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Biomedical subjects

C G Irvin

Publications and source records attributed to C G Irvin.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effects of the perfluorochemical emulsion FMIQ on the radiation response of EMT6 tumours.

The effects of FMIQ, a perfluorochemical emulsion based on perfluoro-N-methyldecahydroisoquinoline, were examined using BALB/c mice and EMT6 mammary carcinomas. The radiobiological effects of FMIQ were similar to those found previously for Fluosol in the same tumour/host system. Although the perfluorochemical content (20% w/v) and oxygen-carrying capacity of FMIQ are similar to those of Fluosol, the formulation of FMIQ offers some advantages over that of Fluosol. For example, FMIQ has greater stability during storage. FMIQ also is formulated without pluronic F-68 and is based on a perfluorochemical (FMIQ) having a shorter tissue dwell time than the perfluorotripropylamine in Fluosol; it therefore may produce fewer side-effects than Fluosol. The lifetime of the circulating perfluorochemical droplets in BALB/c mice was longer than FMIQ than for Fluosol; this could offer an advantage in fractionated radiotherapy. These findings give reason to expect that FMIQ may prove to be a better emulsion than Fluosol for clinical use as an adjunct to cancer therapy.

Animals↗
PubMed1992

The utility of spirometry in the diagnosis of reversible airways obstruction.

Patients with suspected reversible airways obstruction (RAO) sometimes report subjective benefit after bronchodilator treatment despite no objective spirometric improvement. One possible explanation for this is improvement in volume-related or plethysmographic parameters in the absence of spirometric improvement. One hundred patients with RAO were assessed before and after inhaled bronchodilator to determine the prevalence of improvement by plethysmographic parameters in the absence of improvement in spirometric parameters. Spirometry alone (FEV1, FVC, and FEF25-75%) identified reversibility of airflow limitation in 82 patients. Reversibility was identified by body plethysmography (specific conductance [SGaw], thoracic gas volume [TGV], and isovolume maximum expiratory flow rates [IVMEF]) in 15 of the remaining patients. The percent predicted FEF25-75% at baseline was higher in patients who required plethysmography to identify reversibility, but could not be used to predict the lack of a spirometric response for any individual patient. We conclude that spirometry alone fails to identify reversibility in approximately 15 percent of patients, and that most of these patients can be identified by additional plethysmographic measurements of volume-related parameters. At any one point in time, multiple tests must be used together to adequately identify the majority of patients with reversible airways obstruction. Improvement in volume-related parameters may explain why some patients with RAO improve subjectively with bronchodilators but show no spirometric improvement.

Adrenergic beta-Agonists↗
PubMed1992

Preclinical evaluation of Oxygent as an adjunct to radiotherapy.

These studies examine the potential value of a concentrated emulsion of perfluorooctylbromide (perflubron; Oxygent, Alliance Pharmaceutical Corp.) as an adjunct to radiotherapy. The effects of Oxygent on solid tumors were examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus O2, carbogen (95% O2/5% CO2), or hyperbaric oxygen (HBO) increased the effects of radiation on the tumors. Analyses of tumor cell survival curves and measurements of intratumor pO2 showed that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Neither treatment of the animals with carbogen, O2, or HBO alone nor treatment of air-breathing rodents with Oxygent produced changes of similar magnitude. Treatment with a vehicle emulsion containing all the components of Oxygent except the perflubron did not alter tumor radiosensitivity, showing that tumor radiosensitization required the oxygen-transporting perfluorocarbon, and did not result from any biologic or physiologic effects of other components of the emulsion. These studies also examined the effects of Oxygent on the radiation responses of mouse skin and bone marrow. Oxygent selectively increased the radiation sensitivity of tumors relative to these normal tissues, thereby increasing the therapeutic ratio and producing therapeutic gain. Oxygent appears to warrant further testing as an adjunct to cancer therapy.

Animals↗
PubMed1991

Body temperature modulates the effect of platelet-activating factor (PAF) on airways responsiveness in the rabbit.

