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PubMed1991

Dose-response relationship between objective measures of histamine-induced weals and dose of terfenadine.

Terfenadine is a safe non-sedative H1-receptor antagonist. This study aimed to quantify the relative reduction in weal and flare area, thickness and erythema at 4, 8, 12 and 24 h following a single but variable oral dose of terfenadine compared with pre-treatment measurements, in order to compare the dose-effect relationship and time course of the different dosages. In a double-blind randomized cross-over study, 12 healthy volunteers were given 60, 120 or 240 mg of terfenadine or placebo. Twenty micrograms of histamine acid phosphate was then injected intradermally at 4, 8, 12 and 24 h. The weal and flare areas were measured by planimetry, the thickness of the weal by an A-scan pulsed ultrasound device and the redness of both the weal and flare by an erythema-meter. A definite dose-response relationship was demonstrated between the weal and flare areas and the three active treatments. For the weal area, there was a significant difference between 60 mg and 240 mg of terfenadine at 4 h (p less than 0.01), at 8 and 12 h (p less than 0.05). For the flare area there was a similar significant difference at 4 h (p less than 0.01) and at 8 h (p less than 0.05). A dose-response relationship was demonstrated between weal erythema and 120 mg or 240 mg and 60 mg of terfenadine (p less than 0.05). There was a correlation between the plasma levels of the major metabolite and the initial dose of terfenadine, demonstrating their expected proportionality. This metabolite was also demonstrated in tissue fluid.

Adult↗
PubMed1986

Suppression of inflammatory oedema by ibuprofen involving a mechanism independent of cyclo-oxygenase inhibition.

The effects of a non-steroidal anti-inflammatory compound, ibuprofen, on experimentally-induced local oedema responses in rabbit skin were investigated. The accumulation of intravenously-injected 125I-albumin was used to measure oedema. Two peptides were used to increase microvascular permeability: C5a des Arg, whose action is dependent on circulating polymorphonuclear leukocytes, and bradykinin which acts directly on vascular endothelial cells. The peptides were injected intradermally together with either arachidonic acid or PGE2 to potentiate oedema formation. To study the cyclooxygenase inhibitory activity of ibuprofen, the effects of the mediators were potentiated by addition of arachidonic acid. To investigate whether the drug had effects independent of cyclo-oxygenase inhibition, PGE2 was used to potentiate responses. Both local and intravenous ibuprofen suppressed oedema induced by bradykinin + arachidonic acid and C5a des Arg + arachidonic acid, which is consistent with suppression of cyclo-oxygenase in the skin. Local ibuprofen had no effect on responses to bradykinin + PGE2 or C5a des Arg + PGE2. Intravenous ibuprofen had no significant effect on responses to bradykinin + PGE2 but, in contrast, had a marked inhibitory effect on responses to C5a des Arg + PGE2. It is concluded that, in addition to its known cyclo-oxygenase inhibitory activity, ibuprofen can inhibit inflammatory oedema at clinically-relevant doses by an action on circulating poly-morphonuclear leukocytes. These observations in vivo appear to be related to other observations on the effects of ibuprofen on polymorphonuclear leukocyte function in vitro and ex vivo. The observations described may also relate to the protective effects of ibuprofen on experimentally-induced myocardial infarction.

Animals↗
PubMed2005

A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences.

Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty-eight healthy female and male volunteers were studied. Capsaicin (100 microg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2+/-2.0 cm x min at menstrual and 16.4+/-0.9 cm x min at luteal phase (P<0.001). The area was significantly larger in both phases for females compared to males (14.2+/-1.3 cm x min, P<0.0001). Flare area at menstrual phase (69.2+/-4.2 cm(2)) was significantly (P<0.0001) larger than luteal phase (58.6+/-2.1 cm(2)). Females, in both phases, showed larger flare area compared to males (44.9+/-3.6 cm(2), P<0.0001). Area of brush-evoked allodynia was also larger at the menstrual phase compared to the luteal phase (P<0.0001) and males (P<0.0001). A significant difference was found in the capsaicin-evoked pain distribution with a greater response in menstrual phase compared to the luteal phase (P<0.01) and men (P<0.0001). Capsaicin induced trigeminal sensitization and evoked gender specific sensory and vaso-motor responses, with menstruating females generally showing the strongest manifestations. The model may be further applied to explore mechanisms of human trigeminal sensitization.

