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Biomedical subjects

D Proud

Publications and source records attributed to D Proud.

At least 109 records · Page 6Linked to original sources
PubMed1990

A randomized controlled trial of glucocorticoid prophylaxis against experimental rhinovirus infection.

The effects of combined intranasal and systemic glucocorticoid steroids on the local inflammatory response, and symptoms due to experimental rhinovirus infection were studied in 45 adults randomized to prophylaxis with either placebo or steroids. Intranasal beclomethasone (168 micrograms twice a day) was begun 4 days before viral challenge and continued 5 days after challenge. Oral prednisone (30 mg twice daily) was given for 3 days beginning 1 day before challenge. During the first 48 h after viral inoculation, nasal obstruction, nasal mucus weights, and kinin concentrations in nasal lavages were lower in steroid recipients, but subsequent increases in these variables in the steroid group resulted in no significant cumulative differences between treatment groups. These data suggest that steroid prophylaxis may suppress nasal inflammation and cold symptoms during the first 2 days in experimental rhinovirus colds.

Administration, Intranasal↗
PubMed1990

Ketotifen reduces sneezing but not histamine release following nasal challenge with antigen.

We evaluated the effect of pre-treatment with 1 and 2 mg b.i.d. of ketotifen on the early response to nasal challenge in a double-blind cross-over trial. Weekly nasal challenges were performed in 10 allergic subjects after 1 hr and 1, 2, 3 and 4 weeks of ketotifen administration. The response to nasal challenge was monitored by counting the number of sneezes, the assessment of subjective symptoms, and by measuring the levels of histamine and TAME-esterase activity in recovered nasal lavages. The number of sneezes diminished significantly after a single dose of drug with both the 1 and 2 mg doses. Prolonged pre-treatment did not improve the results. The levels of histamine and TAME-esterase activity in recovered nasal lavages were not changed significantly by either pre-treatment at either dose. Although the number of subjects was small, our data suggest that ketotifen diminishes allergic symptomatology by its antihistaminic properties rather than by inhibiting histamine release from mast cells. As we did not look into the effects of ketotifen on other products generated by mast cells (prostanoids, leukotrienes and tryptase), we cannot fully rule out an effect on mast cells.

Adult↗
PubMed1990

Comparison of the in-vivo and in-vitro response to ragweed immunotherapy in children and adults with ragweed-induced rhinitis.

In order to compare results of allergen immunotherapy in paediatric and adult populations, 22 children with a history of ragweed hay fever were matched with an equal number of adults for skin sensitivity to ragweed and all were given a 1-year course of immunotherapy with a partially purified ragweed extract. Biological responses were measured by nasal challenges with ragweed before therapy was started, after 12 weekly injections and when the maintenance dose had been reached and also by methacholine bronchoprovocation tests before and after 12 months of therapy. Skin-test sensitivity to ragweed and control allergens, and ragweed-specific IgE and IgG antibody responses were measured at the same intervals as the challenges and at the end of the study. The effect of the therapy on clinical symptoms was not evaluated. Before therapy the groups of adults and children were comparable by all indices, except for TAME esterase activity in nasal washes during ragweed nasal challenge which was significantly lower in children. During treatment, mediators released during sequential nasal challenges declined to undetectable levels in most patients and changes in nasal ragweed sensitivity were comparable in both groups. Ragweed IgE increases after 12 weeks of therapy and IgG levels at maintenance therapy tended to be higher in the children, but neither difference was statistically significant. At the end of the study IgE and IgG antibody levels were comparable in both groups. Results of methacholine inhalation tests did not change significantly in either group. The decrease in skin sensitivity to ragweed was similar in both groups. We conclude that ragweed immunotherapy leads to immunological and biological consequences that are comparable in children and adults.

Adolescent↗
PubMed1990

Ragweed IgE and IgG4 antibody in nasal secretions during immunotherapy.

