The improved efficacy of a fixed-dose combination of fluticasone furoate and levocabastine relative to the individual components in the treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common chronic disease, which has significant detrimental effect on well-being and quality of life as well as substantial socio-economic impact. Combination pharmacotherapy is utilized by 40-50% of patients to treat their symptoms. OBJECTIVE: To compare the effects of intranasal fluticasone furoate (FF)/levocabastine (LEVO) fixed-dose combination (FDC) with each component alone on allergen-induced nasal and ocular symptoms. METHODS: A randomized, double-blind, placebo-controlled, three-way, incomplete block, cross-over, proof-of-concept study in 71 patients with AR, evaluated FF 100 µg, LEVO 200 µg and FDC (FF 100/LEVO 200 µg), once daily via intranasal spray for 8 days. On days 1 and 8, total nasal symptom score (TNSS) and total ocular symptom score (TOSS) were assessed every 15 min during a 4-h allergen exposure in the Vienna Challenge Chamber. The primary endpoint was Day 8 weighted mean TNSS. RESULTS: After 8 days, FDC resulted in both statistically and clinically significant reductions in mean TNSS compared with FF and LEVO alone [adjusted mean differences (95% CI): FDC vs. FF: -2.26 (-2.90, -1.62); FDC vs. LEVO: -2.57 (-3.21, -1.93)]. All active treatments were significantly superior to placebo [adjusted mean difference (95% CI) from placebo: FDC: -4.1 (-4.86, -3.34); FF: -1.84 (-2.66, -1.03); LEVO: -1.53 (-2.34, -0.72)]. Onset of action was rapid following FDC and LEVO treatment with an approximate two unit reduction in mean TNSS from pre-dose levels by 30 min and 1 h. Mean TOSS was also reduced following all active treatments relative to placebo (range 0.6-0.8 unit reduction). All treatments were equally well tolerated. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that once daily FF/LEVO FDC could provide a clinical therapeutic advantage to existing standard monotherapies in the treatment of moderate-to-severe AR, and support progression to evaluation in larger phase III clinical studies.

Delayed ultraviolet erythema not suppressed by oral prednisolone: a randomized crossover study.

BACKGROUND: The anti-inflammatory potency of topical dermatological corticosteroids in suppressing ultraviolet (UV) erythema is routinely measured. No such model exists to assess the potency of systemically administered steroids. OBJECTIVE: To determine whether or not suppression of delayed UV erythema by a systemic corticosteroid could provide a useful model for assessing the anti-inflammatory potency of systemic corticosteroids. METHODS: We conducted a randomized, placebo-controlled, patient and assessor blinded, crossover study of oral prednisolone effects on the delayed UV-induced erythemal response in normal subjects. Six healthy volunteers were phototested with a xenon arc monochromator and then dosed with 30 mg of oral prednisolone or matching placebo daily for 4 days. Repeat phototesting was performed on the 4th day of dosing. The minimal erythema dose (MED) was assessed immediately after test UV doses were administered and 24 h later. After a 2-week washout period, the dosing and testing were repeated in a crossover fashion. RESULTS: A suppression index (SI) [1/(baseline MED value divided by on prednisolone/placebo value)] allowed comparison of the degree of suppression on and off prednisolone. Oral prednisolone did not significantly suppress the threshold UV erythema response (MED). We may have missed small effects in this study and possibly a larger dose or a longer duration of corticosteroid would have had an effect. Possibly, assessment of corticosteroid potency in suppressing established UV erythema rather than on the development of threshold erythema would have yielded different results. CONCLUSION: The threshold UV erythema suppression model assessed in this study could not distinguish between oral prednisolone and placebo. This UV-erythema suppression test system is not promising as a model to test the anti-inflammatory potency of systemic steroids.

Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects.

Asthmatics, unlike healthy subjects, experience bronchoconstriction in response to inhaled adenosine, and extracellular adenosine concentrations are elevated in the bronchoalveolar lavage fluid and exhaled breath condensate of asthmatic subjects. However, little is known about the location and expression of adenosine receptors in asthmatic airways. The aim of the present study was to investigate the distribution of adenosine A(1) receptors in bronchial biopsy specimens from mildly asthmatic steroid-naïve subjects and then compare the degree of expression with that of healthy subjects. Biopsy sections were immunostained using an adenosine A(1) receptor antibody, the selectivity of which was validated in specific experiments. Image analysis was then performed in order to determine differences in immunostaining intensity. Immunostaining of biopsy sections from the asthmatic subjects revealed strong expression of the A(1) receptor, located predominantly in the bronchial epithelium and bronchial smooth muscle. In comparison, very weak immunostaining was observed in biopsy specimens obtained from healthy subjects. Image analysis revealed that the intensity of positive staining of the asthmatic bronchial epithelium and smooth muscle regions was significantly greater than that observed for the healthy epithelium and smooth muscle. In conclusion, the sensitivity of asthmatics to inhaled adenosine coupled with increased adenosine A(1) receptor expression implies that these receptors play a role in the pathophysiology of this disease.

Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients.

In an open ascending-dose study, granisetron, a specific 5-HT3 receptor antagonist, was administered to 24 paediatric patients (17 male, 7 female, mean age 6.2, range 3-15 years) who were receiving moderately or highly emetogenic chemotherapy for malignant disease. Single doses of 10, 20 and 40 micrograms/kg were administered by intravenous infusion 1 h before chemotherapy. Each dose level was studied in a group of 8 patients. With the 40 micrograms/kg dose, 5 of 8 patients experienced no nausea or vomiting in the 24 h after granisetron treatment. With 20 micrograms/kg, a similar response was seen, but with 10 micrograms/kg only 2 of 8 patients experienced complete antiemetic protection despite additional prophylactic chlorpromazine in this group. Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram. It is concluded that granisetron was very well tolerated by paediatric patients. In addition, there was clear evidence of a major antiemetic effect for at least 24 h after a single intravenous dose of 20 or 40 micrograms/kg.

An overview of the pharmacokinetics of cilomilast (Ariflo), a new, orally active phosphodiesterase 4 inhibitor, in healthy young and elderly volunteers.

The oral pharmacokinetics of cilomilast (Ariflo) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for Cmax and t(1/2) were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily aftermeals were well tolerated following dose titration.

Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin.

BACKGROUND: Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS: In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS: Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS: Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.

STUDY OBJECTIVE: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers. SETTING: Clinical pharmacology unit. DESIGN: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies. SUBJECTS: Ninety-six healthy adult volunteers who were nonsmokers. INTERVENTION: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. MEASUREMENTS AND MAIN RESULTS: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid. CONCLUSION: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

The antiemetic effect of granisetron in lower hemibody radiotherapy.

Radiotherapy-induced emesis is poorly controlled with existing antiemetics. 5-Hydroxytryptamine (5HT3) receptor antagonists are a new class of antiemetics which have been demonstrated to be effective in controlling cytotoxic-induced emesis. We have prospectively studied the antiemetic efficacy of the 5HT3 receptor antagonist granisetron in an open non-randomized efficacy and toxicity study, at two dose levels, in patients receiving lower hemibody radiotherapy for multiple bone metastases. Of the 22 patients studied, 13 patients received 20 micrograms/kg and nine patients 40 micrograms/kg of granisetron, administered as an intravenous infusion 1 h before radiotherapy. Radiotherapy was administered as a single exposure to the lower half body to a midline dose of 8 Gy. A complete response (no nausea or vomiting) was observed in 9/13 patients at the lower dose level and 6/9 patients at the higher level. No major adverse events were recorded. We conclude that granisetron is a well-tolerated and effective antiemetic agent in radiotherapy-induced emesis. Formal comparison with conventional antiemetic agents in this situation is required.

Topical corticosteroid inhibits interleukin-4, -5 and -13 in nasal secretions following allergen challenge.

BACKGROUND: Cytokines and chemokines produced by allergen-reactive T-helper type 2 (Th2) cells may be pivotal to the pathophysiology of allergic disorders. OBJECTIVE: This study was performed to assess the effect of 7 days of topical corticosteroid on nasal allergen challenge (NAC) in terms of eosinophils, cytokines and chemokines obtained by nasal lavage and filter paper methods. METHODS: Patients with grass pollen seasonal-allergic rhinitis (n = 13) out of season received nasal challenge following matched placebo (twice daily into each nostril for 7 days) and fluticasone propionate (100 microg twice daily into each nostril for 7 days). Chemokine and cytokine levels were analysed using a sensitive automated bead immunoassay system at intervals up to 8 h after NAC. RESULTS: Levels of cytokines and chemokines from filter paper were generally higher than from nasal lavage. Fluticasone propionate caused a reduction in symptoms, total leukocyte counts and eosinophils, and abrogation of IL-4, IL-5, IL-6 and IL-13 responses in the filter paper taken in the late phase (P < 0.05 for IL-4 and IL-13, P < 0.01 for IL-5 and IL-6). Levels of chemokines (eotaxin, RANTES, MCP-1, MIP-1alpha, IL-8 and IP-10) were also reduced in the late phase (P < 0.01 at 8 h). However, levels of IL-2, IL-3, IL-7, IL-12 (p40 and p70), -15, TNF-alpha, IFN-gamma and GM-CSF were not affected. CONCLUSION: Fluticasone propionate has selective inhibitory effects on Th2 cytokine synthesis following nasal challenge, while also decreasing release of chemokines, but not affecting levels of Th1 cytokines.

Immunological responses to complex salts of platinum. I. Specific IgE antibody production in the rat.

Ammonium tetrachloroplatinate II ([NH4]2 PtCl4) was used in free and conjugated forms with ovalbumin in an attempt to elicit specific antibody directed against either the free platinum (Pt) salt or the platinum moiety of ovalbumin-Pt conjugates in the hooded Lister rat. Immunization with free Pt salt via intraperitoneal, intramuscular, intradermal, subcutaneous, intratracheal and footpad routes over a wide range of doses (1 microgram-1 mg) employing both B. pertussis and/or aluminium hydroxide gel as adjuvants failed to induce specific IgE antibody, either primary or secondary, as shown by direct skin, PCA test or RAST. Conjugation of (NH4)2 PtCl4 with ovalbumin produced conjugates, with between two and 10 haptenic Pt groups per ovalbumin molecule, capable of inducing IgE antibody directed against the Pt moiety as determined by heterologous PCA challenge, where carrier cross-reactivity was excluded, and by specific RAST, confirmed by RAST inhibition.

Cross reactivity studies with platinum group metal salts in platinum-sensitised rats.

Hooded Lister rats were sensitised to the halide salt of platinum ammonium tetrachloroplatinate(II)[(NH4)2PtCl4] in its conjugated form with ovalbumin. Sensitisation was achieved by intraperitoneal injection with Bordetella pertussis vaccine as adjuvant, followed 21 days later by a further injection in saline. The presence of specific anti-platinum IgE antibody was determined by passive cutaneous anaphylaxis (PCA) and radioallergosorbent test (RAST) using the platinum halide salt conjugated to a heterologous carrier. Sera exhibiting positive reactions were pooled and PCA tests performed on the titrated pooled sera with 3 conjugated platinum group metal salts, 5 platinum group metals in their free salt form and 6 platinum salts with differing ligands. PCA challenges with these compounds resulted in significant cross reactivity between ammonium tetrachloroplatinate(II), ammonium hexachloroplatinate(IV) and the conjugated tetrachloroplatinate. There was very limited cross reactivity with other platinum or platinum group metal salts in either free or conjugated forms. Furthermore, these results were confirmed by RAST inhibition studies.

Immunological responses to complex salts of platinum. II. Enhanced IgE antibody responses to ovalbumin with concurrent administration of platinum salts in the rat.

The effect of platinum group metal salts on IgE antibody synthesis in an animal model was studied with respect to the magnitude and kinetics of the response. In outbred Hooded Lister Rats immunized with 10 micrograms ovalbumin with B. pertussis as adjuvant and boosted with 1 microgram in saline an enhanced secondary response to ovalbumin was obtained when certain halide platinum salts were given concurrently with primary immunization. This phenomenon was limited to ammonium tetrachloroplatinate II, ammonium hexachloroplatinate IV and to a lesser extent the cesium trichloronitroplatinate II. Platinum group metal salts not possessing this characteristic were cis-dichlorodiammine plantinum II, tetra-ammineplatinum II chloride, ammonium aquopentachlororhodate III and ammonium tetrachloropalladate II. Kinetic studies show that the time courses of the primary and secondary responses were not altered in the presence of the platinum salts. In rats immunized with ovalbumin without adjuvant there was no detectable antibody and concurrent administration of platinum salts also had no effects. Thus platinum salts whilst acting synergistically with adjuvant to enhance antibody synthesis do not act as adjuvants in their own right.

Platinum group metal sensitivity: reactivity to platinum group metal salts in platinum halide salt-sensitive workers.

The ability of closely related platinum group metal salts (PGMS) to cross-react with the principal sensitising agent ammonium hexachloroplatinate IV was investigated in refinery workers. Selected subjects were screened by skin prick test, specific RAST, RAST inhibition, and primate PCA tests. These showed--but only in platinum-sensitive subjects--a low prevalence of skin and RAST sensitivity to the other PGMS and limited evidence of hapten specific cross-reactivity.

Enhancement of antibody production by mercury and platinum group metal halide salts. Kinetics of total and ovalbumin-specific IgE synthesis.

The effects of halide salts of mercury, platinum and palladium on the synthesis of total and specific serum IgE and of total IgG were studied in groups of Hooded Lister rats immunised with antigen (ovalbumin) in the presence and absence of an adjuvant (Bordetella pertussis vaccine or aluminium hydroxide). Repeated intraperitoneal injections of mercuric chloride alone rapidly enhanced total IgE levels in control rats, independent of adjuvant. Injections of the platinum salt, however, elevated total IgE levels more slowly and then only in the B. pertussis-treated group. The halide salt of palladium was ineffective. In rats immunised with antigen and adjuvant, mercury treatment rapidly produced enhancement of the titre-specific IgE antibodies, whereas treatment with platinum again raised these levels more slowly. The palladium salt had no such effect.

Development of a microassay for histamine release.

A microassay has been developed to measure histamine release from both washed human leucocytes and whole blood, in which blood samples can be diluted down to 1:20 without affecting their sensitivity to antigen. The sensitivity and reproducibility of the single isotope histamine radioenzymatic assay [REA] was compared to the conventional spectrofluorometric histamine assay. The limit of detection was 0.2 and 2.0 ng/ml, respectively, and the agreement between the two assays was good (r = 0.94). There was also a good qualitative agreement between skin-prick test and histamine release (92%). In order to see if this assay was suitable for small volumes of blood, we measured histamine release to antigen from both diluted whole blood taken by a thumb prick (as a model of the heel prick used in obtaining paediatric blood samples), and undiluted venous blood. There was complete agreement between a positive or negative histamine release response to antigen by diluted thumb prick and undiluted venous blood samples. Leucocyte sensitivity to antigen increased slightly upon dilution, but remained within a ten-fold antigen dilution. The micro-histamine release assay described here offers an opportunity to measure basophil sensitivity to allergens where the availability of the blood is limited (in young babies for example) as well as making possible multiple allergen testing.

The effect of the castor bean toxin, ricin, on rat IgE and IgG responses.

IgE responses are closely regulated in non-atopic humans and low IgE responder animals. After an initial period of IgE production following antigen exposure, IgE synthesis appears to be actively suppressed. Inhalation of the dust of castor beans induces persistent IgE responses in atopic and non-atopic humans alike. This phenomenon was investigated in animals. Hooded Lister rats were immunized intraperitoneally with different preparations of castor bean. These had been heated for different lengths of time, 60 and 15 mins, to inactivate the toxin ricin. Immunization with as much as 100 micrograms of the extract heated for 60 min failed to produce an IgE response, while injection of 100 micrograms of the extract heated for 15 min produced a marked IgE response to castor bean proteins. Thus the component of castor bean extract which induces the IgE response appears to be heat labile. The IgE potentiating component in castor bean was found to enhance IgE responses to other antigens such as ovalbumin and when 0.8 microgram of an unheated castor bean extract was administered together with an optimal dose of ovalbumin, there was a substantial increase in ovalbumin-specific IgE but not IgG in all animals. In addition, total serum IgE but not IgG increased up to 20-fold. The effect of castor bean was more sustainable than that of an established IgE-specific adjuvant, Bordetella pertussis, and was able to boost an IgE response that had diminished and maintain an ongoing IgE response when re-administered at weekly intervals. In addition, it was possible to reproduce the IgE potentiating effects with purified castor bean ricin at 25 ng/rat. The way that it produces this effect is not known but it is possible that ricin blocks the normal IgE suppressive mechanisms that regulate IgE responses.

Plasma histamine and clinical tolerance to infused histamine in normal, atopic and urticarial subjects.

Five subjects with a recent history of urticaria (U), five atopic (A) subjects and a non-atopic (NA) control group were given intravenous infusions of histamine starting at 0.05 micrograms/kg/min, increasing by 0.05 micrograms/kg/min every 30 minutes to a maximum of 0.35 micrograms/kg/min. Plasma histamine levels were monitored every 15 minutes. The infusion was stopped when an objective clinical endpoint was reached, involving either evidence of peripheral vasodilatation (rise of skin temperature by at least 1 degree C) or a 20% fall of peak expiratory flow rate. There were no significant differences in resting plasma histamine in the three groups. Those with urticaria reached the clinical endpoint at a lower infusion rate than non-atopic subjects (U 0.22 +/- 0.02 micrograms/kg/min; A 0.26 +/- 0.02 micrograms/kg/min; NA 0.32 +/- 0.2 micrograms/kg/min. p less than 0.008) they also received a lower total histamine dose (U 1.12 +/- 0.33 mg; A 1.42 +/- 0.38 mg, NA 2.2 +/- 0.51 mg, p less than 0.008). Atopic subjects with a history of asthma, eczema or rhinitis also tolerated histamine poorly, some subjects reaching a clinical endpoint while the plasma histamine level was still relatively low (U 1.52 +/- 0.4 ng/ml, A 0.85 +/- 0.19 ng/ml, NA 1.4 +/- 0.44 ng/ml, p = 0.05). After the histamine infusion was stopped, the fall in the blood level of histamine was slower in urticarial subjects than in the other two groups, with a half-life of 6.2 +/- 1.3 min (A 3.0 +/- 1.2 min, NA 4.0 +/- 0.7 min, p less than 0.02). There were thus differences in the metabolism of histamine in our non-atopic urticarial subjects and increased histamine sensitivity in atopic subjects which require further study.

IgE antibody responses to platinum group metals: a large scale refinery survey.

All 306 South African platinum refinery workers (116 white, 190 coloured) accepted for employment on grounds of absence of evidence of atopy were investigated using the skin prick test and RAST to detect sensitivity to platinum, palladium, and rhodium salts. RAST studies were made for these, together with HSA and DNP-HSA RAST. Of the 306 workers, 38 had a positive skin prick test to the platinum halide salts; of these, one gave a positive reaction to the palladium salt and six to the rhodium salt. There were no isolated positives to the rhodium and palladium halide salts. Total IgE levels were raised in 24 of the 38 (63%) platinum salt prick test positive workers compared with only 43 of the 268 (16%) prick test negative group (p less than 0.001). Positive RASTs were obtained in 62% of those with positive skin tests to the platinum salts. Four of the six giving positive rhodium salt skin tests gave a positive RAST to rhodium salt. Of these, two gave positive RASTS to HSA and all four to DNP-HSA. The palladium salt RAST was negative in the single skin test reactor. In the platinum salt skin test positive group a raised HSA RAST was obtained in 10.5% compared with only 2.5% in the skin negative group. Twenty one per cent of the platinum salt skin positive group had a raised RAST score to DNP-HSA with only 3.5% (4/116) in the skin test negative group, of whom three also had a raised HSA RAST. The latter findings are suggestive of IgE antibody production to new antigenic determinants in HSA produced by conjugation with the platinum salts.

Rectal mucosal histamine release in ulcerative colitis.

1. Rectal dialysis in vivo was used to assess rectal mucosal release of histamine in patients with ulcerative colitis and in control subjects. 2. Rectal mucosal histamine release was significantly increased in ulcerative colitis, whether the patients were in remission or relapse. The highest values were found in active colitis, but in several such patients histamine release was within the control range. Measurement of rectal mucosal electrical potential difference suggested that increased mucosal histamine release in this group of patients was not due to enhanced epithelial permeability. 3. Rectal dialysis appears to be a useful method for assessing mucosal histamine production and the results obtained are consistent with the hypothesis that immediate hypersensitivity reactions could be of importance in some patients with ulcerative colitis.

Symptomatic dermographism: wealing, mast cells and histamine are decreased in the skin following long-term application of a potent topical corticosteroid.

Clobetasol propionate 0.05% ointment and an otherwise identical steroid-free base were applied topically to a 10 cm2 area on the anterior thighs of six patients with symptomatic dermographism for 6 weeks. Four patients showed a significantly decreased wealing response to stroking of steroid pretreated skin compared to that of control sites. There was a parallel decrease in mast cell numbers and histamine levels in skin biopsies taken from the steroid treated areas. At 6 weeks two patients demonstrated a decrease in flare areas following the intradermal injection of compound 48/80 in steroid pretreated skin compared to base treated sites. Flare areas following intradermal injection of histamine in these two patients were equivalent in base and steroid treated skin.