Biomedical subjects
Publications and source records attributed to P Rafferty.
Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are potent and selective inhibitors of Ick in vitro; some compounds are selective for lck over src. Data are shown for two compounds demonstrating that they are potent and selective inhibitors of IL2 production in cells.
Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are novel, potent and selective inhibitors of lck in vitro. Exploration of C-6 position of the pyrrolo[2,3-d]pyrimidine and the terminal phenyl group structure-activity relationship (SAR) is detailed. Compound 1 is orally active in animal models.
A pilot study of tele-oncology linking a cancer centre with a rural district general hospital was carried out; it involved patients, physicians, surgeons, radiologists and nursing staff. Its purpose was to complement the existing on-site outpatient services, providing oncological advice on non-clinic days. During the six months of the trial, 18 videoconferences were conducted. Their median duration was 17 min (range 7-40). Eight videoconferences involved patients directly. Acceptability of videoconferencing to doctors, nurses and patients was assessed by a questionnaire. Patients and staff found the technique acceptable and were satisfied with the results. The addition of a teleradiology system to teleconsultations was found to be important when decisions on patient management were taken. Following the success of this pilot trial, large studies of tele-oncology in the UK with measures of cost-effectiveness are needed.
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BACKGROUND: Although the incidence of bovine tuberculosis in UK cattle has declined markedly, outbreaks still occur. There is often confusion as to how veterinary and human public health agencies should interact in such circumstances. We report an outbreak of bovine tuberculosis which occurred in South West Scotland in 1992. METHODS: The outbreak, which affected two cattle herds, and potentially involved 17 humans, was discovered when visible tuberculous lesions were found at routine post mortem examination of a calf. Investigation of animals and humans, exchange of information between human and veterinary public health agencies, and subsequent control measures followed the guidance of a recently produced protocol. RESULTS: Tuberculin testing of other animals in the index herd revealed 11 reactors. Testing of the herd of origin of these animals revealed 84 reactors out of 261 animals. Movement restrictions were placed on the index herd, and all the animals in the herd of origin were slaughtered. The humans were screened primarily by history and tuberculin skin testing. Eleven of them required chest X-rays (all were normal) and six were given prophylactic chemotherapy with isoniazid. Nobody developed clinical illness. CONCLUSION: The use of an agreed protocol proved to be very helpful to both human and veterinary public health agencies in the investigation and control of an outbreak of bovine tuberculosis. There is a clear need for better human screening tests.
Effect of cetirizine, a potent and specific H1 receptor antagonist, was examined on platelet activating factor-induced bronchoconstriction in 10 patients (5 male, mean [s.e.m.] aged 37.4 [3.6] years) with mild asthma in a placebo controlled, double-blind cross-over study. Airway responses were assessed by measuring specific airway conductance (SGaw). Patients were challenged with a single dose (12-96 micrograms) of PAF that had previously produced a 35% fall in SGaw. PAF challenges were performed after single dose (15 mg) and 1 week's treatment (15 mg twice daily) of cetirizine. There was no significant difference in pre- and post-treatment baseline values of SGaw on different study days and the percentage changes after cetirizine were 38.7 (7.01) and 45.6 (5.52) compared to 50.2 (2.89) and 43.9 (7.26) with placebo respectively. Similarly mean (s.e.m.) area under curve (AUC-SGaw/time course response) was 391 (143) and 514 (85) with cetirizine compared to 565 (37) and 461 (94) with placebo respectively. The difference was not statistically significant. There was no difference in facial flushing and feeling of warmth between cetirizine and placebo. We conclude that PAF induced bronchoconstriction in humans is not mediated by histamine release and that H1 receptor antagonists do not modify PAF induced bronchoconstriction.
Cetirizine is a potent, selective H1 histamine receptor antagonist. The effect of oral and inhaled cetirizine was assessed on the early bronchoconstrictor response to inhaled allergen in 10 mild atopic asthmatic patients in a double-blind, randomized, placebo controlled trial. All were sensitive to Dermatophagoides pteronyssinus and this was used as the provoking allergen. The geometric mean PD20 FEV1 values obtained at allergen challenge were measured as cumulative breath units (c.b.u.) and following oral cetirizine, inhaled cetirizine and placebo were 124.5, 75.7 and 76.7 c.b.u. respectively. These did not differ significantly. We conclude that neither oral nor inhaled cetirizine significantly attenuates the early response to inhaled allergen in atopic asthmatic subjects. However, the method of repeated allergen challenge is likely to be relatively insensitive.
The effect of felodipine, a new selective calcium antagonist, was assessed on histamine and adenosine monophosphate (AMP) induced bronchoconstriction in 9 mild atopic asthmatics. Felodipine did not alter the baseline FEV1, but showed a small significant inhibitory effect upon histamine and AMP induced bronchoconstriction.
