Wheal Formation Research Articles

Dermatographia in oral cavity unveiled: A case study

Dermatographia is a form of physical urticaria, quite uncommon in oral cavity characterized by elevated skin following localized erythema, oedema, and a flare-up reaction around it. It is usually induced by any blunt object or minor trauma and usually does not affect the routine life of the patient. Here we present a case report of a 20 year old male with the chief complaint of elevation on skin from a blunt object. On his physical examination with the consent of the patient we induced the condition in the department by asking the patient to write the letter ‘D’ on his flexural arm using the blunt end of the pen. After 5 min, the elevations on his skin began to appear which raised drastically with time. It remained on the skin for about an hour and then fainted on it’s own over time. During intraoral examination we also induced similar strokes on his buccal mucosa and surprisingly a linear elevation was produced along the line of blunt pen which was reddish in colou. No treatment was provided as the condition did not affect the quality life of the patient. Pharmacological therapy may include oral antihistamines, such as cetirizine or loratadine, to alleviate pruritus and reduce the frequency of wheal formation. Topical corticosteroids, such as triamcinolone acetonide or betamethasone, can be applied to affected sites for localized anti-inflammatory effects. In Ayurveda, the use of internal Ayurvedic medicines like, ‘Aragwadha amritadi kashaya’, ‘Ayaskriti’, ‘Varanadi kashaya’ and ‘Dashamoola hareetaki’ are recommended along with dietary restrictions and life style changes.

Equivalence in intradermal reactions to histamine and compound 48/80 in dogs before and after sedation with dexmedetomidine or a 1:20 combination of medetomidine and vatinoxan.

Intradermal allergen testing (IDAT) is commonly used to formulate allergen-specific immunotherapy, a pillar treatment for canine atopic dermatitis. Many sedatives have shown histaminergic or anti-histaminergic effects and thus been deemed unsuitable for IDAT. The goal of this study was to determine whether, in healthy dogs, dexmedetomidine (Dexdomitor) or a 1:20 combination of medetomidine and vatinoxan (Zenalpha) will affect intradermal reactions compared to unsedated dogs. Ten privately owned healthy dogs were enrolled in this equivalence study. Wheal formation was subjectively and objectively assessed in conscious then sedated dogs. Dogs were randomly sedated with either Dexdomitor (dexmedetomidine [0.5 mg/m2]) or Zenalpha (medetomidine [1 mg/m2/vatinoxan] 20 mg/m2) intramuscularly. Once sedated, five 10-fold histamine (100-0.01 μg/mL) and compound 48/80 (200-0.02 μg/mL) dilutions were intradermally injected into the lateral thorax. The study was repeated on the opposite side with the alternative sedation 1 week later. Quality of sedation, cardiorespiratory function and rectal temperature were recorded every 5 min. There was no difference in the median values of the reactions with either sedative when compared to unsedated dogs. Dexdomitor and Zenalpha achieved an equivalence in both subjective and objective scoring systems for all concentrations tested. A faster median time to sedation (10 vs. 18 min, p = 0.013) was seen with Zenalpha compared to Dexdomitor. Although both sedatives depressed the cardiovascular function, such parameters were less affected by Zenalpha than by Dexdomitor (p ≤ 0.001). Owing to the lack of effects on wheal formation, both sedatives are appropriate for sedating dogs undergoing IDAT. Although, such results should be validated in allergic dogs. Zenalpha may induce more rapid and reliable sedation than Dexdomitor.

