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Anesth Analg 2003;97:402-408
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Dexibuprofen (S(+)-Isomer Ibuprofen) Reduces Gastric Damage and Improves Analgesic and Antiinflammatory Effects in Rodents

A. Bonabello, PhD*, M. R. Galmozzi, PhD*, R. Canaparo, PhD{dagger}, G. C. Isaia, MD{ddagger}, L. Serpe, MD{dagger}, E. Muntoni, MS{dagger}, and G. P. Zara, MD{dagger}

*Research Department, SPA-Societa’ Prodotti Antibiotici S.p.A., Milan, Italy; and Departments of {dagger}Anatomy, Pharmacology and Forensic Medicine and {ddagger}Internal Medicine, University of Turin, Turin, Italy

Address correspondence and reprint requests to Angelo Bonabello, SPA-Societa’ Prodotti Antibiotici S.p.A., Via Biella 8, Milan, Italy. Address e-mail to bonabelloa{at}libero.it


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We determined the analgesic and antiinflammatory actions and the related acute mucosal gastric damage from the active S(+)-isomer ibuprofen (dexibuprofen), in comparison with those of the standard racemic formulation of ibuprofen in rodents. The antinociception was evaluated by hot-plate and tail-flick methods after IV and oral (PO) administration in mice and after PO administration in rats. S(+)-Ibuprofen was at least twice more potent than the ibuprofen racemic formulation. The antiinflammatory action of the test compound, assessed with the abdominal constriction test in mice (IV and PO) and with hind paw edema in rats (IV and PO), was found to be significantly more potent than that of ibuprofen after IV treatment in mice and PO administration in rats. Moreover, the test compound caused significantly less mucosal gastric damage than the racemic formulation administered at identical doses (50 mg/kg PO in rats). In conclusion, the S(+)-ibuprofen isomer was found to be more potent than the racemic formulation in analgesic and antiinflammatory tests and presented fewer gastric toxic effects. On the basis of the results of this work, we suggest that the administration of chemical entities, such as R(-)-ibuprofen, should be avoided if they are not essential for the anticipated therapeutic activity.

IMPLICATIONS: Ibuprofen is a nonsteroidal antiinflammatory drug often prescribed as a racemic formulation. We studied the analgesic and antiinflammatory effects of the active S(+)-isomer. The S(+)-ibuprofen was found to be more potent than the racemic formulation and produced less acute gastric damage.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The nonsteroidal antiinflammatory drugs (NSAIDs) are among the most widely used analgesics worldwide. Inhibition of cyclooxygenase (COX), and, therefore, prostaglandin production, is the common mechanism of action of the NSAIDs. COX exists as two isoforms. In general terms, COX-1 is constitutive and present, for example, in the endothelium, stomach, and kidneys, whereas COX-2 is induced by proinflammatory cytokines and endotoxin in cells in vitro and at the inflammatory site in vivo (1). Accordingly, NSAIDs with a more favorable COX-2/COX-1 ratio should have good antiinflammatory activity with fewer side effects, e.g., on the gastrointestinal tract (2).

Ibuprofen, a chiral 2-arylpropionic acid derivative, is an analgesic, antipyretic, and antiinflammatory drug available over the counter in many countries. In a recent collaborative metaanalysis with individual NSAIDs, ibuprofen had the smallest risk of serious gastrointestinal complications. However, several independent studies in which different in vitro approaches were used to monitor the inhibition of COX-1 and COX-2 did not suggest a preferred inhibition of COX-2 by ibuprofen (1–5). An interesting feature of ibuprofen, which is marketed in most countries as an equal mixture of R- and S-ibuprofen (racemate), is the unidirectional metabolic chiral inversion of the in vitro inactive (not prostaglandin synthesis-inhibiting) R-enantiomer to the prostaglandin synthesis-inhibiting S-form (6–8). This conversion of racemic ibuprofen to active S(+)-isomer may contribute to the variability in analgesia and may explain the poor relationship observed between plasma concentrations of ibuprofen and clinical response in acute pain and rheumatoid arthritis (9,10). The observation that selective inhibitors of COX-2 are associated with a reduced incidence of gastric erosions as compared with conventional NSAIDs suggests that the suppression of gastric COX-1 by NSAIDs is the key mechanism responsible for gastric damage (2,11). However, Wallace et al. (12) showed that the suppression of both COX-1 and COX-2 is necessary for NSAID-induced gastric erosion in rats, suggesting a distinct mechanism through which inhibition of COX-1 versus COX-2 could contribute to erosion.

