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Biomedical subjects

G D Phillips

Publications and source records attributed to G D Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1991

An angiogenic extract from skeletal muscle stimulates monocyte and endothelial cell chemotaxis in vitro.

The purpose of this study was to determine whether the extraction of skeletal muscle with a combination of ethanol and hydrochloric acid yields a product capable of stimulating angiogenesis. The resulting extract stimulated inflammation in the rabbit corneal assay, which was followed by capillary formation. In order to determine whether the observed angiogenesis was stimulated by a factor(s) acting directly on the endothelial cells versus a factor(s) recruiting macrophages that in turn release factors acting on endothelial cells, the muscle extract was tested for endothelial cell and monocyte chemotaxis activity in vitro. The muscle extract stimulated significant endothelial cell chemotaxis at concentrations between 94 and 750 micrograms of protein/ml and significant monocyte chemotaxis at concentrations between 8 and 75 micrograms of protein/ml. Polyacrylamide gel electrophoresis suggests that basic fibroblast growth factor and transforming growth factor-beta may be present in this acid/ethanol extract of skeletal muscle.

Animals↗
PubMed1990

Non-invasive mechanical ventilation for acute respiratory failure.

The value of mechanical ventilation using intermittent positive pressure ventilation delivered non-invasively by nasal mask was assessed in six patients with life threatening exacerbations of chronic respiratory disease. Median (range) arterial oxygen and carbon dioxide tensions were 4.4 (3.5-7.2) kPa and 8.7 (5.5-10.9) kPa respectively, with four patients breathing air and two controlled concentrations of oxygen. The arterial oxygen tension increased with mechanical ventilation to a median (range) of 8.7 (8.0-12.6) kPa and the carbon dioxide tension fell to 8.2 (6.5-9.2) kPa. Four patients discharged after a median of 10 (8-17) days in hospital were well five to 22 months later. One died at four days of worsening sputum retention and another after five weeks using the ventilator for 12-16 hours each day while awaiting heart-lung transplantation. This technique of mechanical ventilation avoids endotracheal intubation and can be used intermittently. Hypercapnic respiratory failure can be relieved in patients with either restrictive or obstructive lung disease in whom controlled oxygen treatment results in unacceptable hypercapnia. Respiratory assistance can be tailored to individual need and undertaken without conventional intensive care facilities.

Acute Disease↗
PubMed1990

Migration of myogenic cells in the rat extensor digitorum longus muscle studied with a split autograft model.

The ability of myogenic cells to migrate perpendicular to the long axis of freely autografted muscles was examined. Rat extensor digitorum longus muscles were divided, and one half was devitalized by repeated freezing in liquid nitrogen while the other half was kept viable in physiologic saline. The halves were reunited with sutures and grafted back into the original muscle bed. At intervals between 5 and 25 days the grafts were removed and examined histologically for the presence of myotubes within the devitalized region. Myotubes were first seen in the devitalized half 10 days postgrafting with the maximum number of myotubes observed after 12 to 15 days. These results indicate that myogenic cells are capable of migration perpendicular to the long axis of the muscle fibers in an autograft.

Animals↗
PubMed1990

Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma.

We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine, histamine, and adenosine 5'-monophosphate (AMP) in nine subjects with asthma. In a double-blind, placebo-controlled study, salbutamol, 2.5 mg administered by nebulization, increased the geometric mean provocation concentrations of methacholine, histamine, and AMP required to produce a 20% decrease in FEV1 from 0.3 to 2.2, 0.4 to 3.8, and 4.0 to 106.7 mg/ml after placebo and active treatment, respectively (p less than 0.01). Thus, this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine, histamine, and AMP to the right in a parallel fashion by 8.8 (0.6 to 29.3)-, 10.3 (1.4 to 33)-, and 26.6 (1.5 to 76.6)-fold, respectively, the difference between the results for AMP and those for histamine and methacholine being statistically significant (p less than 0.01). For six of the nine subjects studied, salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold. There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists. We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism, whereas with AMP, an additional activity is demonstrable, possibly involving inhibition of mast cell-mediator release.