Capsaicin↗
PubMed1998

Antibody responses of rats after immunization with organic acid anhydrides as a model of predictive testing.

OBJECTIVES: The sensitizing properties of organic acid anhydrides (OAA) were evaluated in a rat model. METHODS: The development of specific immunoglobulin (Ig)E and Ig G in serum was investigated after immunization with 14 OAA and 3 OAA conjugates. Brown Norway rats were injected intradermally with 0.1 ml of 0.2 M OAA in liquid paraffin or 1.4 mg of rat serum albumin conjugate in saline. Serum samples were collected after 4 weeks. Antibodies were analyzed with enzyme-linked immunosorbent assay. RESULTS: The serum titers of specific Ig E after immunization with the different free OAA varied from <50 to 6400. The rats immunized with 4-methylphthalic anhydride exhibited the highest titers. The specificity of Ig E was demonstrated by enzyme-linked immunosorbent assay inhibition tests. A good correlation was observed between the Ig E and Ig G titers. Immunization with OAA conjugates showed results parallel to the findings for the free compounds. Importantly, the Ig E titers for the OAA agreed well with findings from guinea pigs and with literature data from epidemiologic studies of exposed workers. CONCLUSIONS: The present animal model may be a valuable tool for predicting the sensitizing potential of OAA and possibly the sensitizing potential of low-molecular-weight compounds in general. Furthermore, the antibody specificity of the haptens and the variations in the magnitude of the antibody titers indicate a valuable approach for studies of quantitative structure-activity relationships.

Anhydrides↗
PubMed1986

A serological mediator in chronic idiopathic urticaria--a clinical, immunological and histological evaluation.

Seven of twelve autologous sera from patients with chronic idiopathic urticaria re-injected intradermally produced a weal at the site of injection. There was no response in 19 control subjects. Patients showing a positive response had a shorter duration of disease and shorter duration of spontaneous weals, and their urticaria was less likely to be exacerbated by pressure. There was some serological evidence of circulating immune complexes in both positive and negative responders to autologous serum, but only two showed complement abnormalities. When six of the serum-positive patients were re-tested after one year, five still showed a positive response with their original stored serum, but only two, whose disease remained active, were positive when challenged with freshly drawn serum, suggesting that a serum mediator is only present when the urticaria is active. A marked neutrophil infiltrate was seen within and around small dermal blood vessels at the injection site in the majority of urticaria patients but this appearance did not correlate with weal formation. In control subjects the cellular response was mild and mainly mononuclear.

Adult↗
PubMed2003

Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice.

Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.

Adenoviridae↗
PubMed2005

A noninfectious simian/human immunodeficiency virus DNA vaccine that protects macaques against AIDS.

Simian/human immunodeficiency virus SHIV(KU2) replicates with extremely high titers in macaques. In order to determine whether the DNA of the viral genome could be used as a vaccine if the DNA were rendered noninfectious, we deleted the reverse transcriptase gene from SHIVKU2 and inserted this DNA (DeltartSHIVKU2) into a plasmid that was then used to test gene expression and immunogenicity. Transfection of Jurkat and human embryonic kidney epithelial (HEK 293) cells with the DNA resulted in production of all of the major viral proteins and their precursors and transient export of a large quantity of the Gag p27 into the supernatant fluid. As expected, no infectious virus was produced in these cultures. Four macaques were injected intradermally with 2 mg of the DNA at 0, 8, and 18 weeks. The animals developed neutralizing antibodies and low enzyme-linked immunospot assay (E-SPOT) titers against SHIVKU2. These four animals and two unvaccinated control animals were then challenged with heterologous SHIV89.6P administered into their rectums. The two control animals developed viral RNA titers exceeding 10(6) copies/ml of plasma, and these titers were accompanied by the loss of CD4+ T cells by 2 weeks after challenge. The two control animals died at weeks 8 and 16, respectively. All four of the immunized animals became infected with the challenge virus but developed lower titers of viral RNA in plasma than the control animals, and the titers decreased over time in three of the four macaques. The fourth animal remained viremic and died at week 47. Whereas the control animals failed to develop E-SPOT responses, all four of the immunized animals developed anamnestic E-SPOT responses after challenge. The animal that died developed the highest E-SPOT response and was the only one that produced neutralizing antibodies against the challenge virus. These results established that noninfectious DNA of pathogenic SHIV could be used as a vaccine to prevent AIDS, even though the immunological assays used did not predict the manner in which the challenge virus would replicate in the vaccinated animals.

AIDS Vaccines↗
PubMed1987

Increase in intradermal vascular permeability caused by pertussis toxin from Bordetella pertussis.

Rabbits that were injected intradermally with pertussis toxin (PT), produced from Bordetella pertussis, showed slight edema and erythema at the injection sites, but not hemorrhage nor necrosis. The edema lesions were stained blue by the intravenous injection of Pontamine Sky Blue 6B dye, suggesting that PT caused increased vascular permeability, similarly to the permeability factor (PF) of cholera toxin. The reaction of the PF of PT could be determined by measuring the diameter of the blue area. The diameter of the blue area bore a good linear relationship to the logarithm of the dose of PT. The activity of the PF was neutralized by anti-PT rabbit serum. Detoxification of PT with formalin did not increase the vascular permeability, but reverted pertussis toxoid showed a PF reaction in proportion to the reverted leukocytosis-promoting and histamine-sensitizing activities of PT. The supernate of a Bordetella pertussis culture also induced a PF reaction and the reaction could be made clear by heating the supernate at 56 C for 30 min, but the supernate of Bordetella bronchiseptica did not induce the reaction at all.

Animals↗
PubMed1977

The effects of prostaglandins E1 and F2alpha on epidermal growth.

The effects of prostaglandins E1 and F2alpha (PGE1 and PGF2alpha) on the growth of guinea pig epidermis have been studied in vivo. The prostaglandins were injected intradermally into guinea pigs, and tritiated thymidine was injected intraperitoneally prior to sacrifice. The autoradiographic labelling indices (L.I.) were assessed and a significant increase was found 4 h after injection of PGE1 -an effect which lasted for up to 72 h. PGF2alpha injections had no significant effect on the L.I.

Animals↗
PubMed2005

Comparison of protective effect of protein and DNA vaccines hsp90 in murine model of systemic candidiasis.

Preventive vaccination by a hsp90-expressing DNA vaccine and recombinant hsp90 protein vaccine, both derived from the Candida albicans hsp90 using BALB-c mouse model of systemic candidiasis, was performed. Hsp90 mRNA was cloned from a clinical isolate of C. albicans, converted to cDNA and cloned into vaccination plasmid pVAX1. Two methods of DNA application were tested: intramuscular (i.m.) and intradermal (i.d.) injection. Recombinant protein was applied by i.d. injection with Freund's adjuvant; the control groups received PBS or Freund's adjuvant only. Mice were vaccinated and after 19 d re-vaccinated. After 3 weeks, the mice were challenged with the live C. albicans in a dose of 5 x 10(6) CFU per mouse. After the challenge, the mice vaccinated i.d. with DNA vaccine survived for 39 and 64% longer compared to those receiving Freund's adjuvant and/or PBS, respectively. The i.m. application of the DNA vaccine did not provide any significant protectivity. The serum level of anti-candida-hsp90 serum IgG antibodies correlated with the survival rate in both i.d. protein and DNA vaccination approaches. We stressed the importance of specific humoral immunity in the mouse model of systemic candidiasis.

Animals↗
PubMed1987

The effect of indomethacin on burn-induced immunosuppression.

Recent interest in the role of prostaglandin inhibitors as immunomodulators following major injury prompted us to study the effect of indomethacin on burn-induced immunosuppression in rats as measured by the delayed-type hypersensitivity (DTH) skin test response, ability to contain an intradermal bacterial challenge (10(8) Staphylococcus aureus 502A injected intradermally), and overall survival from spontaneous burn wound sepsis. Fifty male Sprague-Dawley rats sensitized to keyhole limpet hemocyanin (KLH) were subjected to a 30% full-thickness scald burn. Group 1 (n = 24) received indomethacin at 0.5 mg/kg intraperitoneally once daily with the first dose given immediately following the burn. Group 2 (n = 24) received vehicle only. Prostaglandin E2 measured by radioimmunoassay on day 17 was 2553 +/- 832 pcg/ml serum (+/- SEM) in the vehicle group and 1042 +/- 231 pcg/ml in the indomethacin group (P = 0.058, unpaired t test). Burn injury induced a decrease in the DTH response to KLH and an increase in the Staph lesion size (P less than 0.05) which was not corrected by indomethacin treatment. All animals developed spontaneous burn wound sepsis by day 14. Survival after 17 days in the indomethacin group was 100% compared to that of the vehicle group, 79%, P less than 0.05 (Fisher exact test). We conclude that despite unmeasurable corrections of the burn-induced suppression of the DTH response and local nonspecific bacterial defenses, low-dose indomethacin improves survival following burn sepsis.

