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Biomedical subjects

J Morley

Publications and source records attributed to J Morley.

At least 19 recordsLinked to original sources
PubMed1992

Cyclosporin A in asthma therapy: a pharmacological rationale.

Lymphocytes play a central role in immunological reactions and control the mobilisation and recruitment into lung tissue of eosinophils and mast cells. Since cyclosporin A can profoundly influence lymphocyte activation, it is appropriate to consider this drug as a novel anti-asthma therapy. Inhalation of low doses of cyclosporin A strongly inhibits the influx of inflammatory cells into the airways during acute allergic reactions, even though associated bronchospasm and airway hyper-reactivity are undiminished. It is suggested that cyclosporin A will be an effective anti-asthma therapy with an anti-asthma profile resembling that of established glucocorticosteroids.

Animals↗
PubMed1992

Effects of a potassium channel opener (SDZ PCO 400) on guinea-pig and human pulmonary airways.

1. SDZ PCO 400 evoked dose-related relaxation of isolated airway smooth muscle. For human bronchus precontracted by endogenous tone or addition of carbachol (10(-5) M), IC50 values were 1.74 microM and 1.82 microM respectively. With guinea-pig trachea contracted by endogenous tone, a comparable IC50 (1.79 microM) was observed, but no IC50 (less than 100 microM) could be determined following contraction by carbachol (10(-6) M). 2. Airway obstruction induced by intravenous bombesin in the anaesthetized ventilated guinea-pig was diminished by intravenous injection of SDZ PCO 400 (ID50 54 micrograms kg-1) or by introduction into the duodenum (ID50 1.0 mg kg-1). Inhalation of nebulized SDZ PCO 400 (0.1 mg kg-1) diminished airway obstruction due to intravenous injection of histamine (3.2-5.6 micrograms kg-1) for up to 20 min. 3. Increased bronchoconstrictor responses to bombesin (180-240 ng kg-1) following intravenous infusion of platelet activating factor (PAF) or (+/-)-isoprenaline, or to histamine (1.0-3.2 micrograms kg-1) following intravenous injections of immune complexes, were suppressed following concomitant intravenous infusion of SDZ PCO 400 (ID50 0.3 mg kg-1 h-1, 1.0 mg kg-1 h-1 and 0.1 mg kg-1 h-1 respectively). 4. Intravenous injection of SDZ PCO 400 (0.1 mg kg-1) effected transient (less than 10 min) inhibition of histamine-induced bronchospasm, yet diminished, for prolonged periods [up to 40 min] the enhanced bronchoconstrictor responses to histamine that followed intravenous injections of immune complexes.The capacity of SDZ PCO 400 to resolve such established airway hyperreactivity was prevented by prior intraduodenal instillation of a potassium channel antagonist, glibenclamide (30 mg kg-').5. In sensitized guinea-pigs, SDZ PCO 400 inhaled as a dry powder (5.7 mg kg-') suppressed development of allergic airway hyperreactivity to histamine (1.8-3.2;pg kg-', i.v.), but failed to diminish accumulation of eosinophils or other inflammatory cells within the airway lumen 24 h after inhalation of ovalbumin.6. Preincubation (30 min) of isolated sensitized trachea of guinea-pig with SDZ PCO 400 (10-5-10-4M) did not influence contractile responses to ovalbumin. However in anaesthetized sensitized guinea-pigs,insufflation of SDZ PCO 400 (1.25 mg) as a powder substantially diminished airway obstruction that followed inhalation of ovalbumin. This effect was prevented by prior vagal section.7. It is concluded that SDZ PCO 400 reduces airway obstruction not only through direct actions on airway smooth muscle but also by impairing the expression of airway hyperreactivity, without directly influencing inflammatory events in the airways.

Airway Obstruction↗
PubMed1992

Effects of liposome encapsulated hemoglobin on the reticuloendothelial system.

The effects of different doses (4, 10, and 25%) of liposome encapsulated hemoglobin (LEH) were measured on the Reticuloendothelial System (RES) and Kupffer cells (KC) by i) colloidal carbon clearance in the rat in vivo and in the isolated perfused liver, ii) magnetometry, and iii) histological analysis. At the highest dose, in vivo carbon clearance rates (k) were half the rate as in controls at 2 and 12 hours post-treatment. By 24 hours post-treatment clearance rates were at control levels. Empty liposomes (LIP) caused a 2-fold decrease in k at 2 hours only. With both LEH and LIP, the effects were less severe when rats were given the lower doses. Magnetometric studies showed a decrease in KC phagosomal motion in the LEH-treated (25%) rats at 2 and 24 hours that returned to control levels at 2 weeks. Perfused livers from rats treated with a low dose of LEH cleared carbon at the same rate as LIP and Krebs Ringer Bicarbonate (KRB) controls. Histological examination showed minimal tissue damage in all test groups. Thus, LEH and LIP have some short-term deleterious effects on KC and the RES probably due to RES blockade rather than cellular damage.