Adenosine Monophosphate↗
PubMed1990

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.

Adult↗
PubMed1990

The response of plasma histamine to bronchoprovocation with methacholine, adenosine 5'-monophosphate, and allergen in atopic nonasthmatic subjects.

To investigate the possible role of mast cell histamine release in mediating adenosine 5'-monophosphate (AMP)-induced bronchoconstriction, we have measured the histamine concentration in peripheral venous plasma following inhalation of methacholine, AMP, and allergen in concentrations sufficient to provoke mean maximum decreases in FEV1 of 42.8 +/- 2.2%, 46.5 +/- 3.9%, and 40.9 +/- 4.6%, respectively, in 10 atopic, nonasthmatic subjects. Mean baseline plasma concentrations of histamine were 0.25 +/- 0.02, 0.22 +/- 0.03, and 0.29 +/- 0.03 ng/ml on the methacholine, AMP, and allergen study days, respectively. Plasma histamine did not change following methacholine-induced bronchoconstriction, but increased in 9 out of 10 subjects to a mean maximum value of 0.78 +/- 0.15 ng/ml following inhalation of allergen (p less than 0.005). Following bronchial challenge with AMP, there was a significant elevation in plasma histamine in 9 out of 10 subjects to a mean maximum value of 0.39 +/- 0.03 ng/ml (p less than 0.005). We conclude that AMP-induced bronchoconstriction is associated with the enhanced release of histamine in the airways, probably from airway mast cells. However, the rise in plasma histamine, in being smaller than that occurring with a dose of allergen that provoked a similar degree of bronchoconstriction, suggests that additional mechanisms are operative in mediating the airways response to this nucleotide.

Adenosine Monophosphate↗
PubMed1990

Angiogenic activity in damaged skeletal muscle.

After a muscle is damaged, blood vessels spontaneously grow into the injured region as the muscle fibers regenerate. The stimulus for this vascular ingrowth is currently unknown. We hypothesized that the damaged muscle releases a factor(s) capable of stimulating this revascularization. To test this theory, extracts were prepared from rabbit hind limb muscles and incorporated into Hydron, a slow-release polymer. Pellets of the extract containing Hydron were implanted between the layers of the rabbit corneal stroma as an assay for angiogenic activity. The normally avascular corneas were examined 7 days after surgery for the presence of new blood vessels. Skeletal muscle-derived extract from rabbits elicited positive angiogenic responses in a dose-dependent manner. Four hundred to 500 micrograms of the skeletal muscle-derived extract were required to produce maximum vessel ingrowth. The control, Dulbecco's phosphate-buffered saline in Hydron, failed to stimulate neovascularization.

Angiogenesis Inducing Agents↗
PubMed1990

Wound healing angiogenesis: indirect stimulation by basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) was tested for its ability to stimulate angiogenesis in vivo using the rabbit corneal assay. Basic FGF (50-1,000 ng) was incorporated into 10% Hydron, and 50-500 ng of bFGF were incorporated into 10% Elvax. Human serum albumin (HSA) (10 ng) and 50 ng of transforming growth factor-beta (TGF-beta) served as negative and positive controls. Pellets of the polymers containing test compounds were implanted in the rabbit cornea, examined daily, and after 7 days corneal angiogenesis was scored on a graded scale [(-) for no response and +4 for a maximum response]. Histologic analysis of the corneas was performed on days 2 and 7. Basic FGF (50-500 ng) in Hydron failed to stimulate significant angiogenesis, though it did induce angiogenesis accompanied by inflammation at the 1,000-ng dose. Basic FGF in Elvax elicited inflammation-associated +3 to +4 responses at all doses tested. New blood vessels did not form in response to HSA in Hydron or Elvax, while TGF-beta induced +4 angiogenesis accompanied by vigorous inflammation. In vivo release kinetics for bFGF in Hydron and Elvax were compared, and the release of bioactive bFGF from Hydron and Elvax was demonstrated in vitro. These results suggest that the bFGF and Elvax combination incites an inflammatory response which stimulates indirect angiogenesis, while the same concentrations of bFGF delivered in Hydron produced no inflammation or angiogenesis. Although bFGF alone is a potent mitogen for endothelial cells, it does not appear to directly stimulate in vivo angiogenesis.