We have developed sensitive amplified immunoassays for measurement of IgE and IgG4 ragweed (RW) antibodies in unconcentrated nasal washes. IgE to Amb a I (formerly antigen E) can be assayed to less than 0.1 ng/ml using IgE capture by anti-IgE on microtitre plates and an alkaline phosphatase-conjugated Amb a I with an amplification substrate technique. IgG4 to whole RW extract was assayed to less than 0.01 ng/ml by amplification ELISA using monoclonal anti-IgG4. Nasal washes (NW) (10 ml) and serum were obtained in December from 22 RW-sensitive patients before and after 1 and 2 yr of RW immunotherapy (IT), and assayed for Amb a I IgE or RW IgE and RW IgG4 antibodies Amb a I IgE could be measured in the NW of 15/22 pre IT, 19/22 at 1 yr IT, but only 3/10 at 2 yr IT (compared with pre-IT, P less than 0.05). Mean Amb a I IgE in NW was 0.66, 0.36 and 0.21 ng/ml at pre, 1 yr and 2 yr IT (P-values greater than 0.05). Mean serum RW IgE, was 76, 55 and 27 ng/ml at pre, 1 yr and 2 yr IT (P-values greater than 0.05). Amb a I IgE in nasal washes was correlated with RW IgE in serum (r = 0.56, P less than 0.001, n = 44). RW IgG4 was detectable in NW of 15/22 pre-IT, 18/22 at 1 yr IT and 9/10 at 2 yr IT (P-values greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effects of a single-dose pretreatment with captopril on the immediate response to nasal challenge with allergen.

We performed a double-blind, placebo-controlled, crossover study using 12 subjects to determine the effects of a single 50-mg dose of captopril on the response to nasal challenge with increasing doses of allergen. Levels of kinins, histamine and N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity were measured in nasal lavages, and symptom scores and the number of sneezes were recorded. Captopril had no significant effects on histamine, TAME-esterase, sneezing or symptom scores. Peak postchallenge kinin levels, however, were significantly elevated (p less than 0.05) compared to placebo, while an increase in the magnitude of the dose-response curve was of marginal significance (p = 0.058). Thus, captopril causes increases in the kinin levels in nasal secretions during the allergic response. If increased kinin levels persist or worsen with chronic therapy, it is possible that they could exacerbate allergic symptoms during repeated seasonal exposure.

Adult↗
PubMed1990

Disassociation of the release of histamine and arachidonic acid metabolites from osmotically activated basophils and human lung mast cells.

Upon activation by most stimuli, basophils and human lung mast cells simultaneously release histamine and arachidonic acid metabolites. Hyperosmolar activation was examined, and both cell types were shown to release histamine but little or no leukotriene C4 or D4 (LTC4/D4) and, in the case of mast cells, little or no prostaglandin D2 (PGD2). In addition, hyperosmolar buffers were capable of preventing the formation of LTC4/LTD4 in basophils stimulated by anti-IgE when added simultaneously, or 2, 5, or 10 min after, the addition of anti-IgE. Catabolism of PGD2 and LTC4/D4 was not increased. Experiments with cell lysates demonstrated that intracellular formation, rather than secretion, was arrested in hyperosmolar buffers. We conclude that this selective inhibition of mediator production is a unique response of mast cells and basophils to osmotic activation. Although the mechanism of this selective cellular response is not clear, these in vitro observations have important therapeutic and pathophysiologic implications for the airway response to hyperosmolar stimuli.

Antibodies, Anti-Idiotypic↗
PubMed1990

Studies on the relationships between sensitivity to cold, dry air, hyperosmolal solutions, and histamine in the adult nose.

We have previously reported that elevated osmolality of nasal secretions is linked to the rhinitic reaction to cold and dry air (CDA) that results in inflammatory mediator release and that nasal challenge with hyperosmolal solutions can induce histamine release in randomly selected individuals. These findings led to a comparison of the effect of nasal challenge with hypertonic fluid in 11 subjects who demonstrated a nasal response to CDA compared to 10 subjects without CDA sensitivity. All volunteers were challenged with isosmolal (300 mosmol/kg H2O) and hyperosmolal (800 mosmol/kg H2O) mannitol solutions. Their response was evaluated by symptom scores and quantification of histamine in nasal lavages. CDA responders differed significantly from non-responders in terms of both the total amount and the concentration of histamine in the lavage following hyperosmolal challenge (p less than 0.04 and p less than 0.02, respectively). In addition, CDA responders reported a higher change from baseline for nasal congestion, pruritus, and lacrimation following hyperosmolal challenge, but the scores for rhinorrhea, the volume of the returned nasal lavage fluid following hyperosmolal challenge, and the capacity to reduce the osmolality of the administered hyperosmolal fluid did not differ. Allergic status was not a factor in hyperosmolal reactivity. To investigate possible differences in nonspecific nasal mucosal sensitivity that could account for these findings, all subjects underwent provocation with five increasing doses of histamine, from 0.01 to 1 mg. No significant difference between CDA responders and nonresponders in symptomatology or in the induction of vascular permeability, as assessed by TAME-esterase activity in nasal fluids, could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma.

Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways. Because asthma may represent manifestations of chronic inflammation of the airways, the levels of histamine and six prostanoid mediators were measured in airway fluids obtained by bronchoalveolar lavage (BAL) of 12 normal, 11 allergic rhinitic, and 15 asymptomatic, allergic asthmatic subjects. Simultaneous profiling of prostanoid mediators in individual samples was performed using gas chromatography-mass spectrometry. Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects (p less than 0.01), with concentrations in airway fluids of asthmatic subjects after correction for dilution of 3.8, 0.5, and 1.4 nanomolar, respectively. Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects (p less than 0.01), distinguishing the subjects with lower airway disease from those with another atopic condition. Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects. We conclude that elevated levels of multiple mediators with potent bronchoconstricting activity are present in the airways of subjects with mild asthma, indicating that even mild disease is associated with evidence of airway inflammation. The interactions of bronchoconstricting mediators and airway inflammation may play important roles in the pathogenesis of asthma.

Adult↗
PubMed1990

Kinins are generated in nasal secretions during influenza A infections in ferrets.

Infection of ferrets with influenza A virus results in a disease syndrome that is similar to that observed in humans. To examine the pathophysiology of this disease, ferrets were challenged with either H1N1 influenza virus or placebo. Sign scores and rectal temperatures were recorded periodically during the 9 days after infection. Nasal lavages were also collected during this time period and the content of kinins, histamine, cells, and total protein in these lavages was assessed. In infected animals (n = 17) compared to healthy controls (n = 14), sign scores were first significantly elevated at 30 h postinfection. Sign scores peaked at 48 to 72 h postinfection and then slowly declined, although they remained significantly elevated up to 168 h postinfection. Kinin levels were significantly correlated with signs. Associated with increased sign scores and kinins, elevations were observed in the levels of total protein and cells in nasal lavages of infected animals. In contrast to the increases in kinin levels that were observed during influenza infections, histamine concentrations in nasal lavages did not change in response to infection. We conclude that kinins are generated in nasal secretions during influenza A infections and that these potent vasoactive peptides may contribute to the symptomatology of such infections. The study of influenza infections in ferrets provides a convenient animal model in which to evaluate further the role of kinins in the pathogenesis of upper respiratory tract infections.

Animals↗
PubMed1990

Terfenadine, an H1 antihistamine, inhibits histamine release in vivo in the human.

A double-blind, placebo-controlled clinical trial was performed on 12 subjects with allergic rhinitis to evaluate the effect of 1-wk pretreatment with terfenadine (60 mg twice daily or 300 mg twice daily) on the response to sequential nasal challenges with allergen and histamine. The response to allergen challenge was monitored by counting sneezes and by quantifying the levels of histamine, kinins, TAME-esterase activity, and albumin in recovered nasal lavages. Following histamine challenges, sneezing and the levels of albumin were recorded. Terfenadine significantly reduced sneezing and the levels of histamine, kinins, TAME-esterase activity, and albumin seen after antigen challenge. In addition, terfenadine reduced the increase in sneezing and vascular permeability, as measured by albumin levels, following challenge with histamine. No significant differences were found between the two doses of terfenadine. Our data suggest that terfenadine not only antagonizes the H1 activity of released histamine during the immediate allergic reaction but also, at currently prescribed doses, inhibits the release of histamine.