Dionne and McCullagh (13) studied the analgesic effect of orally administered (PO) ibuprofen active S(+)-isomer in the clinical oral surgery model of acute pain. The administration of 200 mg of S(+)-ibuprofen resulted in an analgesic effect more than that of a racemic mixture containing approximately the same amount of active isomer. The analgesic onset was faster and the peak analgesia greater, and the authors observed a small incidence of adverse effects.

The same results were observed with the ketamine S(+)-isomer in a recent double-blinded, three-way crossover, placebo-controlled study assessing pain evoked by small-/large-area pressure stimuli. The S(+)-isomer was approximately twice as potent as the racemic mixture of ketamine in inhibiting central pain summation (14).

The aim of this study was to evaluate the analgesic and antiinflammatory actions of the active S(+)-isomer ibuprofen in comparison with the racemic formulation. We also studied the acute gastric damage of both preparations.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Male Sprague-Dawley rats weighing 175–200 g and male mice (strain CD1) weighing 20 to 30 g were used in all experiments (Harlan Italy srl, San Pietro al Natisone, Udine, Italy). The animals were fed standard laboratory chow and tap water ad libitum. They were housed on a 12-h light/dark cycle in rooms that were temperature and humidity controlled.

The animals were randomly assigned to different drug-dose tests; the control animal groups received the vehicle treatment, whereas the other animal groups received the test drugs. The experiments were performed according to the Guiding Principles for the Care and Use of Laboratory Animals, the Recommendation from the Declaration of Helsinki, and the European Community legislation No. 86/605. The protocol was reviewed and approved by the Local Animal Committee.

The S(+)-ibuprofen isomer was from Societa’ Prodotti Antibiotici S.p.A. (Milan, Italy) (coded SPA-S-897). Ibuprofen (racemate) was purchased from Francis S.p.A. (Varese, Italy). Acetylsalicylic acid (ASA) and carrageenan were from Sigma (Milan, Italy).

For the Hot Plate Test, the method adopted was described by O’Callaghan and Holtzman (15). One-hundred-forty mice, 10 per group (weighing 20–25 g), or 80 rats, 10 per group (175–200 g), were placed in a stainless-steel container, thermostatically set at 52.5°C ± 0.1°C, in a precision water bath (Terzano, Milan, Italy). Reaction times were measured with a stopwatch before and 30, 60, and 120 min after the administration of the analgesic drugs. The end-point was shown by the licking of the fore or hind paws. Mice and rats scoring <12 and >18 s in the basal test were rejected (30%). An arbitrary cutoff time of 45 s was adopted to avoid serious injuries to the treated animals.

Antinociception was assessed by the tail-flick method of D’Amour and Smith (16), as modified by Dewey et al. (17). Two-hundred-ninety mice (20–25 g), 10 per group, were loosely wrapped, individually, in a thin cotton towel, with the head and the tail exposed. Each animal was then placed on a platform with the tail positioned in a special shallow groove; a focused beam of light was then directed at the tail from above, approximately 2.5 cm from the tip. Movement of the tail from the groove allowed the light beam to hit a sensor, formerly covered by the tail, which then automatically switched off the beam and stopped the timer. The duration of the time required for the tail response after exposure to the thermal stimulus was considered the tail response latency time. The maximum time allowed was 15 s, to prevent tissue damage. Mice were tested once to determine the predose tail response latency, after which they were then dosed and again tested for their tail response latency at 30 min after dosing. For each animal, we calculated the difference between postdose and predose latency time.

The abdominal constriction test was performed with 200 CD1 mice weighing 25–30 g. We used the abdominal constriction test described by Hendershot and Forsaith (18). Mice were injected intraperitoneally with acetic acid (10 mL/kg; 3% solution) to produce the typical reaction, which is characterized by a wave of contractions of the abdominal musculature followed by extension of the hind limbs. The mice were then placed in individual transparent containers, and the number of contractions in a 20-min period was counted from the time of injection.

The acute inflammation was induced by injection of 0.05 mL (0.5 mg) of carrageenan, dissolved in NaCl 0.9%, into the plantar tissue of the right rat hind paw (70 animals), as described by Winter et al. (19). The extent of inflammation was recorded by measuring the volume of the right hind paw (Plethysmometer 7150; Ugo Basile) before and after carrageenan administration. The percentage of antiinflammatory action is considered as the reduction in edema of treated animals compared with controls (20).