Platelet-activating factor (PAF) is a potent mediator known to cause bronchoconstriction and increase airways responsiveness. In vitro studies have shown that the effects of PAF on cell function can be very temperature-dependent. The aim of the current study was to investigate the effect of elevated body temperature on numbers of circulating cells and pulmonary function in anesthetized rabbits in response to PAF. PAF was given intravenously, at a dose of 1.2 micrograms/kg hour, whereas the control experiments were performed after the animals received a saline infusion. Alteration of airways function was assessed by measuring specific pulmonary conductance (SGL) and dose-response relationships to inhaled histamine, where airways responsiveness was expressed as the effective concentration causing 50% of maximal change in specific airways conductance (EC50SGL). The rabbits were studied at two body temperatures: a normal temperature (rectal temperature of 39.8 C), and a higher temperature (rectal temperature 41.2 degrees C). Changes in circulating inflammatory cells, plasma corticosterone concentrations and in hematocrit were also monitored, to examine some potential mechanisms which might explain why body temperature altered airways responsiveness. At the normal body temperature infusion of PAF caused a significant increase in airways responsiveness (p less than 0.025), while at the high body temperature, there was a significant decrease in responsiveness (p less than 0.025). However, at both body temperatures, a profound but similar thrombocytopenia and neutropenia was observed. While plasma corticosterone levels and hematocrit showed increases coincident with the infusion of PAF, this response was unchanged by altering body temperature. We conclude that increased body temperature reduces the effect of PAF on airways responsiveness apparently through a mechanism independent of PAF effects on hemoconcentration, plasma corticosterone or circulating inflammatory cells.

Aerosols↗
PubMed1991

Modulation of tumor oxygenation and radiosensitivity by a perfluorooctylbromide emulsion.

The effect of a concentrated perfluorooctylbromide emulsion (Oxygent) on the radiosensitivity and oxygenation of solid tumors was examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus carbogen or oxygen breathing increased the radiosensitivity of both tumors. Analysis of tumor cell survival data and polarographic measurements of intratumoral pO2 indicated that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Treatments with carbogen breathing alone, with Oxygent plus air-breathing, or with a vehicle emulsion containing all the components except the perfluorocarbon did not produce comparable improvements in tumor radiosensitivity. Concentrated perfluorooctylbromide emulsions appear to warrant further development and preclinical testing as adjuncts to cancer therapy.

Animals↗
PubMed1991

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia.

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1991

Cholinergic mechanisms involved with histamine hyperreactivity in immune rabbit airways challenged with ragweed antigen.

The present study examines the effects of aerosolized ragweed antigen (RAg) on tracheal (TSM) and bronchial (BSM) smooth muscle contraction in rabbits actively immunized with RAg. Airway segments were isolated 48 h after aerosol challenge with either saline or RAg, and airway contractile responses to histamine were measured. Histamine remained a weak agonist in TSM segments after RAg challenge. In contrast, BSM responsivity to histamine was significantly increased after RAg challenge as evidenced by a parallel shift to the left (i.e., Fslope = 3.2; degrees of freedom (df) = 1,224; p = NS and Felev = 19.4; df = 1,225; p less than 0.001) of the mean dose-response relationship. In sham-immunized rabbits, the BSM contractile responses to histamine were similar after aerosol challenge with either RAg or normal saline. After the BSM segments were treated with 10(-6) M atropine, there was no significant difference in histamine reactivity between the RAg- and saline-challenged groups. The augmented BSM contractile response to histamine was only partially inhibited in the presence of either tetrodotoxin or hexamethonium. We conclude that 48 h after a single in vivo exposure to antigen in immune rabbits, the airway contractile responses to histamine in vitro are increased in BSM but not in TSM and that the mechanism of the augmented contractile responses in BSM likely involves the facilitated neural release of acetylcholine from both preganglionic and postganglionic sites.

Acetylcholine↗
PubMed1991

Methylprednisolone achieves greater concentrations in the lung than prednisolone. A pharmacokinetic analysis.

