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PubMed1993

Vanilloids. 1. Analogs of capsaicin with antinociceptive and antiinflammatory activity.

As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.

Analgesics↗

PubMed1987

17-Heteroaroyl esters of corticosteroids. 2. 11 beta-Hydroxy series.

The preparation and topical antiinflammatory potencies of a series of 17-furoyl and -thenoyl esters of 9 alpha-fluoro-11 beta-hydroxy-16 methyl and 9 alpha-chloro-11 beta-hydroxy-16-methyl corticosteroids are described. The 17 alpha-esters were introduced to the 9 alpha-fluoro 11-ketones or to the appropriate delta 9(11) compounds by direct acylation with the appropriate heteroaryl carbonyl chloride in the presence of 4-(dimethylamino)pyridine. Functionalization of the C ring was completed by standard methods. The most extensively studied heterocyclic acyl group was 2-furoyl, but 3-furoyl and 2- and 3-thenoyl derivatives were also investigated. Antiinflammatory potencies were measured in mice by a 5-day modification of the Tonelli croton oil ear assay. The most potent topical antiinflammatory agents were 1e, dexamethasone 17-(2'-furoate) 21-propionate, and 2c, the 21-chloro 17-(2'-furoate) in the 9 alpha-chloro series, both being 6 times as potent as betamethasone 17-valerate. Several other 9 alpha-chloro-11 beta-hydroxy-17-heteroaryl carboxylates (2a, 2b, 2d, and 2g) were at least 4 times as potent as betamethasone 17-valerate. Evaluation of 2c in the clinic confirmed that the compound is a potent topical antiinflammatory agent in humans.

Adrenal Cortex Hormones↗

PubMed2003

Labdane and kaurane diterpenoids from Plectranthus fruticosus.

Six new diterpenoids, three labdane and three kaurane derivatives, have been isolated from an acetone extract of Plectranthus fruticosus together with other already known substances. The structures of these compounds (1-5 and 7) were established mainly by spectroscopic means, particularly by 1D and 2D NMR studies, as well as by some chemical correlations with known diterpenoids. The physical and spectroscopic data of the derivative 11, obtained by hydrolysis of the labdane 2, were identical to those reported for a compound previously isolated from Croton joufra, to which structure 12 had been established erroneously by other authors. Several of the isolated compounds were tested as antimicrobial agents against three bacteria strains and one yeast strain, but only 4 showed a moderate inhibitory activity against Staphylococcus aureus.

Anti-Bacterial Agents↗

PubMed1972

Tumour formation in mice by urethane administered with related carbamates.

A tumour initiating dose of ethyl carbamate was administered to mice by subcutaneous injection together with a dose of one of the homologous esters or an ethyl N-alkyl derivative. The homologues used were the methyl, n-propyl and n-butyl esters, and the derivatives were the N-methyl, N-ethyl and N-n-propyl ethyl esters. The mice were then given promoting treatment with croton oil for 28 weeks.Neither the homologous esters nor the N-substituted derivatives of ethyl carbamate had any influence on the yield of tumours in the skin, lung, or liver. However, increasing the dose of ethyl carbamate increased the yields of tumours.

Animals↗

PubMed1977

Two-stage carcinogenesis with rat embryo cells in tissue culture.

Transformation of rat embryo fibroblasts in vitro has been investigated using initiation with either benzo(a)pyrene (BaP), 7,12-dimethylbena(a)anthracent (DMBA) or benzo(e)pyrene (BeP) and promotion with either phorbol ester (TPA) or croton oil (Cr.Oil). The criteria used to assess in vitro transformation were (a) the efficiency of cloning in liquid medium, (b) abnormal cellular morphology and (c) the development of malignant tumours following s.c. inoculation of newborn rats. The results show that the cloning efficiency, which remained low in the control cells, was increased to a variable extent in the treated groups. Transformation occurred in all groups, but occurred earliest in cells that were initiated and promoted. Initiation with DMBA or BaP and promotion with TPA or Cr.Oil led to the earliest acquisition of malignancy. Correlations were found between the transformation of cells in vitro and the acquisition of malignant potential, and between the carcinogenic action of the compounds in vitro and their action in vivo, but cloning efficiency was not a reliable indicator of in vitro transformation or of malignancy. In most cases in vitro transformation appeared to precede the acquisition of malignancy, but in two cases it occurred later. The studies also show that BeP, which is a tumour initiator in vivo, also acts in this way in vitro. The conclusion drawn from a discussion of these results and of two-stage carcinogenesis in vivo is that two-stage carcinogenesis can be reproduced in tissue culture; this model may be useful in studies of those mechanisms of chemical carcinogenesis that involve the processes of initiation and promotion.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1985

Effect of immunosuppressive agents and sunscreens on UV carcinogenesis in the hairless mouse.