Gastric damage was evaluated in groups of at least 10 rats each, which were given one of the following drugs PO: ASA (100 mg/kg), racemic ibuprofen, and S(+)-isomer ibuprofen (25, 50, or 100 mg/kg). Control rats received an equal volume of the vehicle of 1% carboxymethylcellulose. Six hours later, the animals were anesthetized with halothane, and the stomach was removed and scored for hemorrhagic damage by an observer unaware of the treatments the rats had received. The scoring involved measuring the lengths of the lesions, in millimeters, and summing the values to give an overall gastric ulceration index for each rat (13). The observers of all the tests were blinded to the drug injected when making the efficacy measurements.

The data were analyzed with a software package (SPSS 6.1 for Windows; SPSS Inc., Chicago, IL). The following statistical tests were performed: analysis of variance followed by Bonferroni’s test; the Kruskal-Wallis test followed by the distribution-free multiple comparisons test; the paired Student’s t-test and probit analysis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Mice were treated with S(+)-ibuprofen IV at doses of 25, 50, and 100 mg/kg and with ibuprofen at doses of 50, 100, and 150 mg/kg; 30 min after the injection, antinociception was evaluated in the mouse hot-plate test. Both drugs showed a significant analgesic effect (P < 0.01), with a 50% effective dose (ED50) of 64 mg/kg for S(+)-ibuprofen and 128 mg/kg for ibuprofen. The 50 mg/kg dose of S(+)-ibuprofen was not statistically distinguishable from the 100 mg/kg dose of the racemic formulation (Fig. 1A).



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  		Figure 1. Dose-response curves of S(+)-ibuprofen and the racemic formulation after IV administration in mice (A), PO administration in mice (B), and PO administration in rats (C). The hot-plate test was performed 30 min after IV injection and 60 min after PO treatment. Each point represents the mean of 10 animals. Vertical lines are SEM. *P < 0.05 in comparison with basal values. {Delta}s = difference between postdose and predose latency time.

 
The mice were evaluated after PO administration of the drugs: S(+)-ibuprofen and racemic ibuprofen were given at the doses of 100, 150, and 200 mg/kg. The animals were evaluated 60 and 120 min after drug administration. The time-course study showed that both S(+)-ibuprofen and racemic ibuprofen had a significant analgesic effect (P < 0.01). After the 60-min test, the ED50 of S(+)-ibuprofen was 125 mg/kg, and the ED50 of ibuprofen was 159 mg/kg. Again, no significant difference was observed between S(+)-ibuprofen 100 mg/kg and ibuprofen 200 mg/kg (Fig. 1B).

Rats were given PO S(+)-ibuprofen at doses of 50, 100, and 125 mg/kg and racemic ibuprofen at 50, 100, 200, and 300 mg/kg. The hot-plate test was performed 60 min after drug administration. We observed a dose-dependent analgesic effect for the drugs studied, with an ED50 of 128 mg/kg for S(+)-ibuprofen and an ED50 >300 mg/kg for ibuprofen. Also, in this test, no statistically significant difference was seen between S(+)-ibuprofen at the dose of 50 mg/kg and the racemic formulation at the dose of 100 mg/kg (Fig. 1C).

In the tail-flick test, we studied mice 30 min after treatment with S(+)-ibuprofen, given IV at the doses of 12.5, 25, 50, 75, and 100 mg/kg, and the ibuprofen racemic solution, given at the doses of 12.5, 25, 50, 75, 100, and 150 mg/kg. The analgesic effect of the S(+)-isomer was significantly more potent than that of the racemic formulation; the ED50 values were 54 and 84 mg/kg, respectively (Fig. 2A).



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  		Figure 2. Dose-response curves of S(+)-ibuprofen and the racemic formulation after IV administration (A), IM administration (B), and PO administration (C) in mice. The tail-flick test was performed 30 min after drug treatment. Each point represents the mean of 10 animals. Vertical lines are SEM. *P < 0.05 in comparison with basal values. For each animal, we calculated the difference between postdose and predose latency time ({Delta}s).

 
We also tested mice 30 min after treatment with S(+)-ibuprofen or with ibuprofen racemic solution given IM at the doses of 12.5, 25, 50, and 100 mg/kg. The analgesic effect of the S(+)-isomer was significantly more potent than that of the racemic formulation (P < 0.01); S(+)-ibuprofen had an ED50 of 15 mg/kg, compared with the ED50 of 125 mg/kg for ibuprofen. We observed a statistically significant difference between S(+)-ibuprofen 50 mg/kg and ibuprofen 100 mg/kg (Fig. 2B).

We performed the tail-flick test in mice 60 min after PO S(+)-ibuprofen (25, 50, and 100 mg/kg) and ibuprofen racemic solution (25, 50, 100, and 200 mg/kg). Also, after PO administration, S(+)-ibuprofen was more potent than ibuprofen, with an ED50 of 37 versus 177 mg/kg, respectively. S(+)-ibuprofen 25 mg/kg was more potent than ibuprofen 50 mg/kg (P < 0.05) (Fig. 2C).