Allergens↗
PubMed1990

Effect of ozone inhalation on the response to nasal challenge with antigen of allergic subjects.

The effect of oxidant inhalation on allergic illness is of interest because allergic patients often report increased respiratory symptoms during episodes of poor air quality, and epidemiologic studies demonstrate an association between increased levels of the air pollutant ozone and exacerbations of asthma. The purpose of this study was to characterize the upper respiratory response to ozone inhalation in asymptomatic, allergic subjects and to determine whether ozone pre-exposure increased the acute response to nasal challenge with antigen in these subjects. A group of 12 asymptomatic subjects with a history of allergic rhinitis were exposed in a randomized, cross-over design, at rest, on each of 2 days, separated by 2 wk, to 4 h of clean air or 0.5 ppm ozone in an environmental chamber. Following the exposure period, subjects underwent nasal challenge with four doses of antigen (1 to 1,000 PNU ragweed or grass). Symptoms were rated and nasal lavage performed after each dose. Measurement of histamine and albumin concentration and TAME-esterase activity and determination of cell counts and differentials were performed. Exposure to ozone caused significant increases in upper and lower respiratory symptoms, a mixed inflammatory cell influx with a sevenfold increase in naval lavage neutrophils, a 20-fold increase in eosinophils, and a tenfold increase in mononuclear cells, as well as an apparent sloughing of epithelial cells. There was a significant increase in nasal lavage albumin concentration on the ozone exposure day and a small increase in nasal lavage histamine concentration on both the ozone and clean air exposure days. TAME-esterase activity showed no significant increase overall, but increased at least twofold in 5 of 12 subjects. (ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

The effect of a leukotriene antagonist on the early response to antigen.

The sulfidopeptide leukotrienes (LT) C4, D4, and E4 increase in nasal secretions during the nasal response to antigen challenge, and nasal challenge with LTD4 induces nasal congestion. To further assess the role of leukotrienes, we administered an oral LTD4 antagonist, L-649,923, to 12 patients who had nasal allergy to grass and ragweed pollen, in a double-blind, placebo-controlled, crossover study. Patients were challenged intranasally with increasing doses of pollen on each of 2 days, and the recovered nasal lavage fluids were assayed for histamine, TAME-esterase activity, and immunoreactive LTC4/D4/E4. The patients graded runny nose, congestion, and throat irritation, and sneezes were counted. Significant (p less than 0.01) increases in all parameters were found when comparing antigen challenge with diluent challenge, but no differences were seen among the treatment groups. Thus, oral L-649,923 was not effective in blocking the symptoms of the early nasal allergic response.

Adolescent↗
PubMed1989

Preincubation of human synovial cells with IL-1 modulates prostaglandin E2 release in response to bradykinin.

Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.

Adjuvants, Immunologic↗
PubMed1989

Induction of histamine release from human skin mast cells by bradykinin analogs.