The effect of two immunosuppressive agents, azathioprine and cyclophosphamide, with and without UVB sunscreen protection on UV-induced skin carcinogenesis was studied in the albino hairless mouse. In a daily treatment regime spanning 9 weeks, groups of mice were immunosuppressed with either drug, and were exposed to minimally erythemal doses of a light source simulating the UV portion of the solar spectrum. The accumulated UV exposure alone induced skin tumours in 77% of mice. Azathioprine, but not cyclophosphamide, significantly enhanced the incidence of UV tumorigenesis. Photoprotection by topical application of one of two commonly used UVB sunscreens, 2-ethyl-hexyl-p-methoxycinnamate (2-EHMC) or octyl-N-dimethyl-p-aminobenzoate (o-PABA), reduced the UV tumour incidence to zero in immunologically normal mice and to 8-15% in immunosuppressed mice. Unexpressed latent tumour initiations were revealed in all sunscreen-protected groups by the subsequent application of a tumour promoter, croton oil. In immunologically normal mice 2-EHMC had allowed initiations in 39% of UV-irradiated mice, and o-PABA in 16.5%. However, in UV-irradiated mice immunosuppressed with azathioprine there had been initiations in 78% of mice protected with 2-EHMC and 65% of mice protected with o-PABA. Photoprotected mice immunosuppressed with cyclophosphamide did not show the same increase in UV-initiations (22% with 2-EHMC, 23% with o-PABA). These results provide evidence that azathioprine increases the susceptibility of the skin to UV carcinogenesis. However, UVB sunscreens afford effective protection from overt tumour expression in the absence of a tumour promoter.

4-Aminobenzoic Acid↗

PubMed2001

Analysis of the temporal expression of chemokines and chemokine receptors during experimental granulomatous inflammation: role and expression of MIP-1alpha and MCP-1.

1. Chemokine expression and function was monitored in an experimental model of granulomatous tissue formation after injection of croton oil in complete Freund's adjuvant (CO/CFA) into mouse dorsal air-pouches up to 28 days. 2. In the first week, mast cell degranulation and leukocyte influx (mononuclear cell, MNC, and polymorphonuclear cell, PMN) were associated with CXCR2, KC and macrophage inflammatory protein (MIP)-2 mRNA expression, as determined by TaqMan reverse transcriptase-polymerase chain reaction. KC ( approximately 400 pg x mg protein(-1), n=12) and MIP-2 (approximately 800 pg x mg protein(-1), n=12) proteins peaked at day 7, together with myeloperoxidase (MPO) activity. Highest MIP-1alpha (>1 ng x mg protein(-1), n=12) levels were measured at day 3. 3. After day 7, a gradual increase in CCR2 and CCR5 mRNA, monocyte chemoattractant protein (MCP)-1 mRNA and protein expression was measured. MCP-1 protein peaked at day 21 (approximately 150 pg x mg protein(-1), n=12) and was predominantly expressed by mast cells. A gradual increase in N-acetyl-beta-D-glucosaminidase (NAG) activity (maximal at 28 days) was also measured. 4. An antiserum against MIP-1alpha did not modify the inflammatory response measured at day 7 (except for a 50% reduction in MIP-1alpha levels), but provoked a significant increase in MPO, NAG and MCP-1 levels as measured at day 21 (n=6, P<0.05). An antiserum to MCP-1 reduced NAG activity at day 21 but increased MPO activity values (n=8, P<0.05). 5. In conclusion, we have shown that CO/CFA initiates a complex inflammatory reaction in which initial expression of MIP-1alpha serves a protective role whereas delayed expression of MCP-1 seems to have a genuine pro-inflammatory role.

Animals↗

PubMed2005

The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice.