The antiinflammatory action was evaluated by the abdominal constriction test, and the inflammation of the rat right hind paw was induced by carrageenan and measured with the plethysmometer. For the abdominal constriction test, S(+)-ibuprofen 12.5, 25, and 50 mg/kg and ibuprofen racemic solution 25, 50, and 75 mg/kg were administered IV 30 min before the intraperitoneal injection of acetic acid. Both formulations showed a significant antinociceptive action compared with the controls (P < 0.05). S(+)-Ibuprofen (ED50, 32 mg/kg) was significantly more potent than the racemic formulation (ED50, 52 mg/kg) (Fig. 3A).



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  		Figure 3. Dose-response curves of S(+)-ibuprofen and racemic ibuprofen after IV injection (A) and PO administration (B) in mice. The writhing test lasted 20 min after intraperitoneal injection of acetic acid. The drugs were administered 30 min IV and 60 min PO before the test. Each point represents the mean of 12 animals. Vertical lines are SEM. *P < 0.05 compared with the controls (33.04 ± 5.2 occurrences of writhing syndrome) after PO administration and after IV injection (37.12 ± 1.16 occurrences of writhing syndrome).

 
In addition, S(+)-ibuprofen and ibuprofen racemic solution 25, 50, and 100 mg/kg were administered PO 60 min before the intraperitoneal injection of acetic acid. Both formulations showed a significant antiinflammatory action compared with the controls (P < 0.05); however, S(+)-ibuprofen (ED50, 44 mg/kg) was significantly less potent than ibuprofen (ED50, 31 mg/kg) (Fig. 3B).

In carrageenan-induced rat paw edema, S(+)-ibuprofen 30, 60, and 100 mg/kg and ibuprofen 30, 60, and 120 mg/kg were administered IV, and the effect was evaluated 1, 3, and 5 h after the administration of the inflammatory drug. S(+)-Ibuprofen (ED50 of 91 mg/kg after 3 h) and racemic ibuprofen (ED50 of 88 mg/kg after 3 h) showed a significant dose-dependent antiinflammatory action compared with the control (P < 0.05) (Table 1). In the same test after PO administration, at the doses of 30, 60, and 100 mg/kg for the S(+) product and 30, 100, and 130 mg/kg for the racemic compound, the S(+)-isomer was significantly more potent than the ibuprofen racemic formulation (ED50, 57 versus 124 mg/kg) (Table 2).


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  		Table 1. Comparison Between the Antiinflammatory Action of S(+)-Ibuprofen and Racemic Ibuprofen IV in the Carrageenan Test in Rats
 

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  		Table 2. Comparison Between the Antiinflammatory Action of S(+)-Ibuprofen and Racemic Ibuprofen PO in the Carrageenan Test in Rats
 
To study the acute gastric damage, S(+)-ibuprofen and the racemic formulation were administered PO at the doses of 25, 50, and 100 mg/kg; ASA 100 mg/kg was administered as positive control. Gastric lesions were significantly less pronounced with the use of S(+)-ibuprofen compared with racemic ibuprofen (P < 0.05). S(+)-Ibuprofen 50 mg/kg not only was significantly less damaging than 100 mg/kg of racemic ibuprofen and ASA 100 mg/kg (P < 0.05), but also was less damaging than 50 mg/kg of the racemic formulation (P < 0.05) (Fig. 4).



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  		Figure 4. Ulceration index of S(+)-ibuprofen, racemic formulation, and acetylsalicylic acid (ASA) PO in comparison with controls. Each column represents the mean of 10 animals. Vertical lines are SEM. *P < 0.05 in comparison with control animals.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The data presented in this study demonstrate that the administration of S(+)-isomer of ibuprofen results in analgesic and antiinflammatory action similar to—and, in some experiments, more than—a racemic mixture containing the same amount of the active isomer. Furthermore, the greater therapeutic effect achieved by the S(+)-isomer did not produce an increase in gastric toxicity; on the contrary, it produced less gastric damage than a racemic mixture. In this study, we did not evaluate the R(-)-isomer effect because it is mostly inactive and is in part converted to the active S(+)-isomer (6–8).

In a recent clinical study, 200 mg of S(+)-ibuprofen PO resulted in more analgesic effect than the racemic mixture (14). The 400 mg of the S(+)-isomer also provided larger peak effects and a duration comparable to that of racemic ibuprofen, with residual activity detectable for a long period. Analgesic onset was also faster for S(+)-ibuprofen than for the racemic formulation. In the same study, the incidence of adverse reactions reported by the subjects given the active treatments was similar to the incidence after placebo.

