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PubMed2003

Fos expression in spinothalamic and postsynaptic dorsal column neurons following noxious visceral and cutaneous stimuli.

The spinothalamic tract (STT) has been classically viewed as the major ascending pathway for pain transmission while the dorsal column (DC) was thought to be involved primarily in signaling innocuous stimuli. Recent clinical studies have shown that limited midline myelotomy, which transects fibers in the DC, offers good pain relief in patients with visceral cancer pain. Experimental studies provided evidence that a DC lesion decreases the activation of thalamic neurons by visceral stimuli and suggested that this effect is due to transection of the axons of postsynaptic dorsal column (PSDC) neurons. In our study, Fos protein expression in retrogradely labeled STT and PSDC neurons in the lumbosacral enlargement in rats was used as an anatomical marker of enhanced activation to compare the role of these neurons in cutaneous and visceral pain. The noxious stimuli used were intradermal injection of capsaicin and distention of the ureter. Retrogradely labeled PSDC neurons were found in laminae III-IV and in the vicinity of the central canal. STT neurons were located in laminae I, III-VII and X. Ureter distention evoked Fos expression in PSDC and STT neurons located in all laminae in which retrogradely labeled cells were found, with the maximum in the L(2) spinal segment. The Fos-positive PSDC neurons represented a significantly higher percentage of the retrogradely labeled PSDC neurons (19.3+/-2.3% SEM) than of the STT Fos-positive neurons (13.2+/-1.5% SEM). Intradermal capsaicin injection also evoked Fos expression in both PSDC and STT neurons, but with no significant difference between these two, when expressed as a percentage of the retrogradely labeled cells (11.6+/-2.9% SEM, 10.8+/-1.1% SEM). These results show that both PSDC and STT neurons are activated by cutaneous and visceral noxious stimuli. Their particular role in transmission and modulation of painful stimuli needs to be investigated further.

Animals↗
PubMed1989

Endothelin-1 participation in overt and inflammatory pain.

Endothelin-1 (ET-1) induced hyperalgesia in rats, abdominal constrictions in mice, incapacitation in dogs, and, when injected intradermally into humans, caused wheal and flare responses, which were accompanied by itching. The ET-1 induced constrictions in mice were prevented by indomethacin. In contrast, indomethacin had no effect on the hyperalgesic responses in the rat. These results indicate that ET-1 may play a role in modulating pain.

Animals↗
PubMed2002

Investigation of previously reported mucosal swellings after injection with Citanest Forte.

The purpose of this study was to determine the reason for an apparent increase in the number of mucosal swellings after maxillary infiltration with Citanest Forte (prilocaine HCl 4% solution with epinephrine 1:200,000), 2 years after its introduction in 1971 by Astra Pharmaceutical Co (now AstraZeneca) in the United States. Approximately 70% of these reported reactions were from California, where less than 11% of all cartridges were sold. Comparison with New York State, with 27% of total sales but less than 1% of the reactions, suggested that possible differences in practice characteristics were responsible for the swellings. On the basis of the Bureau of Economic Research and Statistics Survey of Dental Practice, dentists in the Far West (eg, California) were found to schedule appointments with a median length of approximately twice that of their Mid-East colleagues, the implication being that more anesthetic solution was injected per office visit. Follow-up telephone interviews of dentists reporting such reactions at that time verified that they administered more than the recommended 1.8-mL dose. The most important epidemiologic information was that prilocaine HCl 4% solution with epinephrine 1:200,000 had been on sale in Canada 4 years before it was introduced in the US market, with little or no evidence of drug-related effects. Comparison of the US and Canadian prilocaine HCl with epinephrine 1:200,000 specifications revealed that NaCl was added to an already hypertonic prilocaine solution in the US but not in Canada. Comparison of the responses to intradermal injection of US and Canadian prilocaine solutions into the backs of rabbits with follow-up studies of dose-related NaCl injections demonstrated that the added NaCl was responsible for the onset and duration of irritation from the initially marketed US Citanest solutions.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Effect of ricinoleic acid in acute and subchronic experimental models of inflammation.

Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.

Acute Disease↗
PubMed2001

Biphasic response of the regional lymphatics in the normal lymphocyte transfer reaction.