Previous studies in humans and rabbits demonstrated that methylprednisolone appears in the lung in greater concentration than prednisolone. To ascertain which pharmacokinetic properties of these drugs explain this difference, we gave methylprednisolone and prednisolone, 5 mg/kg intravenous bolus, to 23 adult rabbits. To measure the plasma concentration versus time curves for methylprednisolone and prednisolone, samples were obtained predose through 480 min postdose. To measure the bronchoalveolar lavage glucocorticoid concentration versus time curves, lavage was performed once per experiment at seven separate time points from 5 to 480 min post-dose (two to four experiments per time point). Bronchoalveolar lavage fluid (BALF) recovery ranged from 50 to 75% and was similar in both groups. Glucocorticoid concentration in plasma and BALF was determined by high performance liquid chromatography. To normalize for the dilutional effects of lavage, epithelial lining fluid (ELF) recovery was quantitated from BALF volume and BALF and plasma urea concentrations. Pharmacokinetic parameters of the two glucocorticoids were calculated both noncompartmentally and by a three-compartment model. The extrapolated plasma glucocorticoid concentrations at time zero of methylprednisolone and prednisolone are similar, but the volume of distribution and plasma half-life of methylprednisolone are significantly greater than those of prednisolone (p less than 0.05). Although the clearance of the two drugs are not significantly different, methylprednisolone appears to have a slower Cl than prednisolone. The mean residence time (the average time drug remained in body) was significantly longer for methylprednisolone than for prednisolone (p less than 0.05), and plasma glucocorticoid concentrations became significantly different in the two groups by 90 min (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of deficiencies in DNA repair on the toxicity of mitomycin C and porfiromycin to CHO cells under aerobic and hypoxic conditions.

A wild type Chinese hamster cell line (AA8) and three repair-deficient sublines of AA8 (EM9, UV4, and UV5) were used to study the nature of the cytotoxic lesions produced by the bioreductive alkylating agents mitomycin C and porfiromycin under aerobic and hypoxic conditions. The sensitivities of the repair-deficient sublines to the drugs varied markedly: EM9 was similar to AA8, whereas UV4 was exquisitely sensitive and UV5 was of intermediate sensitivity. Moreover, both the relative toxicities of the two drugs and the relative toxicities of each drug under aerobic and hypoxic conditions varied for the different cell lines. These data suggest that there are differences in the spectra of toxic lesions produced by mitomycin and porfiromycin and that there are differences in the lesions produced by these drugs under aerobic and hypoxic conditions.

Aerobiosis↗
PubMed1990

Influence of sleep on lung volume in asthmatic patients and normal subjects.

To assess the effect of sleep on functional residual capacity (FRC) in normal subjects and asthmatic patients, 10 adult subjects (5 asthmatic patients with nocturnal worsening, 5 normal controls) were monitored overnight in a horizontal volume-displacement body plethysmograph. With the use of a single inspiratory occlusion technique, we determined that when supine and awake, asthmatic patients were hyperinflated relative to normal controls (FRC = 3.46 +/- 0.18 and 2.95 +/- 0.13 liters, respectively; P less than 0.05). During sleep FRC decreased in both groups, but the decrease was significantly greater in asthmatic patients such that during rapid-eye-movement (REM) sleep FRC was equivalent between the asthmatic and normal groups (FRC = 2.46 +/- 0.23 and 2.45 +/- 0.09 liters, respectively). Specific pulmonary conductance decreased progressively and significantly in the asthmatic patients during the night, falling from 0.047 +/- 0.007 to 0.018 +/- 0.002 cmH2O-1.s-1 (P less than 0.01). There was a significant linear relationship through the night between FRC and pulmonary conductance in only two of the five asthmatic patients (r = 0.55 and 0.65, respectively). We conclude that 1) FRC falls during sleep in both normal subjects and asthmatic patients, 2) the hyperinflation observed in awake asthmatic patients is diminished during non-REM sleep and eliminated during REM sleep, and 3) sleep-associated reductions in FRC may contribute to but do not account for all the nocturnal increase in airflow resistance observed in asthmatic patients with nocturnal worsening.

Adult↗
PubMed1990

Effect of corticosteroids on diaphragm function and biochemistry in the rabbit.