Animals↗
PubMed1990

The effect of inhaled 15-(s)-hydroxyeicosatetraenoic acid (15-HETE) on airway calibre and non-specific responsiveness in normal and asthmatic human subjects.

15-hydroxyeicosatetraenoic acid (15-HETE) is the predominant oxidative metabolite of arachidonic acid in human lung. We have studied its effects on airway calibre and non-specific bronchial responsiveness (NSBR) in eight normal and eight asthmatic subjects. 15-HETE, at doses up to 70 nmol, had no effect on airway calibre in either group of subjects. However, 3 h after its administration, 15-HETE reduced NSBR in the normal subjects (geometric mean methacholine PD40 Vp30 increased by 2.29-fold from baseline compared with a corresponding 1.14-fold increase after diluent, p less than 0.05). Similarly, 4 h after inhaled 15-HETE, the spontaneous increase in NSBR in the asthmatics was completely inhibited (geometric mean histamine PD40 Vp30 decreased significantly to 0.41-fold of baseline after diluent (p less than 0.01) compared with a 1.1-fold increase after 15-HETE, p less than 0.01). These data suggest 15-HETE may play an autacoid role in airway function.

Administration, Inhalation↗
PubMed1989

Inhaled lysine-aspirin as a bronchoprovocation procedure in aspirin-sensitive asthma: its repeatability, absence of a late-phase reaction, and the role of histamine.

Inhalation of an aerosolized solution of lysine-aspirin has previously been described as a safer technique than oral challenge with aspirin for the diagnosis of aspirin-sensitive asthma. We describe a modification of this method that involves inhalation of serially doubling incremental concentrations of lysine-aspirin by a standardized technique and allows construction of concentration-response curves. In 11 subjects with asthma, mean (SEM) age 48.2 (2.9) years, the geometric mean (range) provocation concentrations of histamine and lysine-aspirin required to produce a 20% decrease in FEV1 from baseline were 0.6 (0.04 to 3.2) and 48.3 (15.5 to 219) mg/ml, respectively. No relationship was found between these values. In seven of nine subjects investigated on two consecutive occasions, bronchoconstriction with lysine-aspirin was repeatable to within a single doubling concentration difference. Bronchoconstriction provoked by lysine-aspirin was more rapid than with oral aspirin and was not followed by any late asthmatic reaction or increase in nonspecific airway hyperresponsiveness. In six subjects, premedication with the selective H1 histamine-receptor antagonist, terfenadine, had no significant effect on bronchoconstriction provoked by inhaled lysine-aspirin, indicating little role for release of histamine in the response. We conclude that inhalation of lysine-aspirin may be used as a bronchoprovocation procedure for the diagnosis and investigation of aspirin-sensitive asthma.

Aerosols↗
PubMed1989

Monitoring in emergency medicine.

Clinical observation is the most valuable monitoring technique we have. Complexity and invasiveness of monitoring increases from prehospital care to Emergency Department, to Anaesthesia and Intensive Care. Many methods of monitoring have specific applications. Non-invasive blood pressure monitoring has no advantages over conventional cuff methods, other than freeing the hands of the operator. Non-invasive cardiac output measurement, transcutaneous oxygen and carbon dioxide measurement are unlikely to play a major role in the foreseeable future in the emergency setting. The most exciting development in recent years has been the widespread availability of pulse oximetry, which allows beat by beat analysis of haemoglobin oxygen saturation.

Emergency Medical Services↗
PubMed1989

Nedocromil sodium is more potent than sodium cromoglycate against AMP-induced bronchoconstriction in atopic asthmatic subjects.

