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Biomedical subjects

I M Richards

Publications and source records attributed to I M Richards.

At least 19 recordsLinked to original sources
PubMed1992

Chasing the elusive animal model of late-phase bronchoconstriction: studies in dogs, guinea pigs and rats.

Antigen inhalation in sensitized dogs, guinea pigs and rats resulted in a marked, late-phase, eosinophil-rich, influx of inflammatory cells into the bronchial lumen. Attempts to demonstrate an associated late-phase bronchoconstriction were disappointing. We were unable to demonstrate a late-phase bronchoconstriction in either rats or dogs, even when dogs were pretreated with metyrapone to reduce blood cortisol levels. In ovalbumin-sensitized guinea pigs, challenged with low doses of ovalbumin, we observed an immediate bronchoconstriction, a late-phase bronchopulmonary eosinophilia but no late-phase bronchoconstriction. However, inhalation of very high doses of antigen in mepyramine-treated sensitized guinea pigs did induce a moderate late-phase bronchoconstriction.

Animals↗
PubMed1991

Biological activity of leukotriene B4 analogs: inhibition of guinea pig eosinophil migration in vitro by the 2,6-disubstituted pyridine analogs U-75,302 and U-75,485.

A "late phase" antigen-induced bronchoalveolar eosinophilia has been demonstrated in ovalbumin sensitized guinea pigs (1,2). This in vivo response to antigen inhalation can be inhibited by a 2,6-disubstituted pyridine analog of LTB4, U-75,302(2) (3). In the present study, the mechanism of the drug action was studied by assessing the activity of U-75,302 and a second analog, U-75,485 to displace [3H]-leukotriene B4 binding at the guinea pig eosinophil membrane, as well as their action as chemoattractants or inhibitors of the directional migration of guinea pig eosinophils in vitro. Radioligand competition experiments demonstrated that both analogs interacted strongly with the high affinity LTB4 binding sites on guinea pig eosinophil membrane. Both analogs are powerful chemoattractants for guinea pig eosinophils since they induced directional migration of guinea pig eosinophils when administered alone. In addition, when the cells were treated with either analog and their chemotaxis response was measured in response to a natural chemoattractant, both U-75,302 and U-75,485 at concentrations of 0.1 to 100 microM dose dependently inhibited the LTB4 induced chemotaxis response. The EC50s obtained for U-75,302 and U-75,485 as inhibitors of LTB4 induced guinea pig eosinophil chemotaxis were estimated to be 11.5 +/- 5.5 microM and 5.4 +/- 2.5 microM respectively. Under the same conditions, they had no significant effect upon eosinophil migration induced by zymosan activated plasma at concentrations below 100 microM. We suggest that the inhibition of antigen-induced eosinophil infiltration in guinea pig airway in vivo by U-75,302 or U-75,485 may be a result of partial antagonism or desensitization at the LTB4 receptor level of guinea pig eosinophils.

Animals↗
PubMed1991

Contribution of leukotriene B4 to airway inflammation and the effect of antagonists.

Inhalation of aerosols of ovalbumin in sensitized guinea pigs produced a marked, bronchoalveolar eosinophilia 24 hr after challenge. The lung eosinophilia was not prevented by the cyclooxygenase inhibitors, indomethacin or PAF antagonists (WEB-2086 and L-652731) but was inhibited by methylprednisolone, the 5-LO inhibitor, U-66858 and a series of structural analogs of LTB4, U-75302, U-77692, U-75485 and U-78489. The effectiveness of LTB4 antagonists but not PAF antagonists in vivo was consistent with in vitro studies in which LTB4 was shown to be far more chemotactic than PAF for guinea pig eosinophils. LTB4 elicited maximal directional migration of guinea pig eosinophils at concentrations from 10(-7) M to 10(-9) M while PAF showed no effect over the same concentration range. The structural analogs of LTB4 were shown to inhibit LTB4 induced chemotaxis of guinea pig eosinophils and produced a dose-related inhibition of binding of LTB4 to guinea pig eosinophil membranes. To add further proof to the hypothesis that LTB4 contributed to the antigen-induced lung eosinophilia we attempted to measure LTB4 release into BAL fluid immediately after and at various time points up to 24 hr after antigen inhalation. However, using a sensitive radioimmunoassay (detection limit 10 pg/ml) very low levels of LTB4 (24.9-67.9 pg/ml) or its metabolite, 20-OH LTB4 (24.9-98.2 pg/ml) were detected in BAL fluid and these levels did not increase significantly following antigen provocation. Inhalation of LTB4 aerosols in unsensitized Brown-Norway rats or inhalation of aerosols of ovalbumin in sensitized Brown-Norway rats also produced a marked "late-phase" eosinophil-rich influx of inflammatory cells into the lungs. The lung eosinophilia in the rat was prevented by two structurally unrelated leukotriene B4 (LTB4) antagonists, U-75302 and Ly255283. These data implicate LTB4 as a mediator of allergen-induced bronchopulmonary eosinophilia. Leukotriene B4 antagonists may provide leads for the development of compounds which inhibit the chronic airway inflammation associated with asthma in man.

Aerosols↗
PubMed1991

Novel inhibitors of pulmonary eosinophil accumulation.

The effects of representatives of three classes of compounds were investigated on antigen-induced bronchopulmonary eosinophilia in sensitized Brown-Norway rats. Rats were sensitized by 3 weekly inhalation provocations with aerosols of ovalbumin. Twenty-four hours after a fourth weekly antigen provocation, cell populations were enumerated following bronchoalveolar lavage (BAL) in animals treated with test compounds or the appropriate vehicle. A marked eosinophil-rich influx of inflammatory cells into the bronchial lumen followed the antigen provocation in sensitized animals. Dose-related inhibitions of antigen-induced lung eosinophilia were demonstrated with: 1) glucocorticoids, given po (methylprednisolone acetate, U-8210) or by inhalation (methylprednisolone suleptanate, U-67590A); 2)the non-glucocorticoid 21-amino steroid, U-75412E, and 3) the leukotriene B4 antagonist, U-75302. The steroids methylprednisolone and U-75412E were tested for glucocorticoid activity using phorbol ester-differentiated U937 (human macrophage) cells. Methylprednisolone but not U-75412E produced a dose-dependent inhibition of lipopolysaccharide-stimulated thromboxane synthesis by the U937 cells. Leukotriene B4 antagonists and the novel 21-aminosteroid, U-75412E, which lacks glucorticoid activity, provide leads for the development of compounds which inhibit the chronic airway inflammation associated with asthma in man.

Administration, Oral↗
PubMed1990

Screening for hydroxychloroquine retinal toxicity: is it necessary?

All the patients (73) in the Rheumatology Department five year study of second line therapy who have taken hydroxychloroquine (Plaquenil) for rheumatoid arthritis for longer than 18 months were reviewed. These patients have their treatment dosage carefully monitored and have been receiving regular ophthalmic examinations. Most patients still taking the drug were assessed with a battery of tests for evidence of retinal toxicity. No retinal toxicity causing visual loss was found. On the basis of these results and a review of the recent literature we no longer routinely screen patients for hydroxychloroquine retinal toxicity in Cardiff.

Arthritis, Rheumatoid↗
PubMed1990

Hypercalcaemia in rheumatoid arthritis revisited.

The prevalence and mechanisms of hypercalcaemia were studied in a series of patients attending a regional referral centre for rheumatic diseases. In a prospective study one case of hypercalcaemia due to primary hyperparathyroidism was found in 251 consecutive patients who were screened over a three month period. In a retrospective study of 39 patients who had been discovered to be hypercalcaemic during the preceding 12 months known cases of hypercalcaemia were found in 38 (97%) cases. Primary hyperparathyroidism was the most common cause (n = 24; 62%), followed by thiazide treatment in five (13%), cancer in three (8%), immobility in three (8%), vitamin D toxicity in two (5%), and chronic liver disease in one (3%). In one case the diagnosis remained unclear after full investigation. This study shows that the causes of hypercalcaemia in rheumatological patients are similar to those in the general population. These observations contrast with previous reports, which suggested that hypercalcaemia may be a complication of rheumatoid arthritis itself.

Adult↗
PubMed1989

Effect of the selective leukotriene B4 antagonist U-75302 on antigen-induced bronchopulmonary eosinophilia in sensitized guinea pigs.

The selective leukotriene B4 (LTB4) antagonist, U-75302, 6-(6-(3-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5-hexa nediol) was examined for its ability to inhibit the "late-phase" bronchopulmonary eosinophilia that occurs 6 to 24 h after inhalation of specific antigen in sensitized guinea pigs. Groups of 6 male guinea pigs, sensitized with ovalbumin, were pretreated with U-75302, 1.0, 10.0, or 30.0 mg/kg, or vehicle 1 h before and 7 h after antigen inhalation. Twenty-four hours after antigen provocation, the lungs were lavaged for the enumeration of inflammatory cell populations. Doses of U-75302 (1.0, 10.0 and 30.0 mg/kg) administered orally produced 12.2%, (p greater than 0.05), 43.2% (p less than 0.05), and 61.1% (p less than 0.05) inhibition, respectively, of the antigen-induced influx of eosinophils into the bronchial lumen. Neutrophil populations were not significantly affected by treatment with U-75302. In a separate study, we compared the histopathological changes that occurred following antigen challenge in U-75302-treated or vehicle-treated guinea pigs. Vehicle-treated, sensitized animals exhibited marked changes in the airway at 8 min, 6 h, and 24 h after antigen challenge. U-75302 treatment produced a significant reduction in eosinophil adherence to peribronchial/peribronchiolar capillaries followed by a dramatic and specific reduction of peribronchial eosinophil infiltration (81% reduction at 6 h and 79% reduction at 24 h). Neutrophil migration appeared unaffected. These data implicate LTB4 as a mediator of antigen-induced bronchopulmonary eosinophilia in the guinea pig.

Animals↗
PubMed1989

Bronchoalveolar eosinophilia in guinea pigs harboring inapparent infections of Paraspidodera uncinata.

During the course of experiments examining the changes in cell populations in bronchoalveolar lavage (BAL) fluid in 3-11-wk-old guinea pigs, a marked increase in the numbers of eosinophils was observed in BAL fluid in untreated control animals from historical levels (observations made over the previous 2 yr) of 8.8 +/- 1.5% to levels greater than 16% and up to 44%. Repeated occurrence of this phenomenon in several different groups of guinea pigs that appeared clinically normal and the impact on our experimental studies led us to attempt to identify the cause of increased inflammatory cell numbers in these guinea pigs. Examination in 2 groups of animals of whole blood and lung tissue for the presence of bacteria or fungi revealed minor bacterial infections in one group but not the other, whereas both exhibited elevated eosinophil numbers. At necropsy, 41.7% and 60% of the animals in the 2 groups harbored the nematode Paraspidodera uncinata. Guinea pigs exhibiting eosinophil numbers in BAL fluid comparable to our historical levels were then inoculated with approximately 100 embryonated eggs of P. uncinata and developed elevated eosinophilia in BAL fluid compared to sham-inoculated animals (significant at 2 of the 3 examination times postinoculation). These findings suggest that P. uncinata is capable of causing changes in inflammatory cell populations in the lungs of guinea pigs and illustrate the importance of subclinical or inapparent infections in experimental design and interpretation.

Animals↗
PubMed1988

A survey of renal function in outpatients with rheumatoid arthritis.

The acute renal side-effects of nonsteroidal anti-inflammatory drugs are well documented. These include interstitial nephritis, hyperkalaemia, renal tubular acidosis, fluid retention, hypertension and nephrotic syndrome. The long-term effects are less well known. We have carried out a cross-sectional survey of an unselected out-patient population with definite or classical rheumatoid arthritis to determine the prevalence of renal problems in this group. Thirty-four patients (20%) were shown to have an abnormality as defined by our criteria but in the majority this was transient or had been previously recognised. Thirteen patients (8%) had a persistent unexplained abnormality but only 1 had merited renal biopsy using established criteria (Patient 1). We conclude that the long-term use of NSAID's is associated with relatively few renal side-effects.

Adult↗
PubMed1988

Development of a prolonged eosinophil-rich inflammatory leukocyte infiltration in the guinea-pig asthmatic response to ovalbumin inhalation.

Considerable attention has recently focused on the role of inflammation in the pathophysiology of asthma, with special emphasis on "late-phase" bronchoconstriction and increased airway hyperreactivity after antigen challenge in sensitized subjects. The present report describes the histopathologic changes in guinea-pig lung and trachea at various time intervals after ovalbumin inhalation in nonsensitized (control) and sensitized animals. Bronchoalveolar lavage (BAL) was also used to assess the accompanying accumulation of intraluminal leukocytes. A distinct leukocyte margination, consisting of neutrophils and eosinophils, was observed in the peribronchial vasculature as early as 8 min postchallenge in sensitized guinea pigs. At 6 h, the eosinophils predominated and migrated to the peribronchiolar smooth muscle layer. Between 6 h and 18 h, eosinophils were seen in tracts between the smooth muscle cell layers, accumulating in large numbers in the bronchial mucosal epithelium. This pattern persisted for at least 7 days postchallenge during which eosinophils remained the dominant cell type present. Peribronchiolar accumulation of neutrophils and mononuclear cells was minimal at all time points studied. Intraluminal mucus eosinophilia developed between 18 h and 7 days. A similar pattern of eosinophil infiltration was observed in the tracheal epithelium. Control, nonsensitized, guinea-pig lungs showed minor changes with little or no eosinophil infiltration at any time after antigen challenge. These findings correlated well with the BAL study in which sensitized guinea pigs exhibited a marked delayed increase in eosinophil counts between 18 h and 7 days compared with that in nonsensitized animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Role of cyclooxygenase products of arachidonic acid metabolism in Ascaris antigen-induced bronchoconstriction in sensitized dogs.

The pharmacologic modulation of Ascaris allergen-induced bronchoconstriction was investigated in beagle dogs sensitized by experimental infection with Ascaris suum ova. Ascaris-induced increases in total lung resistance (RL) and falls in dynamic lung compliance (Cdyn) were unaffected by pretreatment with an antihistamine (pyrilamine) given alone but were significantly attenuated (P less than .05) by the cyclooxygenase enzyme inhibitor, indomethacin. The combination of pyrilamine and indomethacin also produced a significant (P less than .01) inhibition of Ascaris-induced bronchoconstriction, greater than that produced by indomethacin given alone but the difference between the two treatment groups was not statistically significant. The combination of an antihistamine, the cyclooxygenase inhibitor indomethacin and the leukotriene synthesis inhibitor, U-60,257, almost completely abolished Ascaris-induced bronchoconstriction (91% inhibition of Cdyn changes; 93% inhibition of RL changes). The inhibition was significantly greater than that produced by cyclooxygenase inhibition alone. The leukotriene synthesis inhibitor piriprost (U-60,257) given alone or in combination with pyrilamine produced no inhibition of Ascaris-induced changes in RL or Cdyn. The leukotriene antagonist FPL55712 or the thromboxane synthase inhibitor U-63,557A also showed little or no activity in this model, whereas the thromboxane receptor antagonist AH23848 produced a marked inhibition of Ascaris-induced bronchoconstriction. We conclude that Ascaris-induced bronchoconstriction is mediated primarily by cyclooxygenase products of arachidonic acid metabolism. The role of histamine and lipoxygenase products can only be revealed during an effective cyclooxygenase blockade.

Animals↗
PubMed1987

Vascular damage and factor-VIII-related antigen in the rheumatic diseases.

Factor-VIII-Related antigen (VIII R:Ag) is known to be produced by the blood vessel wall. Noxious stimuli increase endothelial release of VIII R:Ag. It might be expected that the development of vasculitis would be associated with increased levels of VIII R:Ag. To investigate this, eight different groups of subjects were studied: 25 patients with systemic sclerosis, 19 with systemic lupus erythematosus, 15 with rheumatoid arthritis (RA) plus vasculitis, 19 with systemic vasculitis and 14 with atherosclerosis. These groups were compared to 29 patients with primary Raynaud's disease, 15 with RA without vasculitis and 50 controls. Results showed that where there was evidence of vascular disease, then VIII R:Ag was elevated. VIII R:Ag appeared to be a more specific marker for vascular damage than erythrocyte sedimentation rate or C-reactive protein. Longitudinal studies in 11 patients showed good correlation between progression of vascular disease and VIII R:Ag.

Adult↗
PubMed1987

Comparison of phenytoin and gold as second line drugs in rheumatoid arthritis.

Phenytoin has known immunosuppressive properties, and a recent pilot study has indicated that it may have a second line effect in rheumatoid arthritis (RA). To evaluate this role 60 patients with active RA were randomly allocated to receive either oral phenytoin or intramuscular gold. The two treatment groups were comparable at the outset (Mann-Whitney U test). Twenty four patients completed 24 weeks of therapy in each group and no unexpected side effects were encountered. All variables except haemoglobin (Hb) improved significantly in the gold group while in the phenytoin group significant improvement was limited to articular index, erythrocyte sedimentation rate (ESR), and Hb. Between group comparison (Mann-Whitney) at week 24 showed a significant advantage of gold over phenytoin for pain score and morning stiffness. Thus phenytoin appears to exert a less potent second line effect than gold and is unusual in influencing laboratory indicators of disease activity more than clinical variables. This is likely to limit its usefulness as a second line drug in RA.

Arthritis, Rheumatoid↗
PubMed1987

Regulatory peptides in the respiratory tract of Macaca fascicularis.

The quantitative distribution and localisation of seven regulatory peptides (vasoactive intestinal peptide (VIP), peptide histidine methionine (PHM), calcitonin gene related peptide (CGRP), galanin, substance P, neuropeptide tyrosine (Y), and bombesin like peptides) were determined by radioimmunoassay and immunocytochemistry in six different regions of the respiratory tract of the cynomolgus monkey, Macaca fascicularis. In general, peptide concentrations were higher in the airways than in lung tissue itself. VIP and PHM were found in greatest abundance and in equimolar concentrations. Concentrations of substance P, neuropeptide Y, and bombesin were substantially lower. Immunocytochemistry localised all the peptides to nerve fibres, whose density generally paralleled the tissue concentrations by radioimmunoassay except in the case of bombesin, which was not detected. VIP, PHM, and galanin were mostly associated with glands of trachea and bronchus and with blood vessels and smooth muscle; CGRP and substance P were found principally beneath airway epithelium and around smooth muscle fibres and blood vessels; neuropeptide Y was found around blood vessels and seromucous glands only. The pattern of peptide distribution in the Macaca fascicularis respiratory tract is similar to that previously reported in human postmortem material, suggesting that the cynomolgus monkey may be a useful model for examining the pathophysiological role of peptides in human respiratory disease.

Animals↗