The effects of corticosteroid administration for 2 weeks on diaphragm histology, biochemistry, and function were assessed in the rabbit at rest and during inspiratory loading to respiratory failure, and compared to the extensor digitorum longus and untreated control animals. There were marked pathologic changes in the diaphragm after corticosteroid administration and significant alterations in diaphragm glycogen level (118.7 +/- 2.8 versus 56.2 +/- 1.0 mmol/kg wet weight, p less than 0.01) and lactate level (5.3 +/- 0.3 versus 3.5 +/- 0.4 mmol/kg wet weight, p less than 0.01) with only minimal changes in the skeletal muscle. Although respiratory muscle endurance in the control group increased from 142 +/- 17 min at baseline to 155 +/- 20 at Week 1 and 183 +/- 13 at Week 2 (p less than 0.05), it fell progressively from 135 +/- 19 min at baseline to 99 +/- 5 at Week 1 and 88 +/- 9 at Week 2 (p less than 0.01) in the corticosteroid-treated animals. On the other hand, there was no significant change in resting Pdimax after corticosteroid administration. In addition, there was no significant change in Pdimax, Pdi/Edi ratio, or glycogen level at the point of respiratory failure, but diaphragm lactate levels were increased (8.5 +/- 0.8 versus 5.3 +/- 0.3, p less than 0.05). When variable degrees of diaphragm dysfunction were induced by phrenic nerve pacing and/or thoracoabdominal binding, the degree of biochemical change associated with diaphragm dysfunction was significantly greater in corticosteroid-treated animals. We conclude that corticosteroid administration in the rabbit alters diaphragm histopathology and biochemistry as well as respiratory muscle endurance, but not strength.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Relationship of diaphragm glycogen, lactate, and function to respiratory failure.

Diaphragmatic function and biochemical changes were studied during respiratory failure induced by incremental inspiratory threshold loading in anesthetized rabbits (1) who were unbound and spontaneously breathing, (2) during lower thoracic and abdominal binding, and (3) while bound and undergoing transvenous phrenic nerve pacing of the diaphragm. There was no evidence of contractile fatigue or alterations in glycogen or lactate concentrations in the diaphragm of unbound spontaneously breathing animals. With thoracoabdominal binding, there was a fall in maximal transdiaphragmatic pressure (Pdimax) and the ratio of diaphragmatic force divided by neural input (Pdi/Edi ratio); there was no change in diaphragm glycogen, but there was a significant rise in lactate. In the bound and phrenic-paced animals Pdimax and Pdi/Edi ratio fell, and there was significant glycogen depletion and lactate accumulation. There was a significant correlation between diaphragm function and the levels of diaphragm glycogen and lactate at the point of respiratory failure. We conclude that (1) respiratory failure induced by incremental inspiratory threshold loading was not associated with either contractile fatigue of the diaphragm or diaphragmatic biochemical changes in unbound spontaneously breathing animals, (2) when mechanisms that preserve diaphragmatic function are circumvented by phrenic pacing and/or thoracoabdominal binding, diaphragm fatigue and biochemical changes occur, and (3) there is a significant relationship between in vivo evidence of contractile fatigue of the diaphragm and diaphragmatic glycogen depletion and lactate accumulation.

Acid-Base Equilibrium↗
PubMed1990

Effect of corticosteroids on respiratory muscle histopathology.

Pathologic alterations induced by corticosteroid administration were evaluated in the respiratory muscles and compared to those in the peripheral skeletal muscles of the rabbit. Alterations in gross and microscopic pathology as well as histochemistry were determined in the diaphragm, intercostal, sternocleidomastoid, extensor digitorum longus, and soleus muscles following 3 wk of intramuscular cortisone injections. Corticosteroid administration induced significant pathologic changes in all the muscles except the soleus. Although gross pathologic changes were greatest in the extensor digitorum longus, microscopic changes were greatest in the diaphragm. Reductions in total muscle fiber volume were similar in the diaphragm, sternocleidomastoid, and extensor digitorum longus muscles. The composition of muscle fiber types and the number of fibers in a muscle were not altered in any of the muscles studied following corticosteroids. There was significant atrophy of individual muscle fibers in all the muscles except the soleus. In the diaphragm, corticosteroids induced atrophy of all fiber types, including type I fibers. Atrophy of type I fibers was not present in the peripheral skeletal muscles or the other respiratory muscles. On the other hand, corticosteroids induced selective atrophy of type IIb muscle fibers in the intercostal and sternocleidomastoid muscles similar to that in the peripheral skeletal muscles. These findings suggest that the effect of corticosteroids on the diaphragm is unique, and one cannot extrapolate form the effect of corticosteroids on peripheral skeletal muscles to that in the diaphragm. In addition, these pathologic changes may have functional relevance, since atrophy of type I fibers may result in a reduction in muscle endurance.