Nedocromil sodium is a new chemical entity which shows similar properties to sodium cromoglycate (SCG) and in addition exhibits a preferential activity in stabilizing mucosal mast cells. We have compared the effect of inhalation of nebulized placebo, SCG and nedocromil sodium on the bronchoconstrictor response to inhaled adenosine monophosphate (AMP) in eight atopic asthmatic subjects aged 25 yr (range 21-32 yr). The geometric mean provocation doses of AMP required to produce a 20% decrease in FEV1 (PD20FEV1) and a 40% decrease in Vmax30 (PD40 Vmax30) following placebo were 4.9 (0.3-14.2) and 1.8 (0.1-8.4) mumol respectively. Prior inhalation of both SCG and nedocromil sodium significantly inhibited the bronchoconstrictor response to AMP with PD20FEV1s of 36.6 (4.0-132.7) and 134 (12.4-560), and PD40 Vmax30 values of 20.5 (1.4-110) and 101.6 (5-560) mumol respectively (P less than 0.001). Nedocromil sodium was 3.9 (FEV1) and 8.0 (Vmax30) times more potent than SCG (P less than 0.001). In conclusion, both drugs inhibit the bronchoconstrictor response to inhaled AMP, and nedocromil is at least 4-8 times more potent than SCG.

Adenosine Monophosphate↗
PubMed1989

The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma.

Selective histamine-H1 receptor antagonists inhibit adenosine 5'-monophosphate (AMP)-induced bronchoconstriction by greater than 80% when expressed as a percentage inhibition of the FEV1 time-response curve following inhalation of the provocation concentration of AMP required to produce a 20% decrease in FEV1 from baseline (PC20). To investigate this further we have determined that, in eight mild atopic asthmatic subjects, terfenadine (180 mg), administered 3 hr pre-challenge, increases the geometric mean PC20 for histamine from 0.4 (range 0.03-3) mg/ml after placebo, to 20.2 (range 0.6-64) mg/ml following active treatment (P less than 0.0001). For AMP, the PC20 increased from 9.3 (range 1.0-113.3) mg/ml after placebo, to 150.2 (range 32.1-1177.7) mg/ml with terfenadine (P less than 0.0001). This 16.2-fold (range, 5.5-47.9) displacement to the right of the AMP concentration-response curve by a selective histamine-H1 receptor antagonist emphasizes the central role of histamine in the airways response to this nucleotide.

Adult↗
PubMed1989

Interaction of inhaled LTC4 with histamine and PGD2 on airway caliber in asthma.

To investigate possible mediator interaction in asthma, the effect of inhaled leukotriene (LT) C4 on bronchoconstriction provoked by histamine and prostaglandin (PG) D2 was studied in nine asthmatic subjects. The provocation doses of histamine, PGD2, and LTC4 required to produce a 12.5% decrease in baseline forced expiratory volume in 1 s (FEV1, PD12.5) and to further this fall to 25% (PD25-12.5) were determined. On three subsequent occasions, subjects inhaled either the PD12.5 LTC4 plus vehicle or vehicle plus the PD25-12.5 of either histamine or PGD2, and FEV1 and maximal flow at 70% of vital capacity below total lung capacity after a forced partial expiratory maneuver (Vp30) followed for 45 min. From these results, predicted time-course curves for LTC4 with histamine and LTC4 with PGD2 were calculated. On two final occasions, airway caliber was followed for 45 min after inhalation of the PD12.5 LTC4 followed by the PD25-12.5 of either histamine or PGD2. During the first 9 min after LTC4-histamine and LTC4-PGD2, the decreases in airway caliber were greater than the calculated predicted response. This interaction, although small, was significant with LTC4-PGD2 for both FEV1 (P = 0.01) and Vp30 (P less than 0.05) and with LTC4-histamine for Vp30 (P less than 0.05) but not for FEV1 (P less than 0.05). We conclude that inhaled LTC4 interacts synergistically with histamine and PGD2 and that this effect, although small, may be a relevant interaction in asthma.

Administration, Inhalation↗
PubMed1989

The effect of oral terfenadine alone and in combination with flurbiprofen on the bronchoconstrictor response to inhaled adenosine 5'-monophosphate in nonatopic asthma.