Because the older antihistamines possessed relatively weak antihistaminic action, as well as sedative and anticholinergic effects, they could not be administered in doses high enough to confer relief to atopic patients with asthma. In contrast, the newer nonsedating, more potent H1-receptor antagonists appear to achieve effective histamine blockade in patients with asthma. Terfenadine and astemizole inhibit bronchoconstriction induced by inhaled allergens by 50% in the early asthmatic reaction. High-potency antihistamines also significantly reduce cough and wheeze as compared with placebo in grass pollen-sensitive asthma patients. Significant reductions in symptom severity and bronchodilator use were found with terfenadine, 120 mg twice daily, although these improvements may be confined to younger patients. Some of the newer antihistamines have demonstrated interesting effects on the late-phase allergic response. Azelastine partially inhibits bronchoconstriction in the allergen-induced late reaction of atopic persons with asthma, possibly by suppressing the release of additional inflammatory mediators. In the skin, cetirizine has been found to reduce eosinophil and neutrophil late-phase infiltration and prostaglandin D2 release. These interesting properties now warrant further investigation in clinical studies.
1. We have assessed the effect of a specific histamine H1-receptor antagonist, terfenadine, in the treatment of atopic asthmatics during the grass pollen season. 2. Eighteen mild, grass pollen sensitive asthmatics (10F, 8M, mean +/- s.e. mean age 34.7 +/- 5.6 years), all of whom were controlled on inhaled beta 2-adrenoceptor agonists alone, took part in a 9 week, double-blind, crossover study using terfenadine 180 mg three times daily and placebo. Throughout the study patients recorded peak expiratory flow rate (PEFR) twice daily, symptoms of cough, wheeze, breathlessness and chest tightness (scored 0-3), and their use of bronchodilators. Methacholine inhalation challenge tests were performed each week. Data were analysed by a method suitable for a two group, two period crossover trial with baseline measurements. 3. Terfenadine significantly reduced symptoms of cough by 76.9% (P less than 0.05) and wheeze by 46.9% (P less than 0.02). Symptoms of breathlessness and chest tightness were reduced by 16.8 and 30.3% respectively but these were not statistically significant. Morning and evening PEFR rose by 5.5 (P less than 0.001) and 6.2% (P less than 0.003) respectively on treatment with terfenadine and bronchodilator use fell by 40.3%. A progressive increase in methacholine sensitivity was seen in both treatment groups throughout the study but did not reach statistical significance. 4. We conclude that treatment with terfenadine during the grass pollen season in sensitive asthmatics reduced their symptoms and bronchodilator requirements and produced a modest improvement in their lung function without affecting the development of increased methacholine sensitivity that occurred during the grass pollen season.
We have studied the effect of cyclo-oxygenase inhibition and H1-receptor antagonism on the early and late bronchoconstrictor responses to inhaled allergen in mild atopic asthmatics. In the first phase of the study histamine inhalation challenge tests were performed in seven mild, atopic asthmatics 2 h after treatment with placebo or flurbiprofen (50, 100 or 150 mg). Flurbiprofen in these single doses had no effect on histamine reactivity. Ten atopic asthmatics participated in the second phase of the study in which the time course of the bronchoconstrictor response to inhalation of allergen was observed on four separate occasions after treatment with (a) placebo, (b) flurbiprofen, 150 mg, (c) terfenadine 180 mg, and (d) the combination of flurbiprofen and terfenadine. On each occasion subjects inhaled a concentration of allergen (Dermatagaphoides pteronyssinus, grass pollen) that had previously been shown to produce a 30% fall in FEV1 (PC30 allergen). The mean maximum fall in FEV1 during the early reaction was 33.2 +/- 3.3% from the post-saline baseline value following placebo and this was reduced to 27.5 +/- 5.3% after flurbiprofen (n.s.), 20.3 +/- 3.2% after terfenadine (P less than 0.05), and 23.1 +/- 2.3 after the treatment combination (P less than 0.05). Seven subjects developed late asthmatic reactions (LAR) after placebo and in these subjects the mean maximum fall in PEFR during the LAR was reduced from 22.6 +/- 3.1% after placebo to 16.7 +/- 3.2% after flurbiprofen (P less than 0.05), 15.2 +/- 2.3% after terfenadine (P less than 0.05) and 11.5 +/- 3.1% after the treatment combination (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
