Flare Reaction Research Articles

Unrecognized Kinetics of Serum Testosterone: Impact on Short-Term Androgen Deprivation Therapy for Prostate Cancer

PurposeTo evaluate the kinetics of serum testosterone (T) recovery following short-term androgen deprivation therapy (ADT), as the understanding thereof is essential for the proper management of prostate cancer (PCa), especially intermittent ADT.Materials and MethodsThis prospective analysis included male sex offenders who voluntarily received leuprolide acetate in order to alleviate sexual aberrance. Thirty-three and 25 patients who received 3 and 6 months of ADT were assigned to Group A and Group B, respectively. Serum T levels were obtained every week during the on-cycle period, then monthly during the off-cycle period for at least 12 months.ResultsThe kinetics of serum T during the on-cycle period were similar in both groups. After flare reaction at week 2, a nadir of 0.45±0.29 ng/mL was achieved. In Group A, an abrupt rebound-upsurge was observed during the first 2 month off-cycle period, which surpassed the baseline level and reached a plateau level of 8.74±2.11 ng/mL during the flare (p<0.001). This upsurge was followed by a gradual decline back to baseline over the following 10 months. In Group B, a gradual increase was observed, and a baseline level of 7.26±1.73 ng/mL was reached at 5 months. Thereafter, an ongoing upsurge that surpassed baseline levels was observed until 12 months (8.81±1.92 ng/mL; p=0.002).ConclusionThe kinetics of serum T recovery during the off-cycle period varied according to the duration of ADT. Serum T should be monitored beyond normalization, as an excessive rebound may improve quality-of-life, but hamper the treatment efficacy of PCa.

Tumor flare reaction in a patient with mantle cell lymphoma.

TO THE EDITOR: Tumor flare reaction (TFR) is a syndrome that clinically presents with painful lymph nodes and/or spleen enlargement, and it can be accompanied by fever, rash, and clear lymphocytosis [1]. Medical literature frequently points out its association with chronic lymphocytic leukemia (CLL) and lenalidomide treatment. In a study by Chanan-Khan et al. [2], it was observed that of 26 (58% of 45 patients) CLL patients who were administered 25 mg/day oral lenalidomide treatment for 21 days in 28-day cycles developed TFR reactions (50% developed grade 1-2 reactions, and 8% developed grade 3-4 reactions). In another study by Ferrajoli et al. [3], it was observed that 10 (28% of 35 patients) CLL patients who were first treated with a dose of 10 mg/day of lenalidomide and then with an increased dose of 25 mg/day developed TFR. While TFR cases after lenalidomide treatment have been frequently reported, TFR has not been reported after Hyper-CVAD plus Rituximab (R-HCVAD) treatment. Herein, we report a patient diagnosed with mantle cell lymphoma who developed TFR after use of high dose cyclophosphamide, doxorubicin, adriamycin and dexamethasone plus rituximab. The patient, who was being followed up for relapse of mantle cell lymphoma, developed fever, throat swelling, pain, and difficulty in swallowing after R-HCVAD treatment. Magnetic resonance imaging (MRI) of the patient's throat showed a mass, sized approximately 65×29 mm at its broadest point, with its borders not clearly identified; the mass caused distinct asymmetry in the hypopharynx and oropharynx, displaced the uvula to the right side, and continued to the epiglottis level. Distinct hypertrophy of the lingual and left palatine tonsils as well as of multiple lymph nodes on both sides were observed in the left submandibular area of the cervical chain of the neck, the biggest of which was sized 20×12.5 mm (Fig. 1). These findings suggested TFR after chemotherapy, and dexamethasone (24 mg/day) was initiated. The patient's fever decreased, and his complaints regressed on the 10th day of the treatment; throat MRI revealed edema and inflammation regression when compared to that observed on the previous MRI scan. A thin area of loculation was observed in the left retropharyngeal and parapharyngeal space and a small mass residue, 2.5×8 mm in size, was observed in the parapharyngeal space, with no clear contrast involvement. The patient's complaints abated completely after dexamethasone treatment; therefore, medications were stopped and follow-up was initiated. Fig. 1 The patient's throat magnetic resonance imaging scan showing a heterogeneously dense mass, sized approximately 65×29 mm at its broadest point, with its borders not clearly identified; therefore, the mass caused distinct asymmetry in the hypopharynx ... Until recently, it was thought that TFR associated with lenalidomide was a condition specific only in CLL patients. However, in 2010, Corazzelli et al. [4], reported three patients with relapsing or refractory Hodgkin lymphoma who developed TFR, and thus, showed that it was not so. Similarly, Eve and Rule [5], showed that three of 25 patients with mantle cell lymphoma who were treated with lenalidomide developed TFR. It was observed that two of the mantle cell lymphoma patients who developed TFR had a mild condition and recovered without any treatment. However, the other patient died of cerebrovascular complications although he was hospitalized owing to the severity of his condition (he had a prolonged reaction and his pain could not be controlled) [5]. While the etiology of TFR is not clearly known, it is thought that some mechanisms may be because of secondary production of cytokines. Studies have shown that lenalidomide does not directly induce apoptosis of or cytokine production by tumor cells, but depending on the dose, it does increase CD40, CD80, CD86, HLA-DR, and CD95 expression by activating B cells [1]. It has been shown that there is distinctive CD40 and CD86 expression in CLL cells on ex vivo lenalidomide administration, and that the expression is associated with TFR [1]. Andritsos et al. [1] have shown that, on pre- and post-treatment evaluation of the lymph nodes, infiltration of Ki67- and CD3-positive, CD8-positive, granzyme B-positive T cells increases. It has been observed that, in patients with Hodgkin lymphoma who are treated with lenalidomide and who develop TFR, cytokines (particularly interleukin [IL]-6, IL7, APRIL, BAFF/BLyS) are released because of B cell activation, and levels of free light chains increase distinctively; these changes are reflected in the clinical properties. Likewise, it has been shown that when the TFR subsides, cytokines and light chain levels decrease to normal levels [5]. Therefore, for patients who develop TFR, it is suggested that dexamethasone be used, as it provides distinctive improvement by especially inhibiting CD40 regulation [1]. The mechanism through which the R-HCVAD treatment leads to TFR is not known, but one of the above-listed mechanisms may play a role.

Wheal and flare reactions in skin prick tests of patients treated with montelukast alone or in combination with antihistamines

Background Because antileukotrienes may inhibit inflammation, it is plausible that montelukast administered for a long time could suppress skin wheal and flare reaction, and thus, it should be discarded prior to the tests. This study assessed the effect of long-lasting treatment with montelukast alone or in combination with antihistamines on wheal and flare in skin pricks tests (SPT) in patients sensitized to perennial allergens.MethodsWe conducted a 32-week, double-blind, placebo-controlled, cross-over and randomized trial that implicated two arms: arm A, 20 patients received levocetirizine, montelukast with or without levocetirizine or placebo; arm B, 20 patients received desloratadine, montelukast with or without desloratadine or placebo. All treatment periods lasted 6 weeks and were separated by 2-week washouts. At baseline and on the last day of each treatment period, SPT were performed in all participants.ResultsBoth levocetirizine and desloratadine in monotherapy, or in combination with montelukast, were effective in reducing wheal and flare in SPT. Monotherapy with montelukast did not change the size of the wheal for either histamine or for house dust mites, in either arm of the study, but significantly reduced the size of flare for histamine in arm A. Addition of montelukast to antihistamine did not exceed efficacy of monotherapy with antihistamine in both arms of the study.ConclusionsSince the size of wheal determines the results of SPT, montelukast, even taken for a long time, does not have to be discarded prior to the tests.

Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. MethodsPatients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. ResultsBy April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q).5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients.Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. ConclusionsThe combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures:Choi:Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase 1/2 Study Of The Safety and Activity Of Escalating Doses Of Lenalidomide Plus Rituximab For Patients With Refractory Or Relapsed Chronic Lymphocytic Leukemia (LLC-Lenar-08)

Phase II trials have shown that lenalidomide alone is active in relapsed and refractory CLL. When the initially dose is reduced from 25mg to 5-10mg associated toxicities as the tumor lysis syndrome (TLS) or tumor flare reaction (TFR) nearly disappeared (J Clin Oncol 2006,24:5343). There is synergistic activity between rituximab and lenalidomide against CLL and non-Hodgkin lymphoma cells in vitro, and recently a Phase II study demonstrated that the combination of lenalidomide and Rituximab is active in patients with recurrent CLL (J Clin Oncol, 2012,31: 584). However neither the dose of lenalidomide nor the optimal schedule of administration has been defined. Furthermore since median age of CLL patients is high the emergence of a nonchemotherapy containing regimen with a lower toxicity seems an attractive approach for them. In 2008 we designed a trial that explore the optimal doses of lenalidomide in combination with rituximab for patients with relapsed or refractory CLL and analized also its safety and efficacy (ClinicalTrials.gov:NCT01185262). Our primary endpoint was to define the recommended dosage regimen for the combination of lenalidomide plus rituximab in patients with relapsed/refractory CLL. From June 2009 to November 2012 a dose escalation study was performed starting at a lenalidomide daily dose of 2,5mg and rituximab (375mg/m2 cycle 1 and 500mg/m2 cycles 2-6/28 days) with cohorts of 3 patients (if no DLT move to a higher dose; if one DLT ocurred in the cohort expand 3 more patients)(Tables 1 and 2). 29 patients has been registered in the trial. 4 of them were screening failures either because did not fullfilled criteria (2) or early withdrawal of patient consent before receiving treatment(2). Median age was 75 years (45-86). Median number of previous lines of treatment were 2 (1-4) and all but 2 patients were treated previously with fludarabine. In the first cohort of 2.5 mg we treated 6 patients and because of persistent neutropenia (more than 7 days grade 4) MTD ocurred. This was because the original protocol did not accept the prohylactic use of G-CSF. From that moment the use of G-CSF was free and based on the investigator criteria but mandatory for all those patients that started with less than 1000 neutrophils/mm3. A total of 33 SAEs were recorded among the 25 patients included in the two periods of the study (before and after the free use of G-CSF)(7/26 respectively) and during all the treatment. Main SAEs were as follows: Infections (23 SAEs with one case of Multifocal leukcoencephalophaty), constipation (2), autoimmune hemolytic anemia (1), allergic reaction to rituximab infusion (1), amyotrophic lateral sclerosis (1), gastrointestinal bleeding(1) and others (4). No case of TLS has been reported and only one case of mild TFR. By June 1st 2013 9/29 patients included has died and one is still receiving treatment. Causes of death were disease progression (5) and infection (4). In our experience the combination of lenalidomide and rituximab was a well tolerated regimen for this old (median age 75y) and heavely pre-treated population. In our experience lenalidomide at 15 mg was defined at the MTD. Neutropenia was the main adverse event associated with the regimen and nearly all patients needed G-CSF support. Clinical eficacy data is on evaluation.Table 1Dose LevelDose of lenalidomideTotal dose of rituximab (Cycle1/Cycle2 & subsequently)I2,5 mg/day375/500 mg/m2II5 mg/day375/500 mg/m2III10 mg/day375/500 mg/m2IV15 mg/day375/500 mg/m2V20 mg/day375/500 mg/m2VI25 mg/day375/500 mg/m2Table 2N patientsDLT2,5 mg3No5 mg4No10 mg4No15 mg82 Disclosures:Tomas:Celgene: Research Funding.

Luteinizing hormone-releasing hormone antagonists for urinary obstruction in prostate cancer

Luteinizing hormone-releasing hormone (LHRH) antagonists rapidly reduce testosterone and are preferred to LHRH agonists in situations when early response is important. The lack of flare reaction, as compared to LHRH agonists, is particularly desirable as it would not aggravate the problem. A 78-year-old man presented with symptoms of urinary tract obstruction. He had a prostate-specific antigen (PSA) of 91.3 ug/L and serum creatinine 146 umol/L. He had a large pelvic mass due to histologically confirmed prostate cancer, resulting in moderate left hydronephrosis and deteriorating renal function (serum creatinine of 163 umol/L). He was started on combined degarelix and bicalutamide on the day of consultation (day 0). The hydronephrosis resolved on the repeat computerized tomography scan performed on day 10. Serum creatinine normalized to under 130 umol/L on day 18. The PSA fell to 11 ug/L on day 18, 2.8 ug/L on day 28, and 0.5 ug/L on day 53. Therefore, LHRH antagonists are particularly useful in urgent situations. It is the preferred choice in these circumstances.

Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study

Background:Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances.Methods:We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors.Results:Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5+). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies.Conclusion:Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.

Phase 2 Study of a High Dose of 186Re-HEDP for Bone Pain Palliation in Patients with Widespread Skeletal Metastases

(186)Re-1-hydroxyethylidene-1,1-diphosphonate (HEDP) is an attractive radiopharmaceutical for the treatment of bone pain arising from skeletal metastatic lesions. Currently, (186)Re-HEDP is most commonly used in European countries. The aim of this study was to investigate the palliative efficacy and adverse effects of (186)Re-HEDP in patients with different types of cancers and skeletal bone pain. Nineteen (8 male, 11 female) patients with various cancers (breast, prostate, renal cell carcinoma, colon, and neuroendocrine tumors) and painful bone metastases were included in the study. A dose of 1,480-3,330 MBq (40-90 mCi) of (186)Re-HEDP was administered intravenously. The patients' level of pain relief was assessed by the Visual Analog Scale for 8 wk after treatment and by a weekly blood cell count to evaluate for hematologic toxicity. The overall response rate was 89.5%, and the mean pain score assessed by the Visual Analog Scale was reduced from 9.1 to 5.3 after 1 wk (P = 0.003). No adverse effects were reported by patients during intravenous administration or for up to 24 h after administration. A flare reaction was seen in 63.2% of patients, mainly during days 1-3, and lasted for 2-4 d. There was no significant correlation between the response to therapy and the flare reactions (P > 0.05). The nadir of platelet reduction occurred at the fourth or fifth week and led to platelet infusion in only 4 patients with a low baseline platelet count and diffuse skeletal metastases. Bone marrow suppression occurred in patients receiving higher doses, but no clinical problems were seen except in 2 patients who required packed cell transfusion similar to their prior transfusions. (186)Re-HEDP is an effective radiopharmaceutical for the palliative treatment of metastatic bone pain and has minimal adverse effects.

Nongranulomatous anterior uveitis in a patient with Usher syndrome

A 34-year-old female with Usher syndrome, but no family history of similar illness, presented with complaints of vision reduction, redness, and photophobia. Biomicroscopic examination showed mildly injected conjunctivae bilateral, small, round keratic precipitates; bilateral +2 cells with no flare reaction in the anterior chamber; and bilateral posterior subcapsular cataracts. No associated posterior synechiae, angle neovascularization, or iris changes were detected; normal intraocular pressures were obtained. Fundus examination demonstrated waxy pallor of both optic nerves, marked vasoconstriction in retinal vessels, and retinal bone spicule pigment formation, with a normal macula. Electroretinography confirmed the diagnosis of retinitis pigmentosa, optical coherent tomography was normal and otolaryngology consultation was conducted.To our knowledge, an association between Usher syndrome and bilateral nongranulomatous anterior uveitis has not been previously reported, and our purpose is to report this association.

Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]

Efficacy and safety of potassium clavulanate/amoxicillin (CLAVAMOX) dry syrup in children with otitis media

To evaluate the efficacy and safety of CLAVAMOX dry syrup (potassium clavulanate/amoxicillin) in children with otitis media, we conducted a postmarketing surveillance from February to September 2006. The analysis was made on the basis of 470 survey sheets collected from 127 medical institutions, of which we investigated 455 cases for safety, and 433 cases for efficacy. The efficacy was 95.2% in the 433 subjects eligible for the efficacy analysis. The clinical improvement rates for major symptoms (otalgia, otorrhea, flare reaction of drum membrane and fever) were 95% or more. The efficacies for the three major offending bacteria of otitis media (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were between 94.6% and 100%. The efficacies for penicillin-resistant Streptococcus pneumoniae (PRSP) and penicillin intermediate resistant Streptococcus pneumoniae (PISP) were 95% or more. Adverse drug reactions (ADRs) were reported in 106 (23.3%) of the 455 subjects eligible for safety analysis. The major ADRs were diarrhea, of which incident was 22.6% (103 of 455). These ADRs were observed at a higher rate in younger age patients. Most of the diarrhea cases were non-serious, reversible on discontinuation or continuation of the drug. No clinically important serious diarrhea cases such as pseudomembranous colitis or dehydration were observed. Our surveillance results demonstrated that CLAVAMOX dry syrup had excellent efficacy and clinically manageable safety in children with otitis media. These findings indicated that this medicine was clinically-useful in children with otitis media.

Comparison of effects of 5 and 10 mg oral desloratadine and levocetirizine on histamine-induced wheal and flare response in healthy volunteers

Background: Levocetirizine and desloratadine are mostly used as H1-antihistamines in the treatment of allergic disease in 5 and 10 mg doses. Objective: In this study, the efficacy of single oral dosages of 5 and 10 mg desloratadine and levocetirizine were compared by using histamine-induced wheal and flare reactions. Methods: Eighty healthy volunteers were randomized for four double-blinded treatment with desloratadine 5 and 10 mg and levocetirizine 5 and 10 mg. Wheal and flare responses were produced by histamine. Measurements were performed just before the ingestion of antihistamines (baseline) and afterward at 30, 60, 240 min and 24 h. The values obtained for each antihistamine were compared with baseline values. Results: It was found that except the flare reactions at 30th min, levocetirizine 5 and 10 mg suppressed histamine-induced wheal and flare reactions more than desloratadine 5 and 10 mg did. There were not any significant differences between desloratadine 5 and 10 mg in all periods. Levocetirizine 10 mg suppressed wheal and flare reactions significantly more than levocetirizine 5 mg only at 24th h. Conclusion: In this study, it was observed that levocetirizine 5 and 10 mg had a higher activity than desloratadine 5 and 10 mg.

Evaluation of the effects of a metabotropic glutamate receptor 5‐antagonist on electrically induced pain and central sensitization in healthy human volunteers

This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare. This was a randomized, double-blind, placebo-controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis. Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy. Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction.

Characterization of clinical photosensitivity in cutaneous lupus erythematosus

Photosensitivity (PS) in lupus erythematosus (LE) is frequently determined by patient report. We sought to characterize self-reported PS in cutaneous LE (CLE). The PS survey was used to classify subject responses into 5 phenotypes: direct sun-induced CLE flare (directCLE); general exacerbation of CLE (genCLE); polymorphic light eruption-like reactions (genSkin); general pruritus/paresthesias (genRxn); and sun-induced systemic symptoms (genSys). In all, 91 subjects with CLE alone or with CLE and systemic LE were interviewed. In all, 81% ascribed to 1 or more PS phenotypes. CLE-specific reactions (direct sun-induced CLE flare or general exacerbation of CLE) were reported by 86% of photosensitive subjects. Higher CLE disease activity (measured by CLE Disease Area and Severity Index activity scores) was suggestive of direct sun-induced CLE flare reactions (P = .09). In all, 60% of photosensitive subjects described CLE-nonspecific reactions: polymorphic light eruption-like rash and general pruritus/paresthesias. These phenotypes often co-occurred with CLE-specific reactions and were predicted by more systemic disease activity as measured by Physicians Global Assessment (PGA) scores in regression analyses (genSkin, P = .02) and (genRxn, P = .05). In all, 36% of subjects reported systemic reactions and higher PGA scores were predictive of the sun-induced systemic symptoms phenotype (P = .02); a diagnosis of systemic LE was not (P = .14). PS was inferred from patient report and not directly observed. Characterization of self-reported PS in LE reveals that patients experience combinations of CLE-specific, CLE-nonspecific, and systemic reactions to sunlight. Sun-induced CLE flares are associated with more active CLE disease. Polymorphic light eruption-like, generalized pruritus/paresthesias, and systemic reactions are associated with more active systemic disease. Recognition of PS phenotypes will permit improved definitions of clinical PS and allow for more precise investigation into its pathophysiology.

Effect of flare reaction to intra-articular injection on cartilage lubricating ability of human synovial fluid

Effect of flare reaction to intra-articular injection on cartilage lubricating ability of human synovial fluid

Mechanically evoked itch in humans

When a newly developed experimental method to vibrate vellus hairs on human skin was applied to the face and arm in healthy subjects, intense itch was reproducibly induced on the face, but not on the arm, without any flare reactions. In contrast to histamine-induced itch, mechanically evoked itch was not characterized as burning or stinging by any subjects, and was resistant to histamine H1-receptor antagonists. When the stimulation was continued for 10min, mechanically evoked itch reached the maximum intensity within 10s, but gradually attenuated after 60 to 90s and was rarely perceivable at the end of stimulation. When the stimulation was discontinued at 90s, mechanically evoked itch rapidly attenuated after the end of stimulation, but took more than 10min before it completely diminished. These results indicate a possible involvement of C-tactile neurons in mechanically evoked itch because they have consistent characteristics such as low mechanical thresholds, intermediate adaptation, after discharge, favorable response to slowly moving stimuli, and fatigue during repeated mechanical stimulation, although it needs to be confirmed by future microneurographic studies. Touch-alloknesis was present in the adjacent skin area until mechanically evoked itch completely diminished, supporting the hypothesis that itch sensitization can be caused by a continuous activation of peripheral itch neurons whether or not they are histamine-sensitive C nerves. In conclusion, this study provides direct evidence of mechanosensitive nerves involved in itch in human skin. The purity of mechanically evoked itch without any pain-related sensory components is a major advantage for investigating the differentiation of itch from pain.

Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis)

We propose that the adrenal gland of an older higher primate female animal model will respond to human chorionic gonadotropin (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically castrated animals will provide proof of concept and a validated animal model for future studies to explore the rise in DHEAS during the menopausal transition of women. Twenty-four 18- to 26-year-old female cynomolgus monkeys were screened for ovarian function and then either ovariectomized (n = 4) or treated with a gonadotropin-releasing hormone agonist (GnRHa; n = 20) to block ovarian steroid production. After a recovery period from surgical procedure or down-regulation, a single-dose challenge (1,000 IU/animal, IM) of hCG was then administered to determine if luteinizing hormone (LH)/chorionic gonadotropin could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH, and urinary metabolites of ovarian sex steroids were monitored before, during, and after these treatments. Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days postadministration of GnRHa. Urinary metabolites of estradiol and progesterone remained low after the surgical procedure or a flare reaction to GnRHa. Circulating DHEAS levels were increased after hCG administration, and the increase in individual animals was proportional to the pretreatment DHEAS at baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to hCG challenge and were subsequently further elevated by the hCG challenge while no concomitant change in ovarian steroid hormone excretion was observed. These data demonstrate a positive adrenal androgen response to LH/chorionic gonadotropin in older female higher primates and suggest a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.

Sphingosine-1-Phosphate-Induced Nociceptor Excitation and Ongoing Pain Behavior in Mice and Humans Is Largely Mediated by S1P3 Receptor

The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute post-traumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in "cation-free" solution and blocked by the nonspecific Cl(-) channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-β-S. Notably, S1P(3) receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P(3)(-/-) mice, whereas in control S1P(1) floxed (S1P(1)(fl/fl)) mice and mice with a nociceptor-specific deletion of S1P(1)(-/-) receptor (SNS-S1P(1)(-/-)), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl(-) conductance that is largely mediated by S1P(3) receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain.

Platelet‐activating factor (PAF) induces wheal and flare skin reactions independent of mast cell degranulation

Platelet-activating factor (PAF) causes wheal and flare responses which are abrogated by H1-antihistamines giving rise to the hypothesis that PAF-induced wheal development is secondary to histamine release from dermal mast cells. But is this hypothesis correct? Wheal and flare responses were induced by intradermal injection of PAF, codeine and histamine in 14 healthy volunteers. Dermal histamine and PGD2 contractions were measured using microdialysis. PAF, unlike histamine and codeine, did not cause a statistically significant rise in mean histamine levels with ten persons showing negligible histamine release. Codeine caused a significant but variable histamine release, ranging from 29 to 282 ng/ml. Codeine, but not PAF or histamine, caused a small but statistically significant release of PGD2. Wheal and flare reactions in human skin induced by PAF are not associated with histamine release and, therefore, appear to be independent of mast cell degranulation.

Food allergy and anaphylaxis – 2038. Insect and sting allergy

This article was originally published online on 23 April 2013 Insect and sting allergy in immunocompetent populations. A comparison. Observation made in diferent subsets of population who had insect and sting allergy (bees, wasps, scorpions, mosquitos parasites etc). 1) Immunocompetent population in the developing world engaged in farming and related activities regularly exposed to all gradient of allergens like dust molds, dander, pets, etc and when they are exposed to insect and mosquito bites, bees and wasps stings even scorpion bites they suffer to a lesser extent. 2) Immunocompromised population in the developed world far away from natural gradient of exposure of nearly all the allergens and when they are exposed to scorpion bite or bees and wasp stings there are reports of fatal reactions and even mosquito and insect bites causes serious wheal and flare reaction, this observation was made specially on the second generation of children from parents of Indian origin now living in USA and other affluent countries, where there is minimal exposure to all the allergens. Based on the observation made on nearly 2 lakh patients it was observed that there is a direct relationship of levels of exposure to all the natural allergens and the immunotolerance achieved by this natural exposure or natural immunotherapy. After above mentioned observations we reached to the conclusion that exposure to natural gradient of allergens, insect bites mosquito bites is troublesome for the immunocompromised populations who follow avoidance of exposure to allergens as a rule and this is a disaster for them there are many deaths reported due to the above mantioned exposure, at the same time the immunotolerant population which is exposed to all sorts of allergens insect bites mosquito bites bees and wasps stings suffers to a lesser extent.