phase was rated as good or excellent by 90%, 83.3%, and 70% of patients receiving dexketoprofen trometamol 25 mg, dexketoprofen trometamol 12.5 mg, and dipyrone, respectively. The number of patients who required remedication during the 6-h period was significantly lower in both dexketoprofen groups. Repeated-dose data were also obtained. No significant differences were found in the efficacy after repeated doses, the number of doses taken, or the mean time elapsed between doses. The overall efficacy at the end of the repeated-dose phase was rated as good or excellent by 84.2%, 66.7%, and 70% of patients receiving dexketoprofen trometamol 25 mg, dexketoprofen trometamol 12.5 mg, and dipyrone, respectively. The frequency of adverse events was similar for all treatments and no serious adverse events were reported during the study.

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.

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)

Previously, we have shown that cultured liver endothelial cells are affected by an energy-dependent injury when incubated in cold University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate solution. Here, we studied the susceptibility of other endothelial cells to this type of injury. Aortic endothelial cells in early-confluent, i.e., still proliferating, monolayer cultures were damaged more quickly during cold incubation in UW solution than during cold incubation in Krebs-Henseleit buffer. At this stage the addition of KCN did not alter the loss of viability in UW solution, but when the culture period was prolonged, cells were protected by the addition of cyanide. A paradoxical, protective effect of KCN could also be observed in late-confluent, i.e., nonproliferating, cultures of coronary endothelial cells incubated in UW solution. Similarly, liver endothelial cells in subconfluent, growing cultures were damaged by the addition of cyanide (loss of viability after 48 h, 3 +/- 1% in UW, 65 +/- 19% in UW + KCN), whereas in late-confluent cultures the addition of cyanide to UW solution was protective (loss of viability after 48 h, 100 +/- 0% in UW, 31 +/- 15% in UW + KCN). Variations of culture period and seeding density and the use of inhibitors of cell proliferation demonstrated that liver endothelial cells acquire their susceptibility to energy-dependent injury along with confluence. Subcultured cells retained this susceptibility for some hours. These results suggest that the energy-dependent injury described previously is not confined to liver endothelial cells and that the occurrence of energy-dependent injury requires a capacity of the cells that develops only after cultures have grown to confluence.

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.

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.

Strains of Proteus spp. were pretreated with colistin (polymyxin E) and resuspended in either Tris buffer or sodium deoxycholate. Leakage of potassium and materials with an absorption maxima at 260 nm increased on resuspension of two pretreated Proteus mirabilis strains in Tris buffer or sodium deoxycholate. The activity of Tris increased up to pH 9 and of sodium deoxycholate up to 1,000 micrograms/ml. Greater leakage occurred with resuspension in Tris buffer than in sodium deoxycholate. Other Proteus strains tested did not produce leakage following similar treatment.

Traditionally sodium bicarbonate has been the buffer of first choice in the treatment of metabolic acidosis. This treatment, however, involves risks of developing a hyperosmolar state, a high sodium concentration in the blood, increased arterial carbon dioxide tension and, as a result of the latter, intracellular and intracerebral acidosis and also cerebral oedema. The buffering effect occurs slowly and as a consequence of this, and of the titration curve of sodium bicarbonate, overcorrection of metabolic acidosis is often seen. Tris buffer was introduced as an alternative and has been claimed to solve most of these problems, but on the other hand it entails a very high risk of peripheral venous thrombosis and thrombophlebitic lesions owing to its local irritative effect. In order to overcome these disadvantages a new mixture of Tris, acetate, bicarbonate and phosphate has been designed. In the studies described it was shown to have an adequate buffering effect and to provide a solution to most of the problems connected with buffering of metabolic acidosis. The new Tris buffer mixture has a buffering effect in blood equivalent to 0.5 mol/l sodium bicarbonate, although its sodium content has been decreased to one-third of pure sodium bicarbonate. Its administration also results in predictable buffering in cerebrospinal fluid and skeletal muscle. In a clinical study it was demonstrated that the new Tris buffer mixture results in sufficient and adequate buffering without significant side-effects.

Irrigation of the urinary tract with alkaline solutions may be used appropriately in some clinical situations to dissolve uric acid stones. Since in vitro studies have suggested that tham-E (pH 10.6) is somewhat more effective than tham (pH 8.6) in promoting dissolution of uric acid, these studies were undertaken to assess the relative toxicities of these two irrigating solutions to the urothelium. Rabbit bladders were irrigated antegrade via a ureterotomy for twenty hours. Tham E produced considerably more mucosal injury than did tham (p = 0.0001). The minimal advantage in rapidity of stone dissolution offered by tham E over tham is more than offset by the considerably increased potential for toxic side effects. The results suggest tham and not tham E should be used for irrigation to dissolve uric acid stones.

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.