We have examined the effect of azelastine hydrochloride, 8.8 mg, on the early and late responses to inhaled allergen in a group of 12 atopic subjects with asthma. On two separate days, 3 weeks apart, patients were administered either oral azelastine, 8.8 mg, or matched placebo. Four hours later they inhaled via nebulizer, a dose of allergen (grass pollen or Dermatophagoides pteronyssinus) that had previously been demonstrated to produce a 25% fall in FEV1. Plasma-histamine concentrations and FEV1 levels were measured at intervals during the subsequent 8 hours. After placebo, allergen inhalation produced rapid bronchoconstriction in all subjects with a maximum mean fall in FEV1 at 30 minutes of 22.8 +/- 3.4% from the postsaline baseline value. Five subjects also developed a late bronchoconstriction response with a fall in FEV1 of greater than 15% from postsaline baseline value between 2 and 8 hours after challenge. Azelastine reduced the bronchoconstrictor response during the first 10 minutes and produced a maximum mean fall at 30 minutes of 21.2 +/- 4.4% from the postsaline baseline value. Azelastine had a marked inhibitory effect, reducing the maximum mean fall from 23.9 +/- 6.3% to 9.6 +/- 3.9% from the postsaline baseline value. Analysis of the area under the FEV1 response time-course curves revealed that azelastine reduced the early response (first 2 hours) by 32.5% (p less than 0.05) (all subjects) and reduced the late response (2 to 8 hours) by 70.2% (p less than 0.05) (n = 5). Azelastine had no significant inhibitory effect on the early increase in plasma histamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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Adenosine-5'-monophosphate (AMP) is a bronchoconstrictor agonist in subjects with atopic and nonatopic asthma. In this study we have investigated the effect of repeated airway challenge with AMP in 10 atopic, subjects without asthma. At the first visit, subjects had repeated inhalation challenges with increasing doubling concentrations of AMP, and the provocation concentration required to reduce FEV1 by 20% of baseline was determined (PC20 AMP). When the FEV1 had returned to within 5% of the baseline, the AMP challenge test was repeated on a further one or two occasions. When the maximum concentration of AMP (400 mg/ml) failed to produce a PC20, a bronchial provocation test with histamine was performed and the PC20 was determined. On the second visit, the effect of three consecutive inhalation challenge tests with histamine on the airway response to this agonist was determined. On the third visit, the duration of induced refractoriness to AMP was assessed. With the first AMP challenge, all subjects demonstrated bronchoconstriction with a geometric mean (GM) PC20 of 332 mg/ml. With a second AMP challenge, five of the 10 subjects became refractory and failed to achieve a PC20. In the remaining five subjects, the GM PC20 increased from 110 to 583 mg/ml. With a third AMP challenge, these subjects also failed to achieve a PC20. The initial GM PC20 histamine for the group was 22.9 mg/ml, which did not change significantly with two further histamine challenges or when the airways were refractory to AMP, suggesting that loss of AMP effect was not related to loss of contractility of airway smooth muscle or down regulation of H1-histamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
We have examined the effect of azelastine, a new H1 histamine receptor antagonist, against bronchoconstriction induced by histamine and allergen. Twelve mild, atopic asthmatics each underwent two histamine and two allergen concentration-response inhalation challenges 4 hr after treatment with either 8.8 mg of azelastine or a matched placebo. Following azelastine the dose of histamine required to provoke a 20% fall in FEV1 (PD20 histamine) rose, from a geometric mean of 0.31 mg/ml to greater than 13.2 mg/ml. Azelastine also significantly inhibited allergen-induced bronchoconstriction, the PD20 allergen rising from 9.3 cumulative breath units (c.b.u.) to greater than 47.9 c.b.u., a greater than 5-fold increase. We conclude that azelastine effectively inhibits both histamine and allergen-induced bronchoconstriction, with considerably greater potency against histamine.
In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.
Until the appearance of nonsedating antihistamines such as terfenadine and astemizole, clinical studies of H1 antagonists in the treatment of asthma yielded disappointing results. The author reviews recent European studies that demonstrate terfenadine's effectiveness in reducing symptoms and improving bronchodilation in patients with mild atopic asthma.
Azelastine is a novel histamine H1 antagonist with putative antileukotriene activity in guinea pigs. With three different doses of oral azelastine, we have performed a dose-response study to determine its protective effect on the airways against histamine-induced bronchoconstriction in 12 patients with mild, atopic asthma. On 4 separate days, patients undertook standardized inhalation-challenge tests with increasing concentrations of histamine (0.03 to 32 mg/ml) 4 hours after placebo or azelastine, 4.4, 8.8, and 17.6 mg, administered double blind and in random order. On 2 additional days, patients underwent methacholine challenge tests after placebo or azelastine, 17.6 mg. Baseline FEV1 between treatment days and 4 hours after placebo and azelastine did not change significantly. The three doses of azelastine, 4.4, 8.8, and 17.6 mg, increased the concentration of histamine required to cause a 20% fall in FEV1 (PC20) from 0.16 mg/ml geometric mean (GM) after placebo to 1.98 (p less than 0.01), 8.8 (p less than 0.01), and 8.1 (p less than 0.01) mg/ml, respectively. GM potency ratios derived from the PC20 values obtained for each patient indicated that the three increasing doses of azelastine displaced the histamine dose-response curve to the right by factors of 12.8, 54.4, and 50.2. Azelastine had no effect on the airway response to methacholine with GM PC20 values of 0.16 and 0.19 after placebo and azelastine, 17.6 mg. Azelastine is a potent H1 histamine-receptor antagonist on human airways in vivo without demonstrable anticholinergic effect.