Inhaled adenosine and adenosine 5'-monophosphate (AMP) cause bronchoconstriction in atopic and nonatopic asthmatics by a mechanism believed to involve histamine release from airway mast cells and an interaction with neural reflexes. In the present study, we have investigated the effect of oral terfenadine 180 mg, flurbiprofen 100 mg, and the drug combination on AMP-induced bronchoconstriction in eight nonatopic asthmatic subjects with a mean age of 53.8 +/- 5.6 yr. The provocation concentrations of histamine and AMP required to produce a 20% decrease in FEV1 (PC20) were determined to be 2.5 (range, 0.2 to 16.3) and 50.1 (range, 1.5 to 841) mg/ml, respectively, representing a potency difference of 17.8-fold on a molar basis. In subsequent time-course studies, the bronchoconstrictor response to inhalation of the PC20 histamine was suppressed completely by terfenadine and the drug combination, but unaffected by flurbiprofen. Terfenadine alone and flurbiprofen alone inhibited bronchoconstriction provoked by the PC20 AMP by 49.8 +/- 5.5% (p less than 0.01) and 31.9 +/- 7.9% (p less than 0.01), respectively, when areas under the FEV1 time curves were compared with placebo, the difference between the two treatments not being significant (p = 0.06). The drug combination inhibited the response to AMP by 60.0 +/- 8.3% (p less than 0.01), this being significantly greater than with flurbiprofen (p less than 0.01), but not with terfenadine alone. These data implicate both histamine and cyclooxygenase products in the bronchoconstrictor response to AMP.

Adenosine Monophosphate↗
PubMed1989

The influence of refractoriness to adenosine 5'-monophosphate on allergen-provoked bronchoconstriction in asthma.

Repeated bronchoprovocation with adenosine 5'-monophosphate (AMP) in atopic, nonasthmatic subjects produces a state of refractoriness to the nucleotide that may be due either to depletion of preformed mediators from airway mast cells or down-regulation of purinoceptors on the surface of these cells. To investigate this further, we compared the effect on immediate allergen-provoked bronchoconstriction of preceding repeated challenges with histamine and AMP in eight atopic, mildly asthmatic subjects. In three successive AMP concentration-response studies, the geometric mean PC20 AMP increased from 275.3 to 1154.3 (p less than 0.01) and 1976.7 (p less than 0.01) mg/ml, respectively, whereas no significant similar increase in PC20 occurred with repeated histamine challenges. Refractoriness to AMP was not associated with any significant decrease in airways responsiveness to histamine. When compared with the response after repeated provocation with inhaled histamine, repeated exposure of the airways to AMP potentiated, rather than inhibited, immediate allergen-induced bronchoconstriction by a mean 57 +/- 22.6% (p less than 0.05) when the data were expressed as the area under the FEV1-time response curve. The ability of airways that have been rendered less responsive to inhaled AMP to exhibit an increased response to allergen suggests that tachyphylaxis to AMP is unlikely to be caused by depletion of preformed mast cell-derived mediators such as histamine.

Adenosine Monophosphate↗
PubMed1989

Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5'-monophosphate.

In this randomized, double-blind, placebo controlled study, the effect of prior inhalation of nebulized sodium cromoglycate (SCG) (7.3 +/- 0.6 mg) and nedocromil sodium (NED) (7.5 +/- 0.6 mg) was observed on adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in 11 non-atopic asthmatic subjects. The geometric mean provocation doses of methacholine and AMP required to produce a 20% decrease in forced expiratory volume in one second (FEV1) (PD20FEV1) were 0.6 (0.1-18.8) and 5.1 (0.8-130.7) mumole respectively. The repeatability of the AMP challenge procedure for PD20FEV1 was within one doubling dose difference. SCG and NED, administered 30 min prior to bronchoprovocation with AMP, displaced the AMP dose-response curve to the right by 9.6 (1.5-41.6) (p less than 0.01) and 22.2 (3.7-89.1) (p less than 0.01)-fold, respectively, the difference between the two drugs being significant (p less than 0.05). There was a significant correlation (r = 0.7, p = 0.02) between the log dose ratios for PD20FEV1 for SCG and NED. We conclