Antinociception produced by nonsteroidal anti-inflammatory drugs in female vs male rats.

The primary aim of this study was to examine sex differences in acute antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Complete Freund's adjuvant (CFA) was administered to adult Sprague-Dawley rats to induce pain and inflammation in one hindpaw; 2.5 h later, vehicle or a single dose of the NSAIDs ibuprofen (1.0-32 mg/kg) or ketoprofen (0.1-10 mg/kg), or the COX-2-preferring inhibitor celecoxib (1.0-10 mg/kg) was injected i.p. Mechanical allodynia, heat hyperalgesia, biased weight-bearing, and hindpaw thickness were assessed 0.5-24 h after drug injection. Ibuprofen and ketoprofen were more potent or efficacious in females than males in reducing mechanical allodynia and increasing weight-bearing on the CFA-injected paw, and celecoxib was longer-acting in females than males on these endpoints. In contrast, ketoprofen and celecoxib were more potent or efficacious in males than females in reducing hindpaw edema. When administered 3 days rather than 2.5 h after CFA, ketoprofen (3.2-32 mg/kg) was minimally effective in attenuating mechanical allodynia and heat hyperalgesia, and did not restore weight-bearing or significantly decrease hindpaw edema, with no sex differences in any effect. Neither celecoxib nor ketoprofen effects were significantly attenuated by cannabinoid receptor 1 or 2 (CB1 or CB2) antagonists in either sex. These results suggest that common NSAIDs administered shortly after induction of inflammation are more effective in females than males in regard to their antinociceptive effects, whereas their anti-inflammatory effects tend to favor males; effect sizes indicate that sex differences in NSAID effect may be functionally important in some cases.

Ketoprofen-loaded rose hip oil nanocapsules attenuate chronic inflammatory response in a pre-clinical trial in mice.

This study aimed to develop nanocapsules containing ketoprofen using rose hip oil (Keto-NC) as oil core, and to evaluate their anti-inflammatory activity in acute and chronic ear edema models in mice. Physicochemical characterization, drug release, photostability and cytotoxicity assays were performed for the developed Keto-NC formulations and compared to ketoprofen-loaded nanocapsules using medium chain triglycerides as oil core (Keto-MCT-NC). Anti-inflammatory activity of orally delivered KP (Ketoprofen-free; 10 mg.kg-1) or Keto-NC (2.5; 5; 10 mg.kg-1) was assessed in mouse acute and chronic ear edema induced by croton oil (CO). Edema histological characteristics were determined by H&E stain, and redox parameters were analyzed in blood plasma and erythrocytes. Keto-MCT-NC and Keto-NC did not exhibit differences regarding physicochemical parameters, including size diameters, polydispersity index, pH, Ketoprofen content, and encapsulation efficiency. However, Keto-NC, which contains rose hip oil as lipid core, decreased drug photodegradation under UVC radiation when compared to Keto-MCT-NC. KP or Keto-NC were not cytotoxic to keratinocyte cultures and produced equal edema inhibition in the acute protocol. Conversely, in the chronic protocol, Keto-NC was more effective in reducing edema (~60-70% on 7-9th days of treatment) when compared to KP (~40% on 8-9th days of treatment). This result was confirmed by histological analysis, which indicated reduction of edema and inflammatory infiltrate. A sub-therapeutic dose of Keto-NC (5 mg.kg-1) significantly reduced edema when compared to control. Finally, KP and Keto-NC exhibited similar effects on redox parameters, suggesting that the advantages associated with Ketoprofen nanoencapsulation did not involve oxidative stress pathways. The results showed that Keto-NC was more efficient than KP in reducing chronic inflammation. These data may be important for the development of strategies aiming treatment of chronic inflammatory diseases with fewer adverse effects.

Crude leaf extracts of Piperaceae species downmodulate inflammatory responses by human monocytes.

In this study, we aimed to evaluate the immunomodulatory effects of crude leaf extracts from Piper gaudichaudianum Kunth, P. arboreum Aub., P. umbellata L., P. fuligineum Kunth, and Peperomia obtusifolia A. Dietr. on an in vitro model of inflammatory response. The crude extracts were previously obtained by maceration of the leaves. The half-maximal inhibitory concentration was determined by the MTT assay using human peripheral blood mononuclear cells. Human monocytes were simultaneously challenged with each crude extract and lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, to induce a strong inflammatory response. After 24 h of incubation, cell-free supernatants were used for evaluating the mediators involved in inflammation: H2O2, TNF-α, IL-8, IL-6, IL-1ß, IL-10, IL-12, FGF-b, and TGF-ß1. We also compared the results with the effects of ketoprofen, a well-known anti-inflammatory drug. The P. gaudichaudianum crude extract downmodulated the production of H2O2, IL-1ß, IL-6, IL-8, and TGF-ß1 by LPS-stimulated monocytes; P. arboreum, IL-1ß, IL-6, IL-8, and TNF-α; P. umbellata and P. fuligineum, H2O2, IL-1ß, IL-6, IL-8, IL-10, and TNF-α; and P. obtusifolia, H2O2, IL-6, IL-8, IL-10, and TNF-α. In general, the crude leaf extracts amplified the anti-inflammatory response when compared with ketoprofen, particularly reducing the production of IL-8, a mediator involved in neutrophil recruitment during tissue damage. Thus, the crude leaf extracts of P. gaudichaudianum, P. arboreum, P. umbellata, P. fuligineum, and Peperomia obtusifolia elicited an anti-inflammatory response against LPS-challenged monocytes. These findings show the anti-inflammatory properties of these crude leaf extracts and offer new perspectives for their use in the treatment of inflammatory diseases.

Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model.

Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.

Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug.

The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freud's Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofen's photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested.

The effect of perioperative analgesic drugs omnopon and dexketoprofen on the functional activity of immune cells in murine model of tumor surgery.

We aimed to investigate the effect of perioperative analgesia with nonselective cyclooxygenase-2 inhibitor dexketoprofen and opioid drug omnopon on the functional activity of immune cells in tumor excision murine model. Lewis lung carcinoma cells were transplanted into hind paw of C57/black mice. On the 23th day tumor was removed. Analgesic drugs were injected 30 min before and once a day for 3 days after the surgery. Biological material was obtained a day before, 1 day and 3 days after the tumor removal. IFN-γ, IL-4, IL-10 and TGF-ß mRNA levels in splenic cells were assessed by quantitative real-time RT-PCR. Cytotoxic activity of splenocytes was estimated by flow cytometry. We found that in splenocytes of mice received opioid analgesia IL-10 mRNA level was increased 2.3 times on day one after the surgery compared to preoperative level (P < 0.05), while in dexketoprofen group this parameter did not change. IFN-γ gene expression level on day 3 after tumor removal was 40% higher in splenocytes of dexketoprofen treated mice as compared with omnopon treated animals (P < 0.05). Cytotoxic activity of splenocytes on day 3 postsurgery was (62.2 ± 2.4)% in dexketoprofen against (50.2 ± 3.3)% in omnopon group. In conclusion, perioperative analgesia with cyclooxygenase inhibitor dexketoprofen in contrast to opioid analgesia with omnopon preserves higher functional activity of murine immune cells in the experimental model of tumor surgery.

Isothiocyanate-drug interactions in the human adenocarcinoma cell line Caco-2.

Isothiocyanates, among which alyssin is counted, are the compounds that have proved chemopreventive properties and the ability to induce the 2 and the 3 detoxification phase by affecting the transcription factor nuclear erythroid 2-related factor (Nrf2). Having a positive effect on the human body, these compounds are used as dietary supplements. Because of the observed increase in the consumption of dietary supplements taken along with the drugs routinely used in medical practice, this study examined the possibility of interactions between alyssin and drugs, which could have an impact on cell metabolism. We have determined the effects of the tested substances and their interactions on the expression and activity of the phase 2 genes, as well as on the drug transport, which could be influenced by affecting the expression of transport proteins that belong to the 3 phase of metabolism. It was also studied whether the transcription factor Nrf2 is responsible for the interactions that occurred. The results showed that the interactions between alyssin and the tested drugs strengthen or weaken the effect of the drugs given separately depending on the concentration of alyssin and the type of drug. Even though Nrf2 is involved in the interaction, it seems that it is not the only factor regulating the interactions between the tested medications.

Anti-inflammatory activity of crude saponin extracts from five Nigerian medicinal plants.

Crude saponin extracts of five medicinal plants used in the treatment of inflammatory diseases like rheumatoid arthritis, gout and haemorrhoids were screened for anti-inflammatory activity using carrageenan-induced rat paw oedema test. These plants were the whole plant of Schwenkia americana Linn (WSA), the rhizomes of Asparagus africanus Lam (RAA), the leaves of Dichrostachys cinerea Linn (LDC), the stem bark of Ficus iteophylla Miq (BFI) and the leaves of Indigofera pulchra Willd (LIP). A modify traditional method of crude saponins extraction was used to give the following percentage yields: WSA-2.74%, RAA-3.59%, LDC-1.62%, BFI-0.81% and LIP-1.57% respectively. Thin-layer chromatography was used to identify the type of saponins present in the extracts. The acute toxicity study of the crude saponin extracts in mice gave the following intraperitoneal LD50: WSA-471.2mg/kg, RAA- 1264.9mg/kg, LDC-1264.9 mg/kg, BFI-118.3mg/kg and LIP-1264.9 mg/kg respectively. The anti-inflammatory study of the extracts showed statistically significant (P<0.05) decreases in the rat paw-oedema as compared to the control. The percentage inhibitions of the extracts after four hours were as follow: WSA-61%, RAA-55%, LDC-72%, BFI-66% and LIP-40% respectively. These values were found to be comparable to that of ketoprofen-63%. The study showed that the anti-inflammatory properties attributable to these plants may be due to their saponins contents.

The effect of intravenous insulin infusion on renal blood flow in conscious sheep is partially mediated by nitric oxide but not by prostaglandins.

To test the effect of insulin on renal perfusion and the participation of NO and PG as mediators of this response, renal blood flow (RBF) was measured in sheep (n = 8) implanted with ultrasonic flow probes around renal arteries and with a systemic arterial pressure (SAP, n = 4) telemetry device. Three protocols were performed: 1) RBF and SAP were recorded (0800 to 1800 h) in fed and fasted sheep, with the latter receiving intravenous (i.v.) infusions (0.5 mL/min) of insulin at 2 or 6 mU/(kg·min); 2) fasted sheep received i.v. infusions of either an inhibitor of NO synthesis (N(G)-nitro-L-arginine methyl ester, L-NAME) alone [0.22 mg/(kg·min), 1000 to 1200 h] or L-NAME (1000 to 1200 h) + insulin during the second hour (6 mU/(kg·min), 1100 to 1200 h); and 3) the same protocol was followed as in protocol 2, substituting L-NAME with ketoprofen [0.2 mg/(kg·min)], a cyclooxygenase inhibitor. In all protocols, plasma insulin and glucose were determined. During insulin administration, euglycemia was maintained and hypokalemia was prevented by infusing glucose and KCl solutions. After the onset of meals, a long-lasting 18% increase in RBF and a 48% insulin increase were observed (P < 0.05), without changes in SAP. Low- and high-dose insulin infusions increased RBF by 19 and 40%, respectively (P < 0.05). As after meals, the increases in RBF lasted longer than the insulin increase (P < 0.05). The L-NAME infusion decreased RBF by 15% (P < 0.05); when insulin was added, RBF increased to preinfusion values. Ketoprofen decreased RBF by 9% (P < 0.05); when insulin was added, RBF increased to 13% above preinfusion values (P < 0.05). In no case was a modification in SAP or glucose noted during the RBF changes. In conclusion, insulin infusion mimics the meal-dependent increase in RBF, independent of SAP, and lasts longer than the blood insulin plateau. The RBF increase induced by insulin was only partially prevented by L-NAME. Ketoprofen failed to prevent the insulin-dependent RBF increase. Both facts suggested that complementary vasodilatatory agents accounted for the insulin effect on sheep renal hemodynamics.

Anti-inflammatory and analgesic effects of ketoprofen in palm oil esters nanoemulsion.

Ketoprofen is a potent non-steroidal anti-inflammatory drug has been used in the treatment of various kinds of pains, inflammation and arthritis. However, oral administration of ketoprofen produces serious gastrointestinal adverse effects. One of the promising methods to overcome these adverse effects is to administer the drug through the skin. The aim of the present work is to evaluate the anti-inflammatory and analgesic effects from topically applied ketoprofen entrapped palm oil esters (POEs) based nanoemulsion and to compare with market ketoprofen product, Fastum(®) gel. The novelty of this study is, use of POEs for the oil phase of nanoemulsion. The anti-inflammatory and analgesic studies were performed on rats by carrageenan-induced rat hind paw edema test and carrageenan-induced hyperalgesia pain threshold test to compare the ketoprofen entrapped POEs based nanoemulsion formulation and market formulation. Results indicated that there are no significant different between ketoprofen entrapped POEs nanoemulsion and market formulation in carrageenan-induced rat hind paw edema study and carrageenan-induced hyperalgesia pain threshold study. However, it shows a significant different between POEs nanoemulsion formulation and control group in these studies at p<0.05. From these results it was concluded that the developed nanoemulsion have great potential for topical application of ketoprofen.

Efficacy of enrofloxacin in the treatment of naturally occurring acute clinical Escherichia coli mastitis.

The efficacy of the combination of systemic enrofloxacin (5mg/kg twice with a 24-h interval, first dose i.v., second dose s.c.) and the nonsteroidal antiinflammatory agent ketoprofen (3mg/kg i.m. or 4 mg/kg per os daily for 1 to 3 d) treatment was compared with antiinflammatory treatment only in dairy cows with naturally occurring acute clinical Escherichia coli mastitis. A total of 132 cows with acute clinical mastitis and with confirmed growth of E. coli in a pretreatment milk sample were randomly allocated to 1 of 2 treatment groups. Response to treatment was evaluated clinically and by bacteriological culturing and determination of N-acetyl-beta-d-glucosaminidase (NAGase) activity on d 2 and 21 posttreatment. Enrofloxacin treatment did not increase bacteriological (90.5% of treated vs. 86.8% of nontreated cured) or clinical cure (46.7% of treated vs. 57.1% of nontreated cured), cow survival (95.3% of treated vs. 92.7% of nontreated), or quarter milk production assessed 21 d posttreatment (21.8 vs. 29.3% return to preinfection level for nontreated cows), nor did it decrease mammary gland tissue damage estimated using determination of milk NAGase activity (24.0+/-0.3 vs. 18.3+/-1.3 pmol of 4-methylumbelliferone per min per microL for nontreated cows). Treatment did not influence the number of study cows remaining in the herd after 6 mo (71.9% of treated vs. 80.6% of nontreated). The only significant effects of enrofloxacin were enhancing the bacteriological cure (odds ratio=3.32 for treated cows) and decreasing the clinical cure (odds ratio=0.05 for treated cows) on d 2 posttreatment. Our results did not support the use of enrofloxacin to treat acute clinical E. coli mastitis.

Quantitative analysis of the ultrasonic vocalization responses elicited in adjuvant-induced arthritic rats for screening analgesic drugs.

Adjuvant-induced arthritic (AIA) rats have been developed as a chronic pain model to evaluate the effects of analgesic drugs. The purpose of the present study was to examine whether there is dose-dependent inhibition of the emission of ultrasonic vocalization (USV) responses by analgesic drugs in AIA rats. It was demonstrated that morphine (1.25-5.0 mg/kg, s.c.) and ketoprofen (2.5-10.0 mg/kg, s.c.) dose-dependently inhibit USV responses. These results suggest that the USV responses elicited in AIA rats are useful for the quantitative evaluation of analgesic drugs.

Ultrasonic vocalization response elicited in adjuvant-induced arthritic rats as a useful method for evaluating analgesic drugs.

Adjuvant-induced arthritic (AIA) rats develop a severe chronic polyarthritis which shares some features in common with human rheumatoid arthritis. The purpose of the present study was to examine whether AIA rats emit ultrasonic vocalizations (USVs) when they are confronted with a healthy 'stimulus rat' in social interactions. We also examined the effects of three analgesic drugs (piroxicam, rofecoxib and ketoprofen) on USV responses using the same paradigm. In social interactions, AIA rats and intact controls emitted USVs in the 22-28 kHz range. Vocalization activities were significantly higher in AIA rats than those in intact controls. Moreover, the USVs of AIA rats were significantly inhibited by the three analgesic drugs. These results suggest that the USV responses elicited in AIA rats are useful for the evaluation of analgesic drugs.

Antioxidant and photoprotective properties of an extract from buckwheat herb (Fagopyrum esculentum MOENCH).

In recent years, the incidence of skin cancer has risen remarkably. Sun light, especially the included ultraviolet (UV)-radiation, is seen as important trigger for the development of skin cancer. Thus, there is an increasing interest in the development of UV-protective substances to use them as sun care products. One approach is the topical application of herbal antioxidants. Plant-derived antioxidants are often extracts and therefore contain a complex mixture of constituents, like flavonoids and polyphenols, which contribute to the overall activity of the extract. In the present study an extract from buckwheat herb was compared to rutin, which is the main constituent of the extract, regarding their antioxidant and radical scavenging activity. Additionally, the photoprotective properties of the extract were compared to those of a commercial UV absorber. The antioxidant activity was quantified regarding the reactivity versus the 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH). The photoprotective properties of the extract were examined by the inhibition of the photosensitized lipid peroxidation of linolic acid. In the DPPH assay, the extract had significantly better antioxidant activity than pure rutin. The extract prevented more effectively the UV-induced peroxidation of linolic acid than rutin itself or the commercial UV absorber. The use of the extract from buckwheat herb seems to be more beneficial than the use of pure rutin. This can be referred to the presence of minor phenolic compounds in the extract. The results indicate that it is advisable to use antioxidants rather than only UV absorber to obtain a maximum of photo protection.

In vitro percutaneous absorption studies and in vivo evaluation of anti-inflammatory activity of essential fatty acids (EFA) from fish oil extracts.

The aim of the present study was to evaluate the in vitro percutaneous absorption and the in vivo anti-inflammatory activity of EPA and DHA fatty acids from three oily extracts, obtained by acetonic extractions from the entrails of different varieties of Mediterranean fishes such as mackerel (Scomber scombrus), sardine (Sardina pilchardus) and horse mackerel (Trachurus mediterraneus). In the first part of our research, we focused our attention on the characterization of the oily extracts to determine their omega-3 polyunsaturated fatty acid content, then, we evaluated the in vitro percutaneous absorption through excised human skin (stratum corneum/epidermis membranes; SCE) of EPA and DHA contained in the extracts. In the second part, the fish oil which guaranteed the best in vitro permeation profile of these omega-3 fatty acids was studied in order to evaluate its inhibiting ability towards the in vivo UVB-induced skin erythema. From the results obtained, all the fish oils tested in this study presented significant amounts of omega-3 fatty acids EPA and DHA, and particularly sardine oil extract showed higher concentrations of these substances compared to the other two fish oils. The in vitro experiments revealed interesting fluxes of these compounds from sardine extract through the stratum corneum/epidermis membranes and an appreciable anti-inflammatory activity against UVB-induced erythema in human volunteers was also observed.

The effects of alpha-viniferin on adjuvant-induced arthritis in rats.

This study was performed to assess the efficacy of alpha-viniferin (Carex humilis Leyss) on adjuvant-induced arthritis in rats. Adjuvant arthritis was induced by a single subcutaneous injection of 0.1 ml complete Freund's adjuvant (CFA) containing 7.5 mg Mycobacterium butyricum suspended in 1 ml sterile paraffin oil into the right hind paw. Forty female Sprague-Dawley rats were injected. Righting reflex was uniformly lost and considered to be the initial point of arthritis development on day 7 after CFA injection. Rats were divided into four groups, and upon development of arthritis, tested groups were orally administered 3 or 10 mg/kg alpha-viniferin or 10 mg/kg ketoprofen every day for 14 days. The control group was orally administered 2 ml of physiological saline solution. Bone mineral density (BMD), radiological changes and edematous volumes were measured for 35 days. Alpha-viniferin suppressed the development of inflammatory edema, and inhibited the bone destruction, noted with a decrease in BMD (p < 0.05). Hind paw edema volume, BMD and radiological changes did not differ significantly in the ketoprofen and alpha-viniferin groups during the entire study period. In conclusion, alpha-viniferin suppressed arthritic inflammation and bony change in rats.

Effect of ketoprofen, lidocaine local anesthesia, and combined xylazine and lidocaine caudal epidural anesthesia during castration of beef cattle on stress responses, immunity, growth, and behavior.

To determine the effects of burdizzo castration alone or in combination with ketoprofen (K), local anesthesia (LA), or caudal epidural anesthesia (EPI) on plasma cortisol, acute-phase proteins, interferon-gamma production, growth, and behavior of beef cattle, 50 Holstein x Friesian bulls (13 mo old, 307 +/- 5.3 kg) were assigned to (n = 10/treatment): 1) control (handled; C); 2) burdizzo castration (B); 3) B following K (3 mg/ kg of BW i.v.; BK); 4) B following LA (8 mL into each testis and 3 mL s.c. along the line where the jaws of the burdizzo were applied with 2% lidocaine HCl; BLA); and 5) B following EPI (0.05 mg/kg of BW of xylazine HCl and 0.4 mg/kg of BW of lidocaine HCl as caudal epidural; BEPI). The area under the cortisol curve against time was lower (P < 0.05) in BK than in B, BLA, or BEPI animals. On d 1 after treatment, plasma haptoglobin concentrations were higher (P < 0.05) in B, BLA, and BEPI than in BK animals. On d 3, haptoglobin and plasma fibrinogen concentrations were higher (P < 0.05) in all castration groups than in C. On d 7, haptoglobin and fibrinogen concentrations remained higher (P < 0.05) in BLA than in B and C animals. On d 1, concanavalin A-induced interferon-gamma production was lower (P < 0.05) in B, BLA, and BEPI than in C, but there was no difference between BK and C animals. From d -1 to 35, ADG was lower (P < 0.05) in B, BLA, and BEPI animals, but not in BK compared with C animals. Overall, there was a higher (P < 0.05) incidence of combined abnormal postures in B than in C, BK and BEPI animals. Although the use of K and EPI decreased (P < 0.05) these postures compared with B alone or B with LA, there was no difference between the K and EPI treatment. In conclusion, burdizzo castration increased plasma cortisol and acute-phase proteins, and suppressed immune function and growth rates. Local anesthesia prolonged the increase in acute-phase proteins. Ketoprofen was more effective than LA or EPI in decreasing cortisol and partially reversed the reduction in ADG following castration. The use of K or EPI was more effective than LA in decreasing pain-associated behavioral responses observed during the first 6 h after treatment. Systemic analgesia with ketoprofen, a non-steroidal antiinflammatory drug, was more effective in reducing inflammatory responses associated with castration than LA or EPI.

Anti-inflammatory, analgesic and anti-pyretic effects of d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), a new non-steroidal anti-inflammatory drug, in rats and guinea pigs.

Anti-inflammatory, analgesic and anti-pyretic effects of d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), a new non-steroidal anti-inflammatory drug (NSAID), were compared with those of indomethacin, diclofenac sodium and ketoprofen in rats and guinea pigs. Anti-inflammatory effect of M-5011 on ultraviolet-induced erythema in guinea pigs was 11.7 and 1.8 times more potent than that of indomethacin and ketoprofen, respectively. Inhibitory effect of M-5011 on carrageenin-induced paw edema was 2 and 1.5 times more potent than that of indomethacin and diclofenac sodium, respectively. Analgesic effect of M-5011 on dry yeast-induced hyperalgesia or adjuvant-induced arthritic pain was equipotent to that of indomethacin, diclofenac sodium or ketoprofen. Anti-pyretic effect of M-5011 on yeast-induced pyrexia in rats was 4.2 and 4.6 times more potent than that of indomethacin and ketoprofen, respectively. Inhibitory effect of M-5011 on prostaglandin E2 production in the exudate of air-pouch inflammation induced by carrageenin was 1.75 times more potent than that in the non-inflamed site (stomach). As a result, gastric ulcerogenic activity of M-5011 was half that of indomethacin in rat. These results suggest that M-5011 shows more potent anti-inflammatory and anti-pyretic effects and equipotent analgesic effect with low gastro-ulcerogenic activity compared with classical NSAIDs.

Role of prostaglandin H synthase-2-mediated conversion of arachidonic acid in controlling 3T6 fibroblast growth.

The specific role(s) of arachidonic acid (AA) and its metabolites in the signaling pathways that regulated fibroblast growth was studied. A Western blot analysis demonstrated that prostaglandin H synthase-2 (PGHS-2) was expressed by 3T6 fibroblast cultures in RPMI 1640 supplemented with fetal calf serum (10%). Dexamethasone, which inhibits AA release and PGHS-2 expression, significantly reduced cell proliferation. Ketoprofen, a dual cyclooxygenase inhibitor, and CGP-28238, a specific PGHS-2 inhibitor, reduced fibroblast proliferation in a dose-dependent manner. These drugs also reduced [3H]thymidine incorporation into the DNA of fibroblasts. These effects were correlated with a decrease in prostaglandin (PG) E2 levels in the cell medium. However, piroxicam at doses that selectively inhibit PGHS-1 did not have a significant effect on fibroblast proliferation. Finally, we showed that the antiproliferative effect of dexamethasone and PGHS-2 inhibitors was significantly antagonized when PGE2 was added to the culture medium. Our results suggest that PGHS-2 and prostaglandins such as PGE2 might play an important role in the regulation of 3T6 fibroblast growth stimulated by growth factors of serum.

Effects of ketoprofen and ibuprofen on platelet aggregation and prostanoid formation in man.

OBJECTIVE: In the present randomized, fourway crossover study we determined the effects of two oral doses each of ketoprofen and ibuprofen on platelet aggregation and prostanoid formation in man. METHODS: Twelve healthy female volunteers received for 2 consecutive days, followed by a 5-day drug-free interval, one of the following: ketoprofen 3 x 25 mg per day, or ketoprofen 3 x 50 mg per day, or ibuprofen 3 x 200 mg per day, or ibuprofen 3 x 400 mg per day. The response criteria, determined before and on the 2nd day of each treatment period, were: maximal platelet aggregation in response to 1.0 mmol.l-1 arachidonic acid measured by the method of Born and Cross, thromboxane B2 (TXB2) concentration in platelet-rich plasma after aggregation measured by radioimmunoassay, and PGE-M, the index metabolite of total body prostaglandin E2 (PGE2) production, assessed by gas chromatography/tandem mass spectrometry using 18O2-PGE-M as internal standard. RESULTS: Platelet aggregation was significantly reduced by ketoprofen 3 x 25 mg per day (-57%) and ketoprofen 3 x 50 mg per day (-85%) as compared to control, whereas ibuprofen 3 x 200 mg per day (-3%) and ibuprofen 3 x 400 mg per day (-22%) had no significant effects. TXB2 synthesis was significantly decreased by ketoprofen 3 x 25 mg per day (-72%), ketoprofen 3 x 50 mg per day (-97%) and ibuprofen 3 x 400 mg per day (-48%) as compared to control; ibuprofen 3 x 200 mg per day did not reduce TXB2 formation significantly (-23%). All four treatments reduced 24-h urinary excretion of PGE-M significantly in the range of -39% (ketoprofen 3 x 25 mg per day) to -53% (ibuprofen 3 x 400 mg per day) without significant differences between treatments. CONCLUSION: Our data show that both ketoprofen dosages were more effective in inhibition of platelet aggregation and platelet thromboxane synthesis than ibuprofen in low or high dosage. Total body synthesis of the E-prostaglandins was inhibited by all drug schedules without significant differences between treatments.