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PubMed1992

Sister-chromatid exchanges induced by vinyl esters and respective carboxylic acids in cultured human lymphocytes.

Vinyl acetate--an efficient inducer of sister-chromatid exchanges (SCEs)--is known to be hydrolyzed in mammalian cells into acetic acid and acetaldehyde, the latter being the likely metabolite responsible for the SCE induction. As similar hydrolysis to acetaldehyde and to a carboxylic acid is also expected for other vinyl esters, five such compounds--vinyl formate, vinyl chloroformate, vinyl propionate, vinyl crotonate and vinyl-2-ethylhexanoate--and five carboxylic acids--formic acid, acetic acid, propionic acid, crotonic acid and 2-ethylhexanoic acid--were tested for their ability to induce SCEs in cultured (72 h) human lymphocytes with a 48-h treatment, starting at 24 h after culture initiation. Vinyl formate, vinyl propionate and vinyl crotonate induced a clear dose-dependent increase in the number of SCEs/cell at concentrations of 0.125-0.5 mM and vinyl chloroformate at 0.063-1 mM, i.e., at roughly the same concentration range as vinyl acetate and acetaldehyde. Vinyl-2-ethylhexanoate required slightly higher concentrations (0.25-4 mM) for SCE induction. All of the carboxylic acids tested also elevated SCEs, but only slightly. Formic acid and crotonic acid produced some SCE increase at a concentration of 10 mM, acetic acid at 5 and 10 mM and propionic acid at 2.5 mM. 2-Ethylhexanoic acid induced SCEs at a lower concentration range (0.63-2.5 mM) than the other acids. The positive concentrations of the first three carboxylic acids lowered the pH of the culture medium immediately after the treatment by 0.5-1.0 pH unit (lowest observed pH 6.53). The pH differences from the control cultures became smaller in measurements done 24 h and 48 h after the beginning of treatment. Propionic acid and 2-ethylhexanoic acid affected medium pH only slightly (maximum drop 0.2 pH units) at the concentrations that induced SCEs. The results lend support to the idea that the efficient SCE induction observed with the vinyl esters results from the formation of acetaldehyde, with carboxylic acids--with the possible exception of 2-ethylhexanoic acid--playing no significant role. The slight SCE induction obtained with the carboxylic acids cannot be explained by lowered pH alone.

Carboxylic Acids↗
PubMed1996

The field bean protease inhibitor can effectively suppress 7,12-dimethylbenz[a]anthracene-induced skin tumorigenesis in mice.

Prolonged topical treatment with protease inhibitors (PIs) both synthetic and of bacterial origin have been shown to prevent carcinogen initiated and croton oil or phorbol acetate promoted skin carcinogenesis in mice. However, no one has yet examined the possibility of a purified PI of plant origin to block skin carcinogenesis by sustained local treatment. We therefore studied this aspect using a purified PI from field bean (FBPI) in Swiss albino mice. Groups of 8-week-old mice were taken and treated differently. Group I mice were treated with 100 microliters of acetone alone, while mice of Group II were treated with a single high (150 micrograms) dose of 7,12-dimethylbenz[a]anthracene in acetone and 2 weeks later they were treated with a high concentration (125 micrograms) of croton oil thrice weekly. Mice of Groups III, IV and V were treated exactly as described for mice of Group II, but 4 h after croton oil treatment they were further treated with an aqueous solution of 1 mg, 2 mg of FBPI or 2 mg of heat-inactivated [corrected] FBPI, respectively. Treatment of all groups was continued until the mice were 25 weeks old, the appearance of tumors being recorded during the period. Our findings showed that treatment of carcinogen and croton oil exposed mice of Groups III and IV with two different doses of FBPI not only brought about appreciable delay in the appearance of tumors but also significant (P < 0.025-0.001) suppression of tumor incidence at nearly all times of promotion. Additionally, it lowered significantly (P < 0.01-0.001) the tumor multiplicity and the tumor appearance rate compared to mice of Groups II and V. These effects of FBPI appeared to be dose related. Lack of response with heat-inactivated FBPI indicated that these actions of FBPI were related to its PI activity. The study thus confirmed that topical treatment with a legume-derived PI can effectively suppress skin carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Inflammation-induced changes in serum modulate chicken macrophage function.

Inflammation-induced changes in serum protein profiles and the effects of such serum on a chicken macrophage cell line HD11 were studied to find whether the changes in serum affect cellular immunity. Four-week-old male broiler chickens were injected subcutaneously with either olive oil or 50% croton oil mixed in olive oil to induce inflammation. The birds were bled at 48h after injection, and serum protein profiles were compared using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and densitometric evaluation. At 48h post-injection the serum from croton oil-injected birds showed distinct changes in protein profiles characterized by a selective increase or decrease in levels of several serum proteins. The protein bands which showed increases had relative molecular weights (Mr) corresponding to 65kilo Daltons (kD), 42kD, and two or more proteins with Mr> or =200kD. The levels of serum albumin (49kD), and a 56kD protein were reduced in croton oil-injected birds. The modulating effects of such serum on HD11 cells were studied using bacterial lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) induced functional activation of these cells. The LPS-induced interleukin-6 (IL-6) production by HD11 cells was not affected by the presence of either olive oil-treated control or croton oil-treated inflammatory serum but nitrite production was enhanced by the inflammatory serum. Similarly, inflammatory serum also enhanced PMA-induced respiratory burst measured using dichlorofluorescein diacetate (DCF-DA) oxidation mediated by reactive oxygen intermediates. These results suggest that inflammatory serum can modulate macrophage function by influencing the production of reactive oxygen and nitrogen species which could affect their phagocytic and bactericidal activities.

Animals↗
PubMed1982

Two-stage skin carcinogenesis in sensitive and resistant mouse strains.

Strains of laboratory mice vary markedly in their susceptibility to two-stage skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating carcinogen and croton oil as promoter. This study has been undertaken in order to clarify the basis of the strain differences. LACA mice were used as the susceptible strain and BALB/c mice as the resistant strain. DMBA was a more effective complete carcinogen in LACA mice than in BALB/c mice. However, dose-response studies with respect to DMBA in the two strains in two-stage carcinogenesis suggested that metabolic activation of DMBA to the active carcinogen was not limiting in the resistant strain. The observed strain differences in response to DMBA in one and two stage carcinogenesis may reflect the ability of DMBA to also act as a promoter in the two strains. The possibility that the strains vary in their ability to repair damaged DNA has, however, not been eliminated. Unlike polycyclic aromatic hydrocarbon carcinogens such as DMBA, phorbol ester promoters (the active components in croton oil) do not appear to require metabolic activation. However, they are degraded and inactivated by epidermal and other cells. Experiments in which the dose and frequency of application of croton oil were increased, and the unrelated promoter anthralin was substituted for croton oil, failed to produce any evidence that differences in promoter degradation contributed to the differences in susceptibility between strains.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Differential diagnosis of AH109A tumor and inflammation by radioscintigraphy with L-[methyl-11C]methionine.

For the evaluation of tumor imaging with L-[methyl-11C]methionine (11C-Met), a basic study on the differentiation of tumor from inflammation with 11C-Met and a comparison of the diagnostic value of the image with that obtained using 67Ga citrate, a conventional scintigraphic agent, are important. 11C-Met accumulations into inflammatory lesions, AH109A tumor and normal tissues of rats were examined by means of a tissue distribution study. Aseptic inflammatory lesions on the back of Donryu rats induced by croton oil and 1.5% carrageenan showed significantly lower accumulations of 11C-Met than the AH109A tumor. Histologically, croton oil induced granulomatous inflammation and carrageenan, acute exudative inflammation. Whole-body autoradiography with 14C-Met, a substitute for 11C-Met, was negative in the carrageenan lesion and showed a slightly increased activity at the periphery of the croton oil lesion, in contrast with the high tumor activity. Whole-body autoradiography with 67Ga citrate was performed to compare the imaging ability with that of 14C-Met; it showed high activities in the tumor, bone, and intestine, and a broad increased activity at the periphery of the croton oil lesion, but was negative in the carrageenan lesion. 11C-Met accumulations in the inflammations were very low and clinical application with positron emission tomography, should be useful for the differential diagnosis of tumor from inflammation.

Animals↗
PubMed2004

Intestinal inflammation alters the susceptibility to pentylenetetrazole-induced seizure in mice.

BACKGROUND: Inflammatory bowel disorders are associated with increased incidence of seizures. Alteration in the endogenous opioid system and overproduction of nitric oxide have been implicated in colitis. The possible contribution of opioid receptors and nitric oxide to increased seizure susceptibility was examined in a putative model of intestinal inflammation. METHODS: The alterations in clonic seizure threshold, induced by pentylenetetrazole, following the induction of intestinal inflammation by the administration of two consecutive daily oral doses of croton oil, was evaluated in mice. This model was used to evaluate the effects of pretreatment with opioid receptor antagonist naltrexone (10 mg/kg, once daily for 4 days or a single dose on the test day), non-specific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg/kg, once daily), and specific inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg, once daily) on seizure threshold in intestinal inflammation. RESULTS: A significant decrease in clonic seizure threshold was observed in mice with intestinal inflammation compared to the control group. Chronic pretreatment with naltrexone per se did not cause any significant change in seizure threshold, but it significantly restored the threshold in croton oil-treated mice to that of the control animals. However, acute naltrexone pretreatment (on the test day) could not restore the decreased seizure threshold to control level. Chronic pretreatment with neither NG-nitro-L-arginine methyl ester nor aminoguanidine altered the seizure threshold in the control animals and in mice treated with croton oil. CONCLUSIONS: Experimental croton oil-induced intestinal inflammation leads to a proconvulsant effect, which may have clinical relevance. Chronic alterations mediated by endogenous opioids may be involved in this process, though a direct opioid-receptor-mediated effect is unlikely. Nitric oxide synthesis, via constitutive or inducible pathways, is not involved in this increased susceptibility.

Animals↗
PubMed1985

[The antiinflammatory effect of budesonide].

The systemic and topical antiinflammatory activities of budesonide (B) were studied in rats and mice and compared with those of commercially available steroids. Betamethasone 17-valerate (BV) was used as the main reference compound, and fluosinolone acetonide (FA), hydrocortisone 17-butyrate (HB) and hydrocortisone 21-acetate (HA) were also used. B given systemically had stronger antiinflammatory effect than BV on carrageenin edema, cotton pellet granuloma, adjuvant arthritis, croton oil edema, PCA reaction, Arthus reaction, contact hypersensitivity and histamine or serotonin skin reaction. The potency of antiinflammatory activity of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was in the order of FA, B, BV, HB and HA. B given locally also produced stronger antiinflammatory effects than BV on carrageenin edema, cotton pellet granuloma, croton oil edema and contact hypersensitivity. The order of potency of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was the same as by systemic application. In general, the ratio of the dose required to cause atrophy of the thymus and adrenals to the dose required to produce the antiinflammatory effect was the greatest with B by both systemic and local application. The results suggest that B has a stronger antiinflammatory activity with fewer systemic side effects than conventional steroid compounds.

Adrenal Gland Diseases↗
PubMed1983

Multistage tumor development in the human esophagus - the first identification of cocarcinogens of the tumor promoter type as principal carcinogenic risk factors in a local life style cancer.

An experimental analysis is described which demonstrates that the epidemiologically established high rate of esophageal cancer among blacks and creoles in Curacao most likely is the result of a multistage process involving initiators and promoters. As part of local lifestyle, the group at risk utilizes for various purposes plant parts of an indigenous bush Croton flavens L. ("Welensali"). Moreover they consume, as an everyday beverage, a "bush tea" made from the leaves of the bush. The roots, leaves and tea are shown to contain a multitude of irritant croton factors which are characterized as diterpene esters of the tigliane type. In mouse skin these exhibit strong promoting activity comparable to that of TPA. As the latter, also the croton factors isolated, show no solitary carcinogenic activity. One cup of Welensali tea contains the equivalent of about 12-times the irritant dose of croton factor F1; in addition, the equivalent of about 1.4-times the irritant dose 50 of the corresponding "cryptic" promoter F1-20-decanoate is present. These amounts are considered sufficient to maintain chronic irritation of the esophagus as an important element of co-carcinogenesis, especially of tumor promotion. Also, persons at risk in Curacao have been exposed at times previously to certain initiators. Mice treated by an initiation/promotion protocol with DMBA (or other initiators) and TPA develop tumors of the forestomach. Therefore, esophageal cancer on Curacao may be considered the first case for cocarcinogens of the tumor promoter type being principal risk factors in a life style cancer.

Animals↗
PubMed1993

In vivo activation of mouse dendritic epidermal T cells in sites of contact dermatitis.

Adult mouse epidermis contains a population of dendritic, Thy-1+, CD3+, CD4-, CD8- and T cell receptor (TcR) V gamma 3/V delta 1+ leukocytes termed dendritic epidermal T cells (DETC). DETC isolated from skin and placed into culture will proliferative vigorously in response to T cell mitogens and T cell growth factors. In the present study, we examined whether DETC can be activated in situ by modulating their epidermal environment. Ear skin of CBA mice was painted with the chemical irritant, croton oil, and the epidermal cells (EC) isolated from such sites were then tested for proliferative responses to exogenous interleukin-2 (IL-2), in the absence of added mitogens. Cells from croton oil-treated skin showed marked IL-2 responsiveness, whereas cells from phosphate-buffered saline-treated skin failed to proliferate. IL-2 responses were seen as early as 2 days after croton oil treatment and peaked between days 5 and 10. gamma delta TcR-bearing cells, most likely resident DETC, were the major population to respond to IL-2, since depletion of gamma delta TcR+ cells, but not alpha beta TcR+ cells, abolished that responsiveness, and since gamma delta TcR+ cell numbers increased markedly in the cultures that contained added IL-2. These results indicate that DETC in normal skin, which are at a state of rest, may be activated when their residential epidermal environment is disrupted externally. This process of DETC activation may be a critical step in the maturation of DETC into effector leukocytes in vivo.

Animals↗
PubMed1990

Effects of topical cyclosporin A on guinea-pig toxic contact dermatitis.

It is known that the topical application of cyclosporin A (CsA) has a significant suppressive effect on allergic contact dermatitis. In this study, we investigated the effect of topical CsA on toxic (non-allergic) contact dermatitis. Topical CsA significantly suppressed the toxic contact reaction to croton oil. This suppressive effect was short-lived and reversible. Significant inhibition of the reaction to croton oil persisted for 3 days after stopping the CsA. The toxic reaction was blocked when CsA was applied within 6 h of the croton oil application, but when application of CsA was delayed until 12 h after the oil application there was no significant suppressive effect. Topical administration of CsA could become a valuable tool for treating toxic and allergic contact dermatitis without producing the adverse reactions caused by systemic therapy.

Animals↗
PubMed1985

Mechanisms of chemically induced skin irritation. I. Studies of time course, dose response, and components of inflammation in the laboratory mouse.

The possibility that chemicals induce skin irritation by multiple mechanisms was studied in laboratory mice. The time course and dose response to topical application of phenol, croton oil, benzalkonium chloride, ethyl phenylpropiolate (EPP), and methyl salicylate were compared. The responses to each chemical were measured as changes in ear thickness following application to one ear. Maximal responses were as follows: methyl salicylate 20 min, phenol 1 hr, croton oil and benzalkonium chloride 6 hr, and EPP 8 hr. The response to EPP included an early, smaller response at 1 hr. Time courses of the responses were not altered by changing the vehicle in which the irritants were applied or by altering the dose. The rates of regression of the inflammatory responses also varied. Although visibly normal, thickness of ears treated with either phenol or benzalkonium chloride remained 0.05 to 1 mm thicker than solvent-treated control ears for 6 weeks. Although the incidence of prolonged thickness was dose related, it was not determined by the intensity of the acute response; doses of other irritants which produced equivalent acute increases in ear thickness did not produce similar changes. The components of the acute responses, i.e., vascular permeability, change in blood flow, and cellular infiltration, to 5 mg methyl salicylate, 2 mg EPP, and 0.05 mg croton oil were compared in studies of tissue histology, changes in vascular permeability by trypan blue and 125I-labeled bovine serum albumin, and change in local surface temperature as an index of blood flow. The histology of the reactions at the time of maximum response to the chemicals differed. Multiple periods of increased permeability and increased surface temperature were produced by the irritants. The permeability and blood flow responses produced by the irritants varied in number, time of occurrence relative to time of application and to time of maximum response, and in magnitude of the changes. Differences in time courses of the responses which were not altered by experimentally varying rate of absorption and in components of the inflammatory response to the three irritants suggest that chemicals induce skin irritation by multiple mechanisms.

Absorption↗
PubMed1995

Effects of prostaglandin antagonist phloretin derivatives on mouse ear edema induced with different skin irritants.

Edema was induced in one ear of male mice of the CFLP strain with solutions of different skin irritants (croton oil 10 microL/35 micrograms, dithranol 10 microL/30 micrograms, capsaicin 10 microL/40 micrograms or arachidonic acid to 10 microL/2 mg per ear). Edema, determined by the edema-disk gravimetric technique, was inhibited in a dose-dependent manner by the intraperitoneally administered prostaglandin antagonists polyphloretin phosphate (PPP) or di-4-phloretin phosphate (DPP). With croton oil-induced mouse ear edema, DPP 10 mg/kg caused a 38% inhibition, PPP 25 mg/kg a 33% inhibition. With dithranol-induced edema DPP 0.5 mg/kg caused a 57% inhibition, while PPP 25 mg/kg was needed to exert a similar effect. Doses of DPP and PPP needed to cause a > 40% inhibition of edema were 10 mg/kg and 25 mg/kg, respectively, for capsaicin, and 25 mg/kg and 100 mg/kg for arachidonic acid. The inhibition of the ear edema by the phloretin derivatives was: dithranol > croton oil > capsaicin > arachidonic acid. This probably reflects the different contributions of prostaglandins to the inflammation.

Animals↗
PubMed2004

Effect of an EGF-cancer vaccine on wound healing and inflammation models.

BACKGROUND: Epidermal growth factor (EGF) and its receptor (EGF-R) are attractive targets for cancer immunotherapy. Tolerance has been broken with an EGF-vaccine and antibodies against EGF have been produced in animals and in cancer patients. EGF also plays an important role in the inflammation stage of wound healing. Because this therapeutic approach may be of importance after surgery procedures in cancer patients, we decided to investigate the possible role of the EGF-vaccine in the croton-oil-induced ear edema and in the wound healing experimental animal models. MATERIALS AND METHODS: Mice were immunized with an EGF-vaccine by intramuscular injections and serum titers against EGF were measured through ELISA techniques. Control animals received saline. RESULTS: Immunized mice produced antibodies against EGF while no antibody titers could be measured in control animals. Croton oil applied to the inner ear surface of EGF-vaccine treated mice caused a 61.3% lower ear punch weight and a 60.2% lower myeloperoxidase activity than control mice. In the EGF-vaccine treated animals, planimetry measurements and histological analysis did not led to significant impairment in tissue repair. CONCLUSIONS: The EGF-vaccination in mice decreased the normal croton-oil-induced inflammation response, without apparent impairment in tissue healing.

Animals↗
PubMed2000

Effects of mu-opioid receptor agonists on intestinal secretion and permeability during acute intestinal inflammation in mice.

We evaluated and compared the effects of mu-opioid receptor agonists on mucosal fluid transport and permeability, during acute intestinal inflammation. We hypothesized that inflammation would sensitize mu-opioid receptors in the submucosal plexus and/or enterocytes enhancing the effects of mu-opioid receptor agonists. Inflammation was induced by intragastric administration of croton oil, whereas controls received saline. Fluid transport was assessed by enteropooling, and intestinal permeability by blood-to-lumen passage of [51Cr] etylenediaminetetraacetate ([51Cr] EDTA). Intestinal inflammation induced a significant increase in enteropooling (1.9 times) and permeability (2.5 times). In saline- and croton oil-treated animals, mu-opioid receptor agonists produced dose-related inhibitions of enteropooling and intestinal permeability. During inflammation, the potency of morphine increased 4.8 and 3.7 times, inhibiting enteropooling and intestinal permeability, respectively; the potencies of fentanyl and PL017 similarly increased by approximately three (enteropooling) and two times (permeability) in croton oil animals. All effects were reversed by naloxone and naloxone methiodide. The results show that inflammation increases the inhibitory potency of mu-opioid receptor agonists on secretion and permeability, suggesting a sensitization of peripheral mu-opioid receptors.

Acute Disease↗
PubMed1975

Immunologic alterations in patients with prostatic carcinoma.

The state of cell-mediated immunity was evaluated in 41 patients with prostatic carcinoma by determining their ability to demonstrate delayed cutaneous hypersensitivity with dinitrochlorobenzene and recall antigens, and to mount an inflammatory response to croton oil, as well as by measuring changes in monocyte chemotactic response. The patients were divided into 2 groups: those with localized disease and those with metastatic carcinoma. Monocyte chemotactic response provides an in vitro quantitative measure of effector cell function and was significantly depressed in the entire group of prostatic cancer patients as compared to non-cancer controls (p less than 0.05). Patients with metastatic carcinoma had a greater defect than those with localized disease (p less than 0.025). After radical prostatectomy a group of patients with localized disease tended to show improvement in monocyte chemotactic response (p less than 0.025). The ability of patients to develop a delayed cutaneous hypersensitivity response was impaired and correlated with the clinical stage of the disease. By using the cutaneous irritant, croton oil, the ability of these cancer patients to mount an inflammatory response was also found to be impaired and showed a close correlation between clinical stage and course of disease. Changes in response to croton oil tended to precede alterations in dinitrochlorobenzene response.

Adult↗
PubMed2000

New steroidal anti-inflammatory antedrugs: methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, and their 9alpha-fluoro derivatives*.

To a series of 21-desoxy-21-chloro-corticosteroids, a metabolically labile methoxycarbonyl group at C-16 has been incorporated. The approach is to synthesize locally active compounds that are hydrolyzed to inactive and readily excretable acid metabolites upon entry into the systemic circulation. Novel antedrugs were evaluated for anti-inflammatory activity and their adverse effects in an acute and semichronic croton oil-induced ear edema bioassay. Binding affinity to glucocorticoid receptors and induction of L-tyrosine-2-oxoglutarate aminotransferase were studied in hepatoma tissue culture cells. After a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID(50) values (nmol/ear resulting in a 50% reduction of edema) were calculated: 540, 618, 454, and 346 nmol for prednisolone (P), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (PClCM), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-9alpha-fl uoro-3, 20-dioxo-1,4-pregnadien-16alpha-carboxylate (FPClCM), and methyl 21-desoxy-21-chloro-9alpha-fluoro-11beta-hydroxy-3,20-dioxo- 1, 4-pregnadien-16alpha-carboxylate (FDPClCM), respectively. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast with the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. The binding affinities for cytosolic hepatoma tissue culture glucocorticoid receptors were 33, 201, 471, 5304, and 3765 nM for P, PClCM, FPClCM, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (DPClCM), and FDPClCM, respectively. Collectively, results of these investigations suggest that modifications of P, which included replacement of 21-hydroxyl group with chlorine and addition of 16-methoxycarbonyl group with or without 17-hydroxyl moiety, retained the topical anti-inflammatory activity of the parent compound P without significant adverse systemic effects.

Animals↗
PubMed2003

Effects of valeryl salicylate, a COX-1 inhibitor, on models of acute inflammation in mice.

The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2mg per ear; 20 microliters) or croton oil (1mg per ear; 20 microliters) to the inner surface of the left ear and the change in the ear's thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after lh at doses of 1.5-45 micrograms per ear; however, only at the dose of 45 micrograms per ear was it able to significantly reduce the croton oil-induced oedema at 6h. Paw oedema was induced by the injection of 25 microliters of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2h, in the early phase (0-4h), and the other, occurring at 48h after carrageenan injection, in the late phase (24-72h). The pre-treatment with VS significantly reduced the paw oedema at 2h, the same effect observed with celecoxib and indomethacin treatments. At 24h, VS did not inhibit oedema but significantly increased it mainly at 48h after carrageenan injection. These results showed that VS was pharmacologically active in these models and suggest that COX-1 may participate in the early and late phases of inflammation in the models studied.

Acute Disease↗
PubMed2001

Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice.

1. We have studied the effect of palmitoylethanolamide (PEA, 2.5 - 30 mg kg(-1), i.p.) on upper gastrointestinal transit in control mice and in mice with chronic intestinal inflammation induced by croton oil. 2. PEA significantly and dose-dependently decreased intestinal transit. The inhibitory effect of PEA (10 mg kg(-1)) was not modified by the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg kg(-1), i.p.), the cannabinoid CB(2) receptor antagonist SR144528 (1 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 25 mg kg(-1), i.p.), yohimbine (1 mg kg(-1), i.p.), naloxone (2 mg kg(-1), i.p.) or hexamethonium (1 mg kg(-1), i.p.). 3. PEA levels were significantly decreased in the small intestine of croton oil-treated mice. In these animals, PEA also inhibited motility and this effect was not counteracted by SR141716A (0.3 mg kg(-1)), or SR144528 (1 mg kg(-1)). 4. Pre-treatment of mice with the amidase inhibitor phenylmethyl sulphonil fluoride (PMSF, 30 mg kg(-1), i.p.) did not modify the inhibitory effect of PEA, either in control or in mice with inflammation. 5. It is concluded that PEA inhibits intestinal motility with a peripheral mechanism independent from cannabinoid receptor activation. The decreased levels of PEA in croton oil-treated might contribute, at least in part, to the exaggerated transit observed during chronic intestinal inflammation.

Adrenergic alpha-Antagonists↗