BACKGROUND: Initially developed for histocompatibility testing, the normal lymphocyte transfer (NLT) reaction involves the intradermal injection of allogeneic lymphocytes from one individual to another. Because of the unique kinetics of the immunological response to allogeneic lymphocytes, the NLT reaction has been considered an informative system for the analysis of transplant immunity. METHODS: In this study, we used bilateral efferent lymph duct cannulations in sheep to examine the regional lymphatic response to the NLT reaction. Our studies used monoclonal antibodies to define lymphocyte population dynamics and DNA flow cytometry to reflect lymphocyte proliferative responses. RESULTS: The results confirmed a biphasic NLT reaction. An unexpected finding was the marked differences between the early and late NLT responses. The early response was characterized by T-lymphocyte proliferation, as reflected by S-phase DNA, which was comparable in both the NLT-stimulated and contralateral control efferent lymphocytes. This bilateral proliferative response was observed in both CD4+ and CD8+ lymphocytes. In contrast, the late response was restricted to the efferent lymph from the NLT-stimulated lymph node. Dual-parameter flow cytometry demonstrated that the dominant component of this unilateral NLT response was CD8+ lymphocytes. CONCLUSIONS: These results suggest important functional distinctions between systemic and regional lymphatic responses to intradermal alloantigens.

Animals↗
PubMed1994

Intravenous magnesium in the treatment of hydrofluoric acid burns in rats.

STUDY OBJECTIVE: To gather preliminary data on the safety and efficacy of IV magnesium in a rat model of hydrofluoric acid burns. MODEL: Forty-seven anesthetized male rats (200 to 300 g) received a standardized burn with 52% hydrofluoric acid. INTERVENTIONS: Animals were anesthetized with 30 to 50 mg/kg ketamine IM and 1 to 3 mg/kg xylazine IM. A standardized chemical burn was created by topical application of 52% hydrofluoric acid. The rats were divided into four treatment groups: group 1 received no treatment; group 2 received intradermal injection of 10% calcium gluconate; group 3 received 80 mg/kg MgSO4 IV; and group 4 received 160 mg/kg MgSO4 IV. After the rats were killed, the burn lesions were excised and examined by a pathologist to determine the grade of burn (which was equal to the clinical degree of burn). MEASUREMENTS AND MAIN RESULTS: Microscopic examination of the burns revealed differences among the four groups. Five of 13 group 1 rats (37%) died within 24 hours of burn initiation. Of group 1 survivors, 50% had grade 2 burns, and the other 50% had grade 3 burns. In group 2, eight of 11 rats (73%) had grade 3 burns. Twenty-five percent of group 3 rats (three of 12) had grade 3 burns, and only 9% of group 4 rats (one of 11) had grade 3 burns. Only the difference in the rates of grade 3 burns for groups 2 and 4 was statistically significant. Although not statistically significant, burns in groups 3 and 4 tended to be smaller in diameter than burns in groups 1 and 2. CONCLUSION: High-dose IV magnesium sulfate reduces the severity of hydrofluoric acid burn compared with conventional intradermal calcium gluconate therapy. Early deaths appeared to be prevented by both calcium and magnesium therapies.

Animals↗
PubMed1993

The use of intradermal carrageenan in calves to estimate the dose of oxindanac, a nonsteroidal anti-inflammatory drug.

A simple and humane model of inflammation, induced by the intradermal injection of 0.3 mL of sterile 2% carrageenan, was characterized in calves by measuring the volume of skin swelling plus histological analysis of skin biopsies. Carrageenan produced a biphasic increase in skin swelling, with an early edematous response followed by a more chronic cellular infiltrate. The swelling and sensitivity to pressure observed in the early response were suitable for testing the antiedematous and analgesic activity of a new nonsteroidal anti-inflammatory drug (NSAID), oxindanac. Pretreatment with intravenous oxindanac at doses from 0.5 to 8.0 mg/kg reduced the volume of swelling and this reached statistical significance (p < 0.05) at 2 mg/kg. The ED50 and ED90 values for inhibition of the peak swelling volume (4 h) were estimated to be 1 mg/kg and 2 mg/kg, respectively. These compare with an ED90 of 2.0 mg/kg for inhibition of serum TxB2 production, an index of platelet cyclo-oxygenase activity. The dose of oxindanac required for antiedematous activity correlated, therefore, with maximal inhibition of serum TxB2. The analgesic activity of oxindanac reached no clear maximum response, but statistically significant difference (p < 0.05) from placebo was reached with doses of 2 mg/kg and above. It is concluded that intradermal carrageenan produced a simple, humane and useful model for dose estimation of a new NSAID in calves.