Abscess↗
PubMed2005

Effect of combined histamine H1 and H3 receptor blockade on cutaneous microvascular permeability elicited by compound 48/80.

The pharmacological consequences of combining a histamine H1 receptor antagonist with a H3 antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H1 antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 +/- 4, 31 +/- 4, 32 +/- 4 and 37 +/- 4%, respectively. Combination treatment with an H1 and H3 antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H3 antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 +/- 4, 45 +/- 4, 49 +/- 4 and 54 +/- 4%. A second H3 antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H1 and a H3 histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H1 or H3 antagonist administered separately. In addition, the antiallergy activity of combining a H3 antihistamine with a H3 antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.

Animals↗
PubMed2004

Calcium/calmodulin dependent protein kinase II regulates the phosphorylation of cyclic AMP-responsive element-binding protein of spinal cord in rats following noxious stimulation.

We have previously reported that intradermal capsaicin injection causes the phosphorylation of cyclic adenosine monophosphate-responsive element-binding protein (CREB) in the spinal cord of rats. The present study was designed to investigate the role of calcium/camodulin protein dependent protein kinase II (CaM kinase II) in the regulation of phosphorylation of CREB after capsaicin injection. We found that capsaicin injection produces a significant upregulation of phosphorylated CREB in the spinal cord of rat. Intrathecal treatment with a CaM kinase II inhibitor, KN-93, significantly blocked the increased phosphorylation of CREB, but did not affect the CREB protein itself. These results suggest that increased phosphorylation of CREB protein may contribute to central sensitization following acute peripheral noxious stimuli, and the effect may be regulated through the activation of CaM kinase cascades.

Animals↗
PubMed1997

Further evidence for the involvement of tachykinin receptor subtypes in formalin and capsaicin models of pain in mice.

The intradermal (i.d.) injection of NK1 receptor antagonists GR 82334 and FK 888 (1-50 pmol/paw), in association with formalin, produced graded inhibition of the early but not the late phase of the formalin test. The NK2, SR 48968 and NK3 SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the formalin model. Co-injection of NK1, (FK 888, GR 82334), NK2 (SR 48968) or NK3 (SR 142801) receptor antagonists with capsaicin dose-dependently attenuated capsaicin-induced licking. In addition, all antagonists were more efficacious when compared with response in the formalin test. The antinociception caused by i.d. injection of the NK3 receptor antagonist SR 142801 against both phases of the formalin test, but not that of NK1 and NK2 receptor antagonists, was significantly reversed by intraperitoneal (i.p.) injection of naloxone (5 mg/kg). Intracerebroventricular (i.c.v.) injection of NK1, NK2 or NK3 receptor antagonists (15-500 pmol/site), all produced significant and dose-dependent inhibition of both phases of the formalin and capsaicin tests. With the exception of the response of SR 48968, which was equipotent in both models of nociception, FK 888, GR 82334 and SR 142801 were about 2-25-fold less potent at the ID50 level against the capsaicin-induced pain. The antinociception caused by i.c.v. injection of NK1, NK2 or NK3 receptor antagonists was reversed by i.p. injection of naloxone (5 mg/kg). These results indicate that tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both formalin- and capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an opioid mechanism sensitive to naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by naloxone when assessed in the formalin test, suggesting a distinct mechanism of action.

Animals↗
PubMed1952

Studies on the generalized Shwartzman reaction. II. The production of bilateral cortical necrosis of the kidneys by a single injection of bacterial toxin in rabbits previously treated with thorotrast or trypan blue.