Intestinal inflammation enhances the potency of mu-opioid receptor (MOR) agonists inhibiting gastrointestinal transit and increases the expression of MOR in mice intestine. The precise mechanisms implicated in the increased expression of MOR during intestinal inflammation are not known. The aim of the study is to evaluate if nitric oxide released during intestinal inflammation could modulate MOR gene expression and affect gastrointestinal transit. Intestinal inflammation was induced by the intragastric administration of croton oil. In CD-1 mice, with and without inflammation, we evaluated the anti-transit effects of morphine in animals treated with NOS inhibitors (L-NAME and L-NIL) and the intestinal levels of iNOS enzyme mRNA. The anti-transit effects of morphine and the expression of MOR mRNA in the gut of wild-type (WT) and iNOS-/- mice were also assessed. Gastrointestinal transit was measured with charcoal meal and mRNA levels determined by real-time PCR. In CD-1 mice, inflammation induced a 10-fold increase (P<0.0001) in iNOS mRNA levels in the gut. The absence of iNOS gene and treatment of CD-1 mice with L-NAME or L-NIL abolished the increased antitransit effects of morphine observed during inflammation. Moreover, although the basal levels of MOR mRNA were similar in WT and iNOS animals (-/-), intestinal inflammation only increased the MOR expression in the gut of WT (P<0.01) but not in iNOS-/- mice. The results suggest that nitric oxide derived from the increased expression of iNOS is implicated in the enhanced effects of morphine and in the upregulation of MOR gene transcription observed during intestinal inflammation.

Animals↗

PubMed2003

Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin.

Interleukin 18 induces both T helper 1 and T helper 2 cytokines, proinflammatory cytokines, chemokines, and IgE and IgG1 production. A role of interleukin 18 in inflammatory cutaneous reactions is still unclear, however. Here we generated keratin 5/interleukin 18 transgenic mice overexpressing mature murine interleukin 18 in the skin using a human keratin 5 promoter. In the contact hypersensitivity model, trinitrochlorobenzene elicited a stronger ear swelling in keratin 5/interleukin 18 transgenic mice compared with control littermate wild-type or immunoglobulin/interleukin 18 transgenic mice in which mature interleukin 18 was expressed by B and T cells under the control of the immunoglobulin promoter. Application of an irritant, croton oil, induced stronger and more sustained ear swelling in keratin 5/interleukin 18 transgenic mice than in immunoglobulin/interleukin 18 transgenic or wild-type mice. Repetitive topical application (weekly for six consecutive weeks) of trinitrochlorobenzene to their ears also elicited a stronger cutaneous inflammation in keratin 5/interleukin 18 transgenic mice than seen in immunoglobulin/interleukin 18 transgenic or wild-type mice. After these six trinitrochlorobenzene applications, the expression of interferon-gamma, interleukin-4, and CCL20 mRNA in the ear tissue was increased and dermal changes, such as acanthosis and eosinophilic, neutrophilic, and mast cell infiltration, were greater in keratin 5/interleukin 18 transgenic mice than in wild-type mice. Furthermore, the repetitive application elicited a significant increase in serum IgE levels and the number of B cells in the draining lymph node in keratin 5/interleukin 18 transgenic mice. These results suggest that overexpression of interleukin 18 in the skin aggravates allergic and nonallergic cutaneous inflammation, which is accompanied by high expression of T helper 1 and T helper 2 cytokines and chemokines in the skin.

Animals↗

PubMed2001

Topical anti-inflammatory activity of a new germacrane derivative from Achillea pannonica.

The topical anti-inflammatory activity of a germacrane derivative [1,4-dihydroxy-germacra-5E-10(14)-diene; DHGD] isolated from Achillea pannonica Scheele (Asteraceae) was investigated employing the Croton oil-induced dermatitis in the mouse ear. Its effects on the oedematous response and on leukocytes infiltration are described. The germacrane derivative significantly inhibited ear oedema in a dose-dependent manner, with an ID(50) of 0.40 micromol/cm(2). DHGD (0.75 micromol/cm(2)) provoked a global inhibition of the oedematous response (61 %) higher than that induced by an equimolar dose of indomethacin (43 %) within 24 hours; the reduction induced by hydrocortisone (0.10 micromol/cm(2)) was 68 %. The effect of DHGD (61 % inhibition) was higher than that of the equimolar dose of indomethacin (51 % inhibition) also on granulocytes recruitment at the site of inflammation. Hydrocortisone (0.10 micromol/cm(2)) reduced the cellular infiltrate by 44 %.