Kinins are potent proinflammatory peptides that induce histamine release from rodent mast cells. We examined the ability of bradykinin, lysylbradykinin and a series of kinin analogs to cause histamine release from human basophils, human lung mast cells and human skin mast cells. At concentrations ranging from 0.1 microM to 1 mM, bradykinin failed to cause histamine release from any of the human histamine-containing cells studied. Lysylbradykinin was also without effect on basophils and lung mast cells, but was a weak secretagogue for human skin mast cells, inducing 5.5 +/- 3% (mean +/- SD) of total cellular histamine release at a concentration of 10(-5) M. Similarly, when sixteen recently developed bradykinin antagonists were examined, these compounds had no effect on basophils or lung mast cells but all sixteen induced dose-dependent histamine release from skin mast cells. The release process was temperature dependent and, at a concentration of 10(-5) M, the antagonists induced 8-27% histamine release. Although preincubation of cells with 10(-3) M bradykinin or des(Arg9) bradykinin significantly inhibited antagonist-induced histamine release, the requirement for such high concentrations of these peptides to cause inhibition suggested that histamine release is not mediated by either B1 or B2 kinin receptors. To understand further the mechanism of histamine release, we examined a series of bradykinin analogs with single amino acid substitutions in the bradykinin sequence. Replacement of proline7 in the bradykinin sequence with D-phenylalanine is the essential change used to convert kinin analogs into antagonists, and 10(-5) M [DPhe7]-bradykinin induced 8-10% histamine release. Other analogs, devoid of antagonist activity, however, such as [DPhe6]-bradykinin and [LPhe7]-bradykinin were able to induce equivalent levels of histamine release. The ability to induce histamine release appears to be related, at least in part, to aromaticity, since [DTrp6]-bradykinin and [DTrp7]-bradykinin induced greater amounts of histamine release than equivalent [DPhe]-analogs, causing approximately 20% histamine release at 10(-5) M. By contrast, [DAla7]-bradykinin was an ineffective stimulus. In summary, a single amino acid substitution can convert bradykinin into a secretagogue for human skin mast cells. The ability of kinin analogs to induce histamine release from skin mast cells, but not lung mast cells or basophils, emphasizes the heterogeneity of human histamine-containing cells.

Basophils↗
PubMed1989

Responses to ragweed-pollen nasal challenge before and after immunotherapy.

To evaluate whether immunotherapy reduces mediator release after nasal challenge, we followed previously untreated patients with ragweed hay fever through 2 years (three seasons) of treatment. Eleven adult patients started immunotherapy after a season of symptom diaries and graded pretreatment challenges with 0.03, 0.3, 3.3, and 16.5 mg of ragweed pollen. Repeat challenges were performed when the treatment dosage reached 0.6, 12.4, and 24.8 micrograms of Amb a I (antigen E) equivalents per injection. After the 0.6 micrograms dose, there was little change, but after the larger doses, there was a significant reduction in histamine and tosylarginine methyl ester-esterase (TAME-esterase) release in two respects. More pollen was required before any mediator appeared, and the amount of mediator released at each stage of the challenge was reduced. There was no significant difference between the responses at the 12.4 and 24.8 micrograms treatment doses. Sneezing after challenge was not apparently changed after immunotherapy; however, patients' seasonal symptom-medication scores were reduced after treatment. These data set the optimal individual treatment dose of ragweed extract for immunotherapy at greater than 0.6 micrograms, but probably not more than 12.4 micrograms in terms of Amb a I equivalents.

Adolescent↗
PubMed1989

Observations on the pathogenesis of nasal priming.

To understand better the response of patients with allergic rhinitis to nasal challenge with antigen, we studied the mechanism of priming, that is, the increased clinical response to daily sequential nasal challenges. Ten subjects with ragweed hay fever were challenged four times with increasing doses of ragweed pollen. The first 2 challenge days were separated by 2 weeks, whereas the last three challenges occurred on sequential days. Nasal lavages, performed before and after each nasal challenge, were evaluated for levels of inflammatory mediators and cellular content. In contrast to control days, a significant (p less than 0.05) increase in the number of sneezes occurred on both priming days. Priming was associated with a significant increase in the level of histamine on both priming days, whereas the second priming day was also associated with an increase in TAME-esterase activity, kinins, and prostaglandin D2 obtained after challenge (p less than 0.05 for all). In the lavages before challenge on the priming days, the total number of cells and the number of neutrophils, eosinophils, and alcian blue-positive cells were significantly increased, but in contrast, basal levels of mediators were not. The net increase in the number of alcian blue-positive cells correlated with the net increase in the amount of histamine released on the priming days (r = 0.661; p less than 0.05). These studies suggest that priming results, in part, from increased mediator release from influxing inflammatory cells.

Eosinophils↗