Omalizumab-Induced Arthralgias in a Patient with Chronic Idiopathic Urticaria

Background: Omalizumab (Xolair) is a recombinant DNA-derived humanized IgG1 κ monoclonal antibody that selectively binds to the high-affinity IgE receptor on the surface of mast cells and basophils, limiting release of mediators of the allergic response. It is the first monoclonal antibody approved for the treatment of refractory chronic idiopathic urticaria in patients over the age of 12 and has been shown to result in clinically significant improvement of itching and wheal formation in these patients. Rarely, inflammatory arthralgias can be a severe side effect of omalizumab. Clinical Case: We report a case of a 38-year-old female patient with chronic idiopathic urticaria who responded well on a therapeutic dosage of omalizumab, but subsequently developed severe inflammatory arthralgias. We decreased her dosage and added methotrexate for complete resolution of her urticarial and arthritic symptoms. Conclusion: In patients with concern for medication-induced inflammatory arthralgias, physicians should consider reducing or discontinuing omalizumab with consideration of patient goals for the treatment of chronic idiopathic urticaria. This article highlights the occurrence of inflammatory arthralgias as a side effect of omalizumab, the importance of eliciting patient goals and preferences for treatment, and proposes a solution to manage these arthralgias while appropriately treating symptoms in patients with chronic idiopathic urticaria.

Delayed Pressure Urticaria Associated With Altitude Chamber Training Responsive to Cyclosporine and Omalizumab.

Delayed pressure urticaria (DPU) is a subset of chronic inducible urticaria. It is characterized by the formation of wheals anytime between 30 minutes and 24 hours after stimulus exposure of localized pressure application. In this case report, we discuss a military flight crew member with no significant past medical history who developed DPU following rapid decompression in an altitude chamber. The chamber training included an uneventful ascent to 45,000 feet, higher than he had been previously, and a rapid decompression. About 16 hours later, he developed pruritic swelling of his hands and feet, along with diffuse deep nodular swelling, erythematous plaques, and erythematous nodules. His DPU was refractory to monotherapy treatment with antihistamines, and he continued to develop lesions in weight-bearing areas. Control of symptoms was achieved through combination treatment of a second-generation antihistamine, a leukotriene receptor antagonist, and an immunosuppressant (cyclosporine). His waiver to return to flight status was denied while on cyclosporine. He was transitioned to a monoclonal antibody that binds free immunoglobin E (omalizumab) with resolution of symptoms and was cleared to return to active duty.

Acute urticaria—what to do?

SummaryAcute urticaria (AU) is the most common cause of wheal formation. By definition, it does not persist for more than 6 weeks. It can occur at any age and is more commonly seen in atopic diathesis. Acute spontaneous urticaria is distinguished from inducible forms. This review highlights the clinical presentation, differential diagnosis, possible triggers, and therapeutic strategies. In childhood as in adulthood, viral infections are very frequently associated with acute urticaria, whereas drugs and food are less frequently described as triggers. However, it is not uncommon for multiple triggers to be present simultaneously. Therapeutically, oral nonsedating H1 antihistamines are mainly used. In some patients, concomitant short-term administration of glucocorticosteroids is also necessary.

A CASE STUDY: VIRECHANA IN URTICARIA

In the present era, dermatological diseases are becoming more common due to increased pollution, changes in lifestyle, food habits and the stressful work environment. Urticaria is one such type characterized by red, raised wheal formation associated with itching. A 28-year-old female patient came in the OPD of Panchakarma with red, raised, itchy lesions over both hands and lower legs for the last five years. She was under steroids and antihistamines for an extended period, but there was no relief. The case was diagnosed as Urticaria. In Ayurveda, it can be correlated with Seetapitta, a Vatapitta pradhana roga. Abhyanga, Seka, Vamana, and Virechana are the treatments told by Acharyas. Here Virechana with Trivrut lehya was given after Snehapana with Aragwada mahathikthaka ghrita. The patient got marked relief from the lesions and itching after follow-up.

In silico Identification of Immune Cell-Types and Pathways Involved in Chronic Spontaneous Urticaria.