Animals↗
PubMed1994

Effect of a neurokinin-1 (NK1) receptor antagonist on oedema formation induced by tachykinins, carrageenin and an allergic response in guinea-pig skin.

The effect of the neurokinin-1 (NK1) receptor antagonist RP67580 in modulating inflammatory oedema formation has been investigated in guinea-pig skin. Oedema formation was measured over 30 min by the extravascular accumulation of intravenously-injected 125I-albumin in the anaesthetised guinea-pig. RP67580 was injected intradermally with the agents under test. Intradermal RP67580 (10 nmol/site) inhibits oedema formation induced by substance P (30 pmol) and neurokinin A (100 pmol), but not that induced by bradykinin (10-1000 pmol) or histamine (10 nmol). Substance P-induced oedema formation is similar in control (saline) and mepyramine (histamine H1 receptor antagonist) pretreated guinea-pigs suggesting a minimal involvement of histamine in substance P induced oedema formation in guinea-pig skin. Oedema formation induced by intradermal carrageenin (0.2%) was not inhibited by RP67580 (1-10 nmol). A significant but partial inhibition of oedema formation induced in a passive cutaneous anaphylaxis (PCA) response was observed. The oedema formation in the PCA was inhibited 50% by mepyramine pretreatment but in the presence of mepyramine no further inhibition of the PCA response by RP67580 was observed.

Animals↗
PubMed2002

Macrophages, but not T and B lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage-mediated neutrophil infiltration depends on mast cell activation.

Bullous pemphigoid (BP) is a subepidermal blistering disease associated with autoantibodies against two hemidesmosomal proteins, BP180 and BP230. Numerous inflammatory cells infiltrate the upper dermis in BP. We have previously shown by passive transfer studies that Abs to the ectodomain of murine BP180 are capable of triggering blisters in mice that closely mimic human BP. Experimental BP depends on complement activation and neutrophil infiltration. In the present study, we investigated the relative contribution of neutrophils, mast cells (MCs), macrophages (Mphi), and lymphocytes and their functional relationship in the immunopathogenesis of this disease model by using mice deficient in these cells. Wild-type, T cell-deficient, and T and B cell-deficient mice injected intradermally with pathogenic anti-murine BP180 IgG exhibited extensive subepidermal blisters. In contrast, mice deficient in neutrophils, MCs, and Mphi were resistant to experimental BP. MCs play a major role in neutrophil recruitment into the dermis. Furthermore, Mphi-mediated neutrophil infiltration depends on MC activation/degranulation.

Animals↗
PubMed1989

Angiotropin treatment prevents flap necrosis and enhances dermal regeneration in rabbits.

Angiotropin is a potent angiogenesis factor isolated from the serum-free media of cultured, lectin-activated peripheral monocytes. In vitro, the purified substance stimulates migration, phenotypic differentiation, and tube formation, but not proliferation of capillary endothelial cells. When injected intradermally, angiotropin induces, in dose-dependent fashion, angiogenesis associated with skin hyperplasia. We have developed a flap model with insufficient blood supply and a model for contraction-free defect healing in rabbit skin. We show that (1) local pretreatment with angiotropin can prevent flap necrosis and (2) dermal regeneration after wounding can be augmented by angiotropin. From these results, we conclude that angiotropin might be of use as an adjuvant to healing in surgery.

Angiogenesis Inducing Agents↗
PubMed1995

Streptozotocin: inherent but not expressed skin sensitizing activity.

We have shown previously that the alkylating agent streptozotocin (STZ) fails to induce responses in the murine local lymph node assay, a predictive test for contact sensitizing potential. In the present study, we demonstrate that this same compound when injected intradermally into the ears of mice provokes a dose-dependent induction of draining lymph node cell proliferation. These data indicate that the intrinsic immunogenicity of STZ is not displayed in the local lymph node assay under conditions of conventional topical exposure, secondary to a failure to cross the lipophilic stratum corneum in sufficient quantities. This finding has implications for the discernment of structure-activity relationships in contact sensitization.

Animals↗
PubMedDate not supplied

Oxidative burst response to monosodium urate crystals in patients with Behçet's syndrome.

OBJECTIVE: An erythematous response to intradermal injection of monosodium urate crystals (MSU) has been demonstrated in Behçet's syndrome (BS). To further elucidate the pathogenesis of this response, the effects of MSU on in vitro oxidative burst reaction of neutrophils and monocytes were investigated. METHODS: Peripheral blood mononuclear cells from patients with Behçet's syndrome (BS), rheumatoid arthritis (RA), familial Mediterranean fever (FMF) and healthy controls (HC) were incubated with 100 ng/ml phorbol myristate acetate (PMA) and MSU at different dosages (25-500 microg/ml). Oxidative burst reaction was evaluated in neutrophils and monocytes by flow cytometry. RESULTS: In patients with BS, oxidative burst of neutrophils was significantly increased compared to HC at 125 microg/ml and 250 microg/ml dosages of MSU (p < or = 0.001 and 0.004 respectively). In patients with FMF; there was also an increased oxidative burst reaction at 75 microg/ml, 250 g/ml and 500 microg/ml (p < or = 0.007; 0.001 and 0.004 respectively). In patients with BS, oxidative burst of monocytes was increased only at 125 g/ml dosage of MSU (p < or = 0.002). However, in patients with FMF monocyte burst response was increased at 25 microg/ml, 75 microg/ml and 125 g/ml (p < or = 0.004; < 0.0001; < 0.0001 and 0.002 respectively). In RA group, stimulation with PMA resulted in a higher oxidative burst reaction than FMF and BS (p < or = 0.000 and p < or = 0.008). No correlation was observed between oxidative burst of neutrophils or monocytes and intradermal responses to MSU crystals. CONCLUSION: Oxidative burst reaction with MSU is augmented in neutrophils and monocytes of BS. However, the response is not specific and is unassociated with skin dermal test which has a high specificity for BS.

Adult↗
PubMed1993

Attempts to cultivate Mycobacterium leprae in fat tissue.

The behaviour of M. leprae in fat tissue was studied. Preadipocyte cells were infected with M. leprae and injected intradermally (I.D.) into nude mice. Adipose nodules obtained by in vivo differentiation of infected cells were maintained in vivo for 3 months and subsequently incubated in vitro for 3 months. Counts of bacilli showed no increase over this 6 months period. It is concluded that undifferentiated preadipocyte and mature fat cells are not permissive for M. leprae. The morphological changes observed following passage of M. leprae into adipose nodules might be related to the process of adipose cell differentiation.

Adipose Tissue↗
PubMed2002

Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IB study.

The primary objective of this phase I study was to determine the safety of an autologous tumor vaccine given by intradermal injection of lethally irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected autologous melanoma and sarcoma cells. Secondary objectives included validation of the gene delivery technology (particle-mediated gene transfer), determining the host immune response to the tumor after vaccination, and monitoring patients for evidence of antitumor response. Sixteen patients were treated with either of two different doses of GM-CSF-treated tumor cells. One patient received treatment with both doses of tumor cells. No treatment-related local or systemic toxicity was noted in any patient. Patients administered 100% treated cells (i.e., with a preparation of tumor cells that had all been exposed to GM-CSF DNA transfection) had a more extensive lymphocytic infiltrate at the vaccine site than did patients given 10% treated cells (a preparation of tumor cells in which 10% had been exposed to GM-CSF transfection) or nontreated tumor. The generation of a systemic immune response to autologous tumor by a delayed-type hypersensitivity response to the intradermal placement of nontransfected tumor cells was noted in one patient. One patient had a transient partial response of metastatic tumor sites. The entire procedure, from tumor removal to vaccine placement, was accomplished in less than 6 hr in all patients. Four of 17 patient tumor preparations produced greater than 3.0 ng of GM-CSF per 10(6) cells per 24 hr in vitro. The one patient with greater than 30 ng of GM-CSF per 10(6) cells per 24 hr in vitro had positive DTH, a significant histologic inflammatory response, and clinically stable disease. This technique of gene transfer was safe and feasible, but resulted in clinically relevant levels of gene expression in only a minority of patients.

Biolistics↗
PubMed2001

Assessment of ropivacaine as a local anesthetic for skin infiltration in skin surgery.

BACKGROUND: There has been limited examination of the use of ropivacaine, a relatively new amide local anesthetic, for skin surgery following local infiltration. Initial studies of ropivacaine show it to have a rapid onset and long duration of action. OBJECTIVE: To establish the injection characteristics of different concentrations of ropivacaine and to compare the pain of infiltration of ropivacaine with lidocaine 2% + epinephrine 1:80,000. METHOD: A double-blind placebo-controlled study was carried out on 18 healthy volunteers. Four concentrations of ropivacaine (1, 2, 5, and 7.5 mg/ml) were injected intradermally. Normal saline was used as the control. Sensation for pinprick was used to assess the onset and duration of anaesthesia. Pain of infiltration of ropivacaine and saline was additionally compared with lidocaine 2% + epinephrine 1:80,000. RESULTS: Pain of ropivacaine infiltation increased with increasing strength, but only 5 mg/ml was significantly more painful than the control P =.002). Lidocaine and epinephrine infiltration was significantly more painful than the control P =.0002) and 7.5 mg/ml ropivacaine (P =.0005). Mean times to reach full anesthesia were 74 seconds for 5 mg/ml and 51 seconds for 7.5 mg/ml. Mean times to regain full sensation were estimated as 692 minutes for 5 mg/ml and 773 minutes for 7.5 mg/ml. A vasoconstrictor effect was noted in the ropivacaine sites. CONCLUSION: Ropivacaine has a rapid onset and long duration of action. Ropivacaine produces vasoconstriction which may be clinically relevant. Even at maximum strength ropivacaine is less painful to inject than lidocaine with epinephrine.

Adult↗
PubMed1988

On the interaction between H1- and H2-histaminergic receptors in the histamine release and the realization of its vascular effects in rat skin.

The influence of the H1- and H2-histaminergic blockers promethazine and cimetidine, respectively, as well as of a combination of both drugs on the histamine release from rat ear skin, induced by compound 48/80, was studied. Cimetidine did not interfere with the effects of comp. 48/80, while promethazine increased almost three times the histamine-releasing effects of comp. 48/80. This effect of promethazine was reduced when the latter was combined with cimetidine. Cimetidine and promethazine did not produce any per se effect on the histamine content of the ear skin tissue. The two histaminergic blockers antagonized the vasodilation induced by exogenous histamine injected intradermally, the combination of the drugs in the higher dose used being most efficient. The effect of the combination was more pronounced as compared to that of promethazine when applied alone in the corresponding dose (25 mg/kg) and was almost equal to the effect of cimetidine administered alone in a dose of 200 mg/kg. The results suggest an important role for H2-histaminergic receptors in the skin vessels of rat as well as in the prevention of the mast cell degranulation at least in cases when it is induced by comp. 48/80.

Animals↗
PubMed2005

NewFill for skin augmentation: a new filler or failure?

BACKGROUND: New injectable materials for skin augmentation that promise to be the ideal filling material are introduced every year. Recently, we treated three patients with adverse reactions to a new substance for skin augmentation: polylactic acid (NewFill, Ashford Aesthetics Inc, Belgium). OBJECTIVE: To present three cases in which serious adverse reactions had occurred after skin augmentation with a new filling substance, polylactic acid (NewFill). Because an identical substance (Sculptra, Aventis Pharmaceuticals, Bridgewater, NJ, USA) was recently introduced in the United States, we want to alert future users of these substances to possible adverse events. MATERIALS AND METHODS: We report three cases with serious adverse events more than 12 months after skin augmentation with polylactic acid (NewFill). They were treated with intralesional steroid therapy and topical imiquimod application. RESULTS: Both intralesional steroid therapy and topical imiquimod application lead to moderate results. If feasible, surgical excision is the best available option. CONCLUSIONS: Great care should be taken when polylactic acid is used for intradermal injection because giant cell granulomatous reactions may be the result. Other than surgical excision, effective treatment options are lacking.

Adult↗
PubMed2005

Leishmania major: species specific delayed hypersensitivity reaction induced by exogenous secreted antigen in the guinea pig.

The cellular response to Leishmania major (L. major) is usually evaluated in vivo by the delayed-type-hypersensitivity (DTH) test using leishmanin. Leishmanin can give false-positive reactions in areas where there is a background of leishmaniasis. In a previous study, it was shown that a 56 kDa antigen purified from promastigote and culture supernatant of L. major induce strong DTH reactions in sensitized guinea pigs. In this study, the species-specificity of this antigen was further investigated. Three groups of guinea pigs were sensitized with L. major, L. tropica, and L. infantum and both flanks of sensitized animal were injected intradermally with purified 56 kDa antigen or soluble leishmania antigen (SLA). The extent of indurations were measured after 24, 48, and 72 h. In animals which were sensitized with three species of leishmania, only those immunized with L. major showed skin reactions to purified antigen by an increase in skin thickness. Since complex antigen mixtures such as SLA and leishmanin show cross-reactivity and can be non-specific, the result obtained here suggest that 56 kDa antigen may be a useful diagnostic tool for species specific diagnosis in field studies of leishmaniasis.

Animals↗