Administration, Topical↗

PubMed2002

Studies on the anti-inflammatory activity of phytopharmaceuticals prepared from Arnica flowers.

Phytopharmaceuticals prepared from flowerheads of Arnica montana of Spanish origin and of the new type "Arbo", which can be easily and economically cultivated, were studied for their capability to impair activation of the transcription factors NF-kappa B and NF-AT. Both proteins are responsible for the transcription of genes encoding various inflammatory mediators. Additionally, their influence on the release of the cytokines IL-1 and TNF-alpha were examined. The inhibitory activities correlate with their quantitative and qualitative content of sesquiterpene lactones (Sls). Moreover, it was shown that the inhibitory potency of 11 alpha,13-dihydrohelenalin derivatives being the main Sls in the Spanish flowers depend on their esterfication. Compounds with unsaturated acyl moieties, such as methacrylate and tiglinate, exhibited a stronger activity in the NF-kappa B EMSA as well as in the croton oil ear test in mice than the acetate derivative.

Animals↗

PubMed2002

Anti-inflammatory sesquiterpene lactones from Lourteigia ballotaefolia.

Three sesquiterpene lactones were isolated from Lourteigia ballotaefolia (H. B. K.). 9beta-hydroxy-atripliciolide-8- O-tiglate ( 1) was isolated for the first time from this plant and was previously reported in Conocliniopsis prasiifolia (DC) K. et R., 9beta-hydroxy-atripliciolide-8- O-(5'-acetoxytiglate) ( 2) had been already reported in this species. The minor component, 9beta-(tigloyloxy)-atripliciolide, is a new compound. The anti-inflammatory activity of compounds 1 and 2 was evaluated using the croton oil ear test in mice.

Animals↗

PubMed2003

Inhibition of Na+,K+-ATPase activity by (-)-ent-Kaur-16-en-19-oic acid and its derivatives.

The diterpene, (-)- ent-kaur-16-en-19-oic acid, from Croton oblongifolius was identified as an Na +,K +-ATPase inhibitor. This compound exhibits an IC 50 of 2.2 x 10( -5 )M against crude enzyme Na +,K +-ATPase from rat brain. The semi-synthetic derivatives, (-)-methyl kaur-16-en-19-oate, (-)-kaur-16-en-19-ol, (-)-16beta,17-epoxykauran-19-oic acid and (-)-17-hydroxykaur-15-en-19-oic acid were also tested and their IC 50 were 5.5 x 10 (-4), 5.0 x 10( -4), 4.8 x 10( -4) and 6.0 x 10 (-4) M, respectively.

Animals↗

PubMed2004

Anti-inflammatory activity of Leontopodium alpinum and its constituents.

The aerial parts and roots of Leontopodium alpinum Cass. (Asteraceae) were investigated for their in vivo topical anti-inflammatory activity using the inhibition of Croton oil-induced ear dermatitis in mice. For both of the plant parts, the dichloromethane extract induced a dose-dependent oedema reduction, being more active than the methanol and 70% aqueous methanol ex-tracts. Moreover, the dichloromethane extract of the aerial parts was more active than that of the roots (ID50 = 221 and 338 pg/cm2, respectively). Fatty acids make a significant contribution to the anti-oedema activity of the dichloromethane extract of the aerial parts, whereas bisabolane sesquiterpenes, tricyclic sesquiterpenes, coumarins and lignans are involved in the activity of the root extract. Two bisabolane derivatives reduced also the polymorphonuclear neutrophil leukocytes accumulation in the inflamed tissue, while a 7a-silphiperfol-5-ene type sesquiterpene and a coumarin derivative inhibited the in vitro chemotaxis of these inflammatory cells.

Animals↗

PubMed2005

Aloeresin I, an anti-inflammatory 5-methylchromone from cape aloe.