BackgroundThe immunopathogenesis of chronic spontaneous urticaria (CSU) is poorly understood, but recent research suggests that patients can be divided into autoallergic and autoimmune subtypes. Given that not all patients can be controlled with current treatment regimens, including anti-IgE monoclonal antibodies, a better understanding of the immune pathways involved in CSU may enable the repurposing of monoclonal antibodies used for other dermatologic diseases (e.g., Th2 and Th17 inhibitors). Therefore, we investigated the implicated immune cells and pathways by reanalyzing publicly available transcriptomic data.MethodsMicroarray data of CSU and healthy control (HC) skin and blood were obtained from the Gene Expression Omnibus (GSE72542, GSE57178). Differentially expressed genes were defined as a false discovery rate <0.05 and a |log2 fold change| ≥1. Pathway analyses were conducted using ToppGene and KEGG. Cell-type enrichment was determined by CIBERSORT and xCell and was correlated with clinical characteristics.ResultsTh2 (IL-4/13 signaling) and Th17-related (IL-17/23 signaling) pathways were upregulated in lesional compared to non-lesional and HC samples. In non-lesional versus lesional samples, CIBERSORT analysis revealed increased regulatory T-cells (Treg) and resting mast cells. xCell analysis established that Th1 and Th2 scores were not significantly different between lesional and HC samples. However, Th2 scores in both lesional and non-lesional samples correlated positively with disease severity. Few differentially expressed genes and pathways were identified between CSU and HC blood samples.ConclusionOur results support the involvement of Th2 and Th17-related genes and pathways in CSU. Th2 scores associate with disease severity, which indicates the clinical relevance of these findings. Increased resting mast cell and Treg scores in non-lesional samples may suggest local suppression of wheal formation. Moreover, disease activity seemed to be restricted to the skin as there were limited findings from blood. Larger studies using next-generation sequencing will be helpful to confirm these results.

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

Solar urticaria is a rare, immunologically mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a 'photoallergy' model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.

Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults.

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in‐line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post‐injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well‐tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post‐injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post‐removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson’s rho ± 0–0.4). The large volume injections tested, 1–20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

Methylprednisolone-induced anaphylaxis diagnosed by intradermal skin test: a case report

BackgroundGlucocorticoids rarely cause anaphylaxis. Common methods for the determination of allergens include in vivo skin prick test (SPT) and intradermal skin test (IDST) and the in vitro basophil activation test (BAT). However, to our knowledge, the best strategy for diagnosing glucocorticoid-induced anaphylaxis has not been elucidated.Case presentationA 10-year-old boy was admitted to our hospital because of 2 weeks of fever and arthralgia. He had not been treated with glucocorticoids before, including methylprednisolone (mPSL). He was suspected to have bacterial myositis and was treated with ceftriaxone. However, his symptoms persisted for > 2 weeks. Autoinflammatory arthritis was suspected, and he was treated with mPSL sodium succinate (MPS) pulse therapy (30 mg/kg). After 15 min of mPSL injection, he had wheezing and generalized wheal formation with decreased oxygen saturation. As anaphylaxis was suspected, mPSL was discontinued, and olopatadine and oxygen were administered. The symptoms improved considerably without the use of epinephrine and disappeared in 30 min. One month after discharge, SPT, IDST, and BAT were performed without discontinuing his prescribed oral prednisolone. SPTs for MPS, hydrocortisone sodium succinate (HCS), prednisolone sodium succinate (PSS), dexamethasone sodium phosphate (DSP), and betamethasone sodium phosphate (BSP) were negative. IDSTs for MPS, HCS, and PSS were positive, whereas those for DSP and BSP were negative. By contrast, BATs for MPS, HCS, and PSS were negative. Although glucocorticoid-induced hypersensitivity caused by nonmedicinal ingredients such as lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol has been reported; the glucocorticoids tested in this patient did not contain any of these nonmedicinal ingredients. As the glucocorticoids that were positive on IDST share a succinate ester, this might have caused MPS-induced anaphylaxis.ConclusionsWe report the case of MPS-induced anaphylaxis diagnosed by IDST but not BAT. In case reports of glucocorticoid-induced anaphylaxis in the literature, most patients were diagnosed with SPT or IDST. These results suggest that BAT should be considered when IDST and SPT are negative. Further studies are necessary to clarify the best strategy for diagnosing glucocorticoid-induced anaphylaxis.

Toll-Like Receptor 7 (TLR7) Mediated Transcriptomic Changes on Human Mast Cells.

BackgroundMast cells are skin immune sentinels located in the upper dermis, where wheal formation and sensory nerve stimulation take place. Skin inflammation is occasionally accompanied by mast cell-driven responses with wheals, angioedema, or both. Immunoglobulin E (IgE) antibodies are regarded as typical stimuli to drive mast cell activation. However, various causative factors, including microbial infections, can drive IgE-independent mast cell response. When infected, the innate immunity orchestrates an immune response by activating receptor signaling via Toll-like receptors (TLRs).ObjectiveIn this study, we determined the effect of TLR7 stimulation on mast cells to investigate the possible mechanism of IgE-independent inflammatory response.MethodsHuman mast cell (HMC) line, HMC-1 cells were treated with TLR7 agonist and the morphologic alteration was observed in transmission electron microscopy. Further, TLR7 agonist treated HMC-1 cells were conducted to RNA sequencing to compare transcriptomic features.ResultsHMC-1 cells treated with TLR7 agonist reveals increase of intracellular vesicles, lipid droplets, and ribosomes. Also, genes involved in pro-inflammatory responses such as angiogenesis are highly expressed, and Il12rb2 was the most highly upregulated gene.ConclusionOur data suggest that TLR7 signaling on mast cells might be a potential therapeutic target for mast cell-driven, IgE-independent skin inflammation.

Eosinophils, a Jack of All Trades in Immunity: Therapeutic Approaches for Correcting Their Functional Disorders.

Eosinophils are primitive myeloid cells derived from bonemarrow precursors and require the intervention of interleukin (IL)-5 for their survival and persistence in blood and tissues. Under steady-state conditions, they contribute to immune regulation and homeostasis. Under pathological circumstances, eosinophils are involved in host protection against parasites and participate in allergy and inflammation. Mostly, in asthma, eosinophils provoke airway damage via the release of granule contents and IL-13 with mucus hypersecretion and differentiation of goblet cells. Then, tissue remodeling follows with the secretion of transforming growth factor-β. Eosinophils are able to kill helminth larvae acting as antigen-presenting cells with the involvement of T helper (h)-2 cells and subsequent antibody response. However, they also exert pro-worm activity with the production of suppressive cytokine (IL- 10 and IL-4) and inhibition of nitric oxide. Eosinophils may play a pathogenic role in the course of chronic and autoimmune disease, e.g., inflammatory bowel disease and eosinophilic gastroenteritis, regulating Th2 responses and promoting a profibrotic effect. In atopic dermatitis, eosinophils are commonly detected and may be associated with disease severity. In cutaneous spontaneous urticaria, eosinophils participate in the formation of wheals, tissue remodeling and modifications of vascular permeability. With regard to tumor growth, it seems that IgE can exert anti-neoplastic surveillance via mast cell and eosinophil-mediated cytotoxicity, the so-called allergo-oncology. From a therapeutic point of view, monoclonal antibodies directed against IL-5 or the IL-5 receptors have been shown to be very effective in patients with severe asthma. Finally, as an alternative treatment, polyphenols for their anti-inflammatory and anti-allergic activities seem to be effective in reducing serum IgE and eosinophil count in bronchoalveolar lavage in murine asthma. Eosinophils are cells endowed with multiple functions and their modulation with monoclonal antibodies and nutraceuticals may be effective in the treatment of chronic disease.

Sensitization against skin resident fungi is associated with atopy in cholinergic urticaria patients

BackgroundCholinergic urticaria (CholU) is a common type of chronic inducible urticaria, characterized by small itchy wheals that appear upon physical exercise or passive warming. Malassezia globosa, a skin resident fungus, has been identified as an antigen that induces mast cell/basophil degranulation and wheal formation through specific IgE, in Japanese patients with atopic dermatitis and CholU. In this study we aimed in assessing the rate of IgE sensitizations against skin resident fungi in European CholU patients.MethodsWe assessed serum IgE levels to Malassezia furfur, Candida albicans and Trichophyton mentagrophytes using routine lab testing and Malassezia globosa using a newly established ELISA. We correlated the results to wheal formation and other clinical features.ResultsFour patients (of 30 tested) had elevated levels of IgE against Malassezia furfur and Candida albicans and two had elevated levels of IgE against Trichophyton mentagrophytes. Four sera (of 25 tested) had elevated levels of IgE to the Malassezia globosa antigen supMGL_1304. Sensitization to one skin fungus was highly correlated with sensitization to the other tested fungi. We saw highly significant correlations of sensitization to supMGL_1304 with wheal size in the autologous sweat skin test (rs = 0.7, P = 0.002, n = 19), the Erlangen atopy score (rs = 0.5, P = 0.03, n = 19), total IgE serum levels (rs = 0.5, P = 0.04, n = 19) and a positive screen for IgE against common airborne/inhalant allergens s (sx1; rs = 0.54, P = 0.02, n = 19).ConclusionsSensitization to skin resident fungi including Malassezia globosa is uncommon in European CholU patients, but is associated with atopy and pronounced wheal formation upon dermal contact with their own sweat.Trial registration German Clinical Trials Registry DRKS-ID: DRKS00004277

Acute anti-inflammatory and anti-nociceptive activities of crude extracts, alkaloid fraction and evolitrine from Acronychia pedunculata leaves

Ethnopharmacological relevanceAcronychia pedunculata (family: Rutaceae) is one of the commonly used medicinal plants in Sri Lankan traditional medicine. Different parts of this plant are used for the treatment of inflammatory conditions in the form of medicinal oils and herbal porridge. Aim of the studyThe present study aimed to evaluate the anti-nociceptive activity and anti-inflammatory activity with their mechanisms and the acute toxicity of crude extracts of the fresh leaves of A. pedunculata for scientific validation of the ethnopharmacological claims for this plant. Further, attention has been focused on the isolation of active compounds from active fractions of the crude extracts. Materials and methodsThe acute anti-inflammatory effect of the aqueous (AELA) and 70% ethanol crude extracts (EELA) and alkaloid fraction of A. pedunculata leaves were evaluated by the determination of inhibition of hind paw oedema induced by carrageenan in Wistar rats. Evolitrine was identified as the major alkaloid with significant bioactivities by column chromatography and NMR. The anti-nociceptive and anti-histamine activities of EELA and evolitrine were evaluated by acetic acid induced writhing and wheal formation tests respectively. In addition, in-vitro (2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay) and in-vivo (lipid peroxidation assay) anti-oxidant activity, nitric oxide (NO) inhibitory activity and acute toxicity of EELA were evaluated. ResultsAcute anti-inflammatory activity of AELA and EELA were dose-dependent. EELA was more active than AELA. The 200 mg/kg body weight (b. w.) dose of EELA was found as the minimum effective dose with maximum inhibition (78%) of oedema at 5th hour compared to the negative control (p < 0.05). Evolitrine was isolated and identified as an active anti-inflammatory and analgesic compound from active alkaloid fraction of EELA. Evolitrine showed activity enhancement when compared with crude EELA. The anti-inflammatory and analgesic activities of evolitrine (50 mg/kg b. w.) were comparable to that of reference drugs indomethacin (5 mg/kg b. w) and acetylsalicylic acid (100 mg/kg b. w.). The significant (p < 0.05) anti-histamine activity, DPPH scavenging in-vitro anti-oxidant activity, in-vivo lipid peroxidation inhibitory activity in-vivo, NO inhibitory activity of EELA as compared with relevant negative controls, were identified as probable mechanisms which mediated its anti-inflammatory action. Further, EELA showed a high safety margin in the limited dose acute toxicity study. ConclusionThe findings of the current study rationalize the usage of leaves of A. pedunculata in Sri Lankan traditional medicine as an analgesic and anti-inflammatory agent. Possible mechanisms mediating this activity included anti-histamine, anti-oxidant and NO inhibitory activities. Evolitrine is the major analgesic and anti-inflammatory compound isolated from the active alkaloid fraction of EELA.

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin.

Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6weeks. Spleen tyrosine kinase mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE-mediated histamine release from mast cells in an ex vivo human skin model. Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC-MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed. Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a)-induced histamine release in a concentration-dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC90 and dose-dependently attenuated anti-IgE-induced histamine release. GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8μM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

Cetirizine per os: exposure and antihistamine effect in the dog

BackgroundCetirizine is an antihistamine used in dogs, but plasma concentrations in relation to effect after oral administration are not well studied. This study investigated cetirizine exposure and the plasma cetirizine concentration-antihistamine response relation in the dog following oral administration of cetirizine.ResultsEight Beagle dogs were included in a cross-over study consisting of two treatments. In treatment one, cetirizine 2–4 mg/kg was administered per os once daily for 3 days. The other treatment served as a control. Wheal diameter induced by intra-dermal histamine injections served as response-biomarker. Cetirizine plasma concentration was quantified by UHPLC-MS/MS. Median (range) cetirizine plasma terminal half-life was 10 h (7.9–16.5). Cetirizine significantly inhibited wheal formation compared with the premedication baseline. Maximum inhibition of wheal formation after treatment with cetirizine per os was 100% compared with premedication wheal diameter. The median (range) IC50-value for reduction in wheal area was 0.33 µg/mL (0.07–0.45). The median (range) value for the sigmoidicity factor was 1.8 (0.8–3.5). A behavioral study was also conducted and revealed no adverse effects, such as sedation.ConclusionThe results indicate that a once-daily dosing regimen of 2–4 mg/kg cetirizine per os clearly provides a sufficient antihistamine effect. Based on this experimental protocol, cetirizine may be an option to treat histamine-mediated inflammation in the dog based on this experimental protocol but additional clinical studies are required.

Role of TF-Triggered Activation of the Coagulation Cascade in the Pathogenesis of Chronic Spontaneous Urticaria

To overview recent understanding of the relationship between the blood coagulation cascade and chronic spontaneous urticaria (CSU). The relationship between severities of CSU and the increase of coagulation markers, and the effectiveness of anti-coagulants, such as warfarin, suggest a causative role of the blood coagulation in the pathogenesis of CSU. However, mechanisms of the initiation of blood coagulation, and the link between blood coagulation and wheal formation in urticaria, remained unclear. In blood vessels, vascular endothelial cells and eosinophils may express tissue factor (TF), which triggers the activation of extrinsic coagulation cascade. We recently revealed that histamine and TLR agonists synergistically induce TF expression by endothelial cells and produce active forms of coagulation factors, such as Xa and IIa, which may induce plasma extravasation. The exposure of skin mast cells to the exuded plasma may then induce degranulation of the skin mast cells via various receptors, releasing a massive amount of histamine, resulting in wheal formation observed in CSU. Further elucidation of the mechanism of blood coagulation and the pathway of mast cell activation by activated coagulation factors may be a target for the development of new and more effective treatments for CSU.

The role and relevance of mast cells in urticaria.

This review presents evidence that the skin mast cell, in particular the MCTC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non-lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD2 and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.

Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation

Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. MethodsDogs were anesthetized with IV propofol and received intradermal (ID) injections (50μL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34+/CD45+ cells) were employed and β-hexosaminidase in cell-free supernatants were measured to assess degranulation. ResultsA significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of β-hexosaminidase. The rank order of drug-induced hMC β-hexosaminidase release was similar to that for flares. ConclusionsA variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.

Rabies vaccination in dogs using a dissolving microneedle patch

Because humans get rabies primarily through dog bites, stray dog population control and mass or mandatory vaccination of domestic dogs and other animals has virtually eliminated human rabies in industrialized countries. However, thousands of people in developing countries die of rabies each year due to the inability to control dog populations and implement mass vaccination because of financial, logistical and other challenges. The availability of an easier-to-administer and more cost-effective vaccine may help to address some of these issues. Here, we propose the use of dissolving microneedle patches for simple and potentially cost-effective rabies vaccination, and assess the safety and immunogenicity of microneedle patch vaccination using a rabies DNA vaccine in dogs. The vaccine was stable upon formulation and storage for at least 3weeks at 4°C in a microneedle patch. For vaccination, the patches were applied to the inner ear by hand without an applicator. Microneedle patches were well tolerated in the skin, with mild erythema, minimal wheal formation and complete resolution of skin reactions within 7days, and generated no systemic adverse events. Microneedle patches were at least as immunogenic as intramuscular injection at the same dose, as demonstrated by similar serum neutralizing antibody titers. A ten-fold lower vaccine dose administered by microneedle patch generated a weaker immune response compared to full-dose intramuscular vaccination. We conclude that dissolving microneedle patches may provide an innovative approach to mass vaccination of dogs.