In a pharmacokinetic study, Geisslinger et al. (21) showed that S(+)-ibuprofen given PO to healthy volunteers produced a larger plasma concentration more rapidly than the same amount of S(+)-ibuprofen contained in the racemic compound. These data could explain, in part, our animal results in efficacy after PO administration of the enantiomer compared with the racemic formulation.

Many studies indicate that the S(+)-enantiomers of arylpropionic NSAIDs are the pharmacologically active enantiomers. The greatest efficacy of arylpropionic S(+)-enantiomers was observed in animal analgesia models. For example, in a rat formalin model, intrathecal injection of S(+)-ibuprofen resulted in a potent suppression of the flicking behavior in the second phase of this test (22). Subsequently, S-flurbiprofen was found to be significantly more potent than R-flurbiprofen in the same model (23). After IV administration, S(+)-flurbiprofen was also more potent than the R(-)-isomer in reducing inflammation-evoked activity in nociceptive rat spinal neurons. When injected locally into the inflamed knee, S(+)-flurbiprofen, but not R(-)-flurbiprofen, reduced the hyperexcitability of spinal cord neurons (21). Similar data were obtained by studying antinociceptive actions of spinal NSAIDs in the formalin test in rats (24).

In an animal model after PO and IV administration, S(+)-ketoprofen showed an increased antinociceptive effect in phenylbenzoquinone-induced writhing in mice. With a similar test in rats, S(+)-ketoprofen was more potently analgesic than diclofenac by both IV and PO administration. There was no significant difference between the analgesic effect of S(+)-ketoprofen treatment and the twofold dose of the racemic form in mice and rats. Similar results were observed with the carrageenan-induced paw edema model in the rat.

Our results do not support the hypothesis that R(-)-ibuprofen can contribute to the analgesic and antiinflammatory action of the racemate formulation, and this can be due to differences in the models used. In our experiments, the racemate formulation produced more gastric lesions than S(+)-ibuprofen.

As with other NSAIDs, gastrointestinal intolerance, including peptic ulceration, is the most common adverse reaction to ibuprofen. This adverse event seems to be related to inhibition of the synthesis of mucosal protective prostaglandins; it appears, therefore, that the S(+)-enantiomer, which is the active isomer, could be more ulcerogenic than its antipode. From several animal studies, Mayer and Testa (25) concluded that pure S(+)-ibuprofen does not produce more gastric toxicity than the racemic formulation. The observation that selective inhibition of COX-2 spares prostaglandin synthesis and is associated with a greatly reduced incidence compared with conventional NSAIDs led to the hypothesis that the suppression of gastric COX-1 by NSAIDs is the key mechanism responsible for erosion formation. In two experimental models in rats, using ulcerogenic doses of different NSAIDs, Laudano et al. (26) observed that the higher inhibitory COX-1 selectivity of NSAIDs led to the production of a more marked gastrointestinal injury. However, this remains an unproven hypothesis. Mice in which the gene for COX-1 was disrupted exhibited reduced gastric prostaglandin synthesis but no gastric injury. Several studies in recent years have suggested that COX-2 can contribute to gastric mucosal defense, at least in some circumstances. Using an in vivo rat model, Wallace et al. (12) showed that inhibition of both COX-1 and COX-2 is required for the development of gastric erosion after NSAID administration. Neither a COX-1 inhibitor nor a COX-2 inhibitor caused macroscopically or histologically detectable gastric damage when given at doses known to be effective at selectively inhibiting the target enzyme in vivo. However, the administration of both inhibitors invariably resulted in the development of gastric erosion.

Our results are in agreement with a previous study in which repeated administration of S(+)-enantiomer and racemic ibuprofen in rats caused the expected dose-dependent gastrointestinal toxicity. The extent of the mucosal lesions tended to be slightly more marked in animals exposed to the racemate than in rats treated with the S(+)-enantiomer (26).

In conclusion, the S(+)-ibuprofen isomer was found to be more potent than the racemic formulation of ibuprofen with respect to its analgesic and antiinflammatory properties, and it produced less acute gastric damage. Therefore, administration of the racemic formulation should be avoided if it is not essential for the therapeutic activity expected.


   Acknowledgments
 
We thank Gabriele Buffa and Claudio Rossi for technical assistance and Franca Costi for general assistance.


   References
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 Abstract
 Introduction
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 Discussion
 References
 

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Accepted for publication April 7, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press