Animals↗
PubMed1991

Platelet activating factor-induced pulmonary accumulation of 111Indium-oxine labelled neutrophils in anesthetized guinea pigs.

The thoracic accumulation of neutrophils labelled with 111Indium-oxine in response to infusion of platelet activating factor (PAF, 18 ng/kg/min x 5 min, i.v.) was studied using an automated isotope monitoring system (AIMSplus) in anesthetized guinea-pigs. Loss of cell associated radioactivity in vitro was less than 1% over 4 hr. Labelled neutrophils maintained their functional capacity (oxidative response to the cell stimulants N-formyl-L-methionine-L-leucine-L-phenylalanine and phorbol myristate acetate) and greater than 95% viability (ethidium bromide/acridine orange stain) in vitro. Total thoracic radioactivity increased significantly from baseline in response to PAF with a slight tachyphylaxia in the neutrophil-accumulation after a repeat PAF infusion. The highest ratios of radiolabel (tissue/blood) were found in the spleen much greater than liver greater than lung.

Analysis of Variance↗
PubMed1991

Intrathoracic accumulation of 111In-labeled neutrophils in guinea pigs in response to PAF.

The intrathoracic content of neutrophils, labeled with 111In-oxine has been measured in the anesthetized guinea pig by using an automated isotope-monitoring system. Intravenous infusion of platelet-activating factor (PAF; 5.6, 10, or 18 ng.kg-1.min-1 over 5 min) caused a dose-related abrupt intrathoracic accumulation of neutrophils, which dispersed from the thorax within 20 min. Repetition of this procedure after 1 h gave responses of comparable magnitude and duration. Anti-platelet antiserum pretreatment did not influence the response of neutrophils to PAF. Iloprost infusion (10 ng.kg-1.min-1 over 15 min) did not affect the response of neutrophils to PAF, whereas accumulation of radiolabeled platelets in the lung was totally suppressed by this dose. Intrathoracic accumulation of neutrophils in response to PAF can be considered to be independent of platelet activation.

Animals↗
PubMed1991

The ventilatory and oxygen costs in the anesthetized rhesus monkey of inhaling drugs used in the therapy and diagnosis of asthma.

We examined in male Rhesus monkeys the effects on oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), heart and respiratory rates, and functional residual capacity (FRC) of breathing normal saline (NS), salbutamol (albuterol), methacholine (MCh), sodium cromoglycate (SCG), epinephrine (adrenaline), and terbutaline in doses commonly prescribed to human infants and children. We studied 10 anesthetized and intubated monkeys with a mean age and weight of 6.0 yr and 9.1 kg, respectively. VO2 increased over control, by 46.5% after salbutamol (p less than 0.0005), 25% after methacholine (p less than 0.001), 13.2% after epinephrine (p less than 0.01), and 16% after terbutaline (p less than 0.001), but it did not increase after either SCG or NS. VE increased by 82% after MCh and salbutamol (p less than 0.001), less dramatically after epinephrine and terbutaline at 50.5 and 31.5% (p less than 0.02 and p less than 0.001), respectively, and not at all after SCG and NS. Heart rate response was greatest after salbutamol, and nodal and ventricular arrhythmias were noted in four of 10 monkeys after MCh challenge. FRC did not change significantly except after salbutamol, where there was a small rise of 1.8 ml/kg (p less than 0.05).

Administration, Inhalation↗
PubMed1991

The effects of varying inflation and deflation pressures on the maximal expiratory deflation flow-volume relationship in anesthetized rhesus monkeys.