Animals↗
PubMed1990

Effect of cooling on the responsiveness of canine tracheal muscle.

Airway cooling causes bronchoconstriction in many persons who have asthma. To determine the direct effect of cooling on the response of tracheal muscle to parasympathetic and muscarinic stimuli in situ, the temperature of a segment of canine cervical trachea was adjusted to 37 degrees, 30 degrees, or 25 degrees C by superfusing temperature-controlled saline over its epithelial surface. The contractile response of the tracheal muscle to electrical stimulation of the vagus nerves and to intra-arterial acetylcholine was then determined. Cooling the segment to 25 degrees C decreased the contraction induced by parasympathetic stimulation. However, cooling did not alter the contraction induced by intra-arterial acetylcholine. Parallel studies were conducted in vitro using nine excised tracheal muscle strips taken from the same section of trachea in three additional dogs. Cooling the tracheal muscle to 25 degrees C in vitro increased the maximal contraction induced by both electrical field stimulation and by acetylcholine. Thus, cooling in situ does not alter the response of tracheal muscle to muscarinic stimuli and inhibits the response to parasympathetic stimuli. These data indicate that augmentation of the tracheal muscle response elicited by cooling in vitro does not reflect the response in situ. They suggest that a direct effect of cooling on airway smooth muscle response to parasympathetic and muscarinic stimuli does not account for cooling-induced bronchoconstriction in vivo.

Acetylcholine↗
PubMed1989

Penetration of corticosteroids into the lung: evidence for a difference between methylprednisolone and prednisolone.

Little is known about the penetration of corticosteroids, such as methylprednisolone and prednisolone, into the lung, despite their common use in the treatment of inflammatory lung diseases. To compare methylprednisolone and prednisolone concentrations in the bronchoalveolar space, we administered these two corticosteroids in a randomized, crossover fashion to 17 adult rabbits. A loading dose was administered and was followed by a continuous infusion for 180 minutes to achieve steady-state plasma concentrations between 200 to 2000 ng/ml. Serial plasma samples were obtained during the infusions. Bronchoalveolar lavages (BAL) were performed at 180 minutes with sterile saline. Plasma and BAL fluid (BALF) were assayed for methylprednisolone and prednisolone concentration by high-performance liquid chromatography. Corticosteroid concentrations were normalized to urea concentrations in plasma and BALF. Generally, BALF corticosteroid concentration increased as plasma concentration increased. At plasma concentrations greater than 800 ng/ml, BALF methylprednisolone concentrations increased exponentially, whereas the increase for prednisolone remained linear. BALF methylprednisolone was five times as high as that of prednisolone when plasma corticosteroid concentration was in the 2000 ng/ml range. With this continuous infusion technique, methylprednisolone has a higher degree of bronchoalveolar penetration than prednisolone, and these differences are greater at higher plasma concentrations.

Adrenal Cortex Hormones↗
PubMed1989

Effect of PAF on parasympathetic contraction of canine airways.

Platelet-activating factor (PAF) increases the bronchoconstrictor response of mammalian airways to cholinergic agonists and is thus implicated as a potential mediator of airway hyperreactivity. This study further defines the nature of the increase in airway responsiveness induced by PAF. We employed an in situ canine tracheal preparation, which allows differentiation of the effects PAF has on airway smooth muscle contraction from confounding effects it has on inducing airway edema and secretions. We found that PAF, infused regionally into tracheal arteries, increases the responsiveness of the trachealis muscle to parasympathetic stimuli in a dose-dependent manner. This effect occurred within 15 min. To determine whether the increase in trachealis muscle responsiveness resulted from effects localized to the trachea, we compared the effect of PAF on the tracheal segment with effects of the lower airways of the lung. Delivered to the arteries perfusing the tracheal segment, PAF did not increase lung resistance during vagus nerve stimulation. These data indicate that airway hyperresponsiveness elicited by PAF results from regional stimulation and/or release of mediators that augment tracheal contractility and that this effect is distinct from systemic effects elicited by PAF.

Animals↗