Intravenous injection of thorotrast or trypan blue rendered rabbits susceptible to the production of bilateral cortical necrosis of the kidneys by a single intravenous injection of small amounts of meningococcal or Serratia marcescens toxin. This reaction was not produced when thorotrast or trypan blue were injected after toxin had been given. A single intradermal injection of toxin produced hemorrhagic skin lesions resembling the local Shwartzman reaction in rabbits given thorotrast 6 hours previously. These animals also developed bilateral cortical necrosis of the kidneys. When the order of injection was reversed, and thorotrast given after toxin, neither skin nor kidney lesions occurred. The skin and kidney lesions in thorotrast-treated rabbits were, like the local and generalized Shwartzman reactions, completely prevented by treatment with nitrogen mustard, in doses sufficient to produce polymorphonuclear leukopenia. The significance of these reactions, and their relationship to the previously described response to toxin in cortisone-treated rabbits, are discussed.

Animals↗
PubMed1990

Oxygen-derived free radicals mediate the cutaneous necrotizing vasculitis induced by epinephrine in endotoxin-primed rabbits.

To assess the possible role of oxygen-derived free radical in the pathogenesis of cutaneous necrotizing vasculitis (Thomas reaction) induced by epinephrine in endotoxin-primed rabbits, animals were treated with superoxide dismutase (intraperitoneal or local), catalase, allopurinol, or ibuprofen 2 h before inducing the reaction. This is done by an earlobe intravenous injection (10 micrograms) of endotoxin followed by an intradermal injection (100 micrograms) of epinephrine in the shaved abdomen; 18-24 h later, a hemorrhagic-necrotic lesion can be observed at the site of the epinephrine injection. The reaction was completely inhibited by superoxide dismutase, catalase, and ibuprofen, while allopurinol afforded only partial protection. Thus, oxyradicals seem to participate in the pathogenesis of this reaction.

Animals↗
PubMed1996

Keloid excision and recurrence prophylaxis via intradermal interferon-gamma injections: a pilot study.

Keloids are an abnormal response to wound healing distinguished by an overproduction of collagen. Thickened bundles of collagen in the reticular dermis oriented haphazardly in relation to the overlying epithelium are found in keloids, in contrast to thinner collagen fibers in a more orderly arrangement that are found in normal scars. Previous clinical trials of intralesional interferon-gamma (IFN-G) injections by Larrabee et al. and Granstein et al. showed a decrease in lesion size. These findings led to a conclusion that IFN-G would be a useful adjunct to surgical excision of keloids to aid in preventing recurrence. We performed a double-blind, placebo-controlled trial in patients with two or more keloids treated with excision and subsequent local injections of IFN-G or placebo.

Adolescent↗
PubMed1998

Persistence of antibodies in children after intradermal or intramuscular administration of preexposure primary and booster immunizations with purified Vero cell rabies vaccine.

BACKGROUND: The use of intradermal (i.d.) injections of purified Vero cell rabies vaccine (PVRV) for preexposure prophylaxis has not been well-established. We studied the safety and immunogenicity of i.d. and intramuscular (i.m.) PVRV injections for primary and booster preexposure immunizations. METHODS: One of two rabies preexposure PVRV regimens comprising three doses of either 0.1 ml i.d. or 0.5 ml i.m. administered during 28 days was assigned at random to 190 school children. One booster dose was given 1 year later either i.d. or i.m., according to their initial randomization group. Serologic results were available from 155 (82%) children at 1 year after primary immunization and 118 (62%) children at 2 years after booster. RESULTS: Although children vaccinated i.d. had significantly lower rabies-neutralizing antibody titers after primary immunization as well as after booster than children vaccinated i.m. (P< 0.001 for all time points), there were no significant differences in the percentages of children with adequate titers (> or =0.15 IU/ml) between the i.d. and i.m. groups after both primary and booster immunizations. Mild local reactions were more frequent after i.d. vaccination. Mild or moderate systemic reactions were infrequent and similar after i.d. and i.m. vaccinations. Fever and headache were reported by < or =6%. The reactions after booster were not different from those of post-primary immunization. CONCLUSIONS: Purified Vero cell rabies vaccine appears to be safe and immunogenic for primary and booster preexposure immunizations. An i.d. PVRV preexposure regimen should be useful especially for rabies-endemic countries with low per capita income.

Antibodies, Viral↗