Deflation flow-volume curve analysis is a pulmonary function test sensitive to small airways dysfunction that is suitable for use in infants and children who are intubated. This test relies upon deflation flow-volume (DFV) curve analysis, which is a technique to obtain maximal expiratory flow-volume curves (MEFV) by forced deflation of the lungs in infants who are intubated. The method mimics the voluntary forced flow-volume curves that adults and older children undertake. We studied 10 anesthetized male Rhesus monkeys of the same weight as human infants but developmentally equivalent to older children. We reviewed the effects on forced deflation vital capacity (DVC) and flows at various subdivisions of vital capacity (PEF, MEF50, MEF25, MEF10) of systematically varying the required inspiratory and deflation pressure during the course of 56 consecutive deflation maneuvers. Inflation pressures of +40 and +50 cm H2O caused a marked but transient bradycardia along with a (probably spurious) short-lasting fall to 89% mean arterial oxygen saturation (SaO2). Increasing positive and negative pressures increased DVC and expiratory flows. The highest mean DVC was 75.6 +/- 1.3 ml/kg, PEF was 128.0 +/- 3.5, MEF50 was 85.9 +/- 2.2, MEF25 was 74.3 +/- 1.9, and MEF10 was 38.5 +/- 2.9 ml/kg/s, all obtained at the pressure gradient of 90 cm H2O (+50/-40 cm H2O) at the start of the deflation maneuver. At this gradient, the intraindividual coefficients of variation were: DVC = 0.8%, PEF = 3.1%, MEF50 = 2.2%, MEF25 = 2.1%, MEF10 = 5.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Histamine(H1) antagonists and airway hyperreactivity in the guinea-pig.

Ketotifen inhibits development of airway hyperreactivity in guinea-pigs exposed to PAF, (+/-)isoprenaline, immune complexes or endotoxin. Ketotifen is not a competitive histamine(H1) antagonist, so that it cannot be concluded that there is mandatory involvement of histamine in the development or expression of these forms of airway hyperreactivity. This conclusion has been reinforced by determining the efficacy of other histamine(H1) antagonists as inhibitors of PAF-induced airway hyperreactivity. When compounds were administered intravenously, at a dosage (1 mg/kg) which fully abolished responses to intravenous histamine, the observed rank order for inhibition of PAF-induced hyperreactivity was: ketotifen greater than cetirizine greater than acrivastine greater than KB-2413 greater than oxatomide greater than azelastine greater than terfenadine = astemizole = clemastine = mepyramine = loratadine = saline. Terfenadine may lack inhibitory activity because of a capacity to induce airway hyperreactivity in the guinea-pig. It can be concluded that inhibition of the development of airway hyperreactivity is not a characteristic of histamine(H1) antagonists.

Airway Resistance↗
PubMed1991

Development of airway hyperreactivity in the guinea-pig following allergic reactions.

It has been reported previously that acute allergic reactions in the anaesthetized guinea-pig do not evoke changed airway reactivity to histamine, animals sensitized to ovalbumin in aluminum hydroxide and exposed to allergen intravenously or by inhalation develop increased responsivity to histamine that persists for several hours. Animals that have been sensitized passively, by intravenous injection of antibody and exposed to allergen by intravenous injection, or which receive freshly prepared immune complexes by intravenous injection develop comparable airway reactivity.

Animals↗
PubMed1991

Changes in airway sensitivity to histamine are not necessarily paralleled by changed sensitivity to acetylcholine.

In allergic asthmatics, it has been shown that airway sensitivity to histamine closely parallels sensitivity to methacholine, a finding which underlies the widely-held view that airway hyperreactivity of asthma is non-selective. We have been interested to evaluate the capacity of various agents to influence reactivity to intravenous injections of both histamine and acetylcholine in the anaesthetized guinea-pig. Intravenous infusion of PAF or (+/-)isoprenaline are procedures which increase airway reactivity to histamine, but leave reactivity to acetylcholine unaffected; by way of contrast, there is comparable enhancement of hyperreactivity to both histamine and acetylcholine following endotoxin infusion. These observations do not accord with the concept that obstruction of the airways per se accounts for changed reactivity of the airways and question the presumption that PAF might be a pivotal mediator of airway hyperreactivity in allergic asthma.

Acetylcholine↗
PubMed1991

SDZ MKS 492.

SDZ MKS 492 (R(+)-(8-[( 1-(3,4-Dimethoxyphenyl)-2-hydroxyethyl)amino]-3,7-dihydro-7-(2- methoxyethyl)-1,3-dimethyl-1H-purine-2,6-dione) relaxes airway smooth muscle in vitro and impairs, or reverses, spasm of guinea-pig airways in vivo. Effects on bronchospasm in the guinea-pig may additionally include actions on airway hyperreactivity, since SDZ MKS 492 can inhibit the development, or expression, of airway hyperreactivity due to infusion of PAF, (+/-)isoprenaline, endotoxin or injection of immune complexes. In addition to influencing airway tone, inhaled SDZ MKS 492 diminishes the pulmonary accumulation of macrophages, eosinophils and neutrophils that follows inhalation of allergen by actively sensitized guinea-pigs. SDZ MKS 492 offers the prospect of a monotherapy for asthma, combining bronchodilator and anti-inflammatory activities with prophylactic efficacy.

Animals↗