A new diglucoside having a 5-methylchromone moiety was isolated from a commercial sample of Cape aloe, the dried exudate from Aloe ferox Miller, and named aloeresin I. Its structure was established as 1 on the basis of spectral and chemical evidence. Aloeresin I (1) (1 micromol/cm2) reduces in vivo the oedematous response (39 %) induced by Croton oil in the mouse ear with the same potency as aloesin, one of the most abundant Cape aloe constituents, and to a higher extent than aloeresin H (2). Indomethacin (0.3 micromol/cm2), the reference anti-inflammatory compound, provokes 61 % oedema inhibition.

Aloe↗

PubMed2005

Glaucopines A and B, new cyathane diterpenes from the fruiting bodies of Sarcodon glaucopus.

Glaucopine A (1) and B (2), two new cyathane diterpenes, have been isolated from the mushroom Sarcodon glaucopus: their structures have been determined on the basis of spectral data. Their topical anti-inflammatory activity was evaluated using the Croton oil ear test in mice: compounds 1 and 2 (1 micromol/cm2) provoked edema reduction (62 % and 55 %, respectively) similar to that induced by the reference non-steroidal anti-inflammatory drug, indomethacin (0.3 micromol/cm2, 61 % edema reduction).

Animals↗

PubMed1996

Antiviral and antiphlogistic activities of Hamamelis virginiana bark.

A crude hydroalcoholic extract from Hamamelis virginiana bark was subjected to ultrafiltration (UF) with a cut-off limit of 3 kDa to obtain a higher and a lower molecular weight fraction. Characterisation of the fractions was attempted with TLC, HPLC, acidic hydrolysis, and chromatography over Sephadex LH-20. The UF-concentrate was shown to consist mainly of oligomeric to polymeric proanthocyanidins (PA). This fraction was found to exhibit significant antiviral activity against Herpes simplex virus type 1 (HSV-1). In addition, the UV-concentrate displayed radical scavenging properties, inhibited alpha-glucosidase as well as human leukocyte elastase (HLE), and exhibited strong antiphlogistic effects in the croton oil ear edema test in the mouse. With the exception of the antioxidant potential and the inhibition of HLE-action the lower molecular fraction possessed weaker activities and contained mainly hamamelitannin, catechin, and further, unidentified constituents.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Doxycycline and tissue repair in rats.

Iterations in collagen turnover are integral to tissue repair. Repair gone awry, as a result of excess collagen accumulation or degradation, can contribute to pathologic ventricular remodeling. Pharmacologic interventions that would attenuate either aspect of faulty repair have therefore attracted interest. Tetracyclines, which inhibit both collagen synthesis and degradation, as well as angiogenesis, may hold promise, unrelated to their antimicrobial properties, in this regard. Assessment of their potential in rodent hearts with experimental injury can be problematic, given the often microscopic nature of tissue repair and brief involvement of matrix metalloproteinases (MMPs). We therefore selected a subcutaneous model in which granulation and fibrous tissues form over several weeks in response to croton oil and where fibrous tissue is subsequently resorbed because of high levels of collagenolytic activity. Untreated rats were compared with those given daily oral doxycycline (40 mg/kg). We harvested pouch tissue and exudate weekly for 5 weeks to assess hydroxyproline concentration and MMP activity (gelatin substrate zymography) of pouch wall and mononuclear cell count of pouch exudate. At week 2, neovascularization in pouch wall was measured by means of intravenous infusion of carmine-red dye in gelatin. The resultant "vascular cast" was solubilized and dye content quantitated with the use of spectrophotometry. Serum was assayed weekly for type I collagen carboxyterminal telopeptide (ICTP), a marker of collagen degradation. During weeks 1 and 2 and compared with untreated controls, doxycycline-treated rats had attenuated pouch tissue weight, collagen concentration, MMP2 lytic activity and vascularity, and reduced exudate volume and mononuclear cells. In vitro, doxycycline inhibited tissue gelatinolytic activity in a dose-dependent manner. At weeks 4 and 5, pouches were larger and collagen concentration was higher in doxycycline-treated rats, and serum ICTP levels were reduced at weeks 3 and 4. During the initial phase of pouch development, doxycycline exerts an inhibitory effect on tissue formation, likely mediated through its attenuation of angiogenesis and modulations of collagen turnover. As repair proceeds in subsequent weeks, doxycycline retards collagen degradation and pouch resorption by inhibiting MMPs. Doxycycline offers a multifaceted pharmacologic profile with which to modify various aspects of tissue repair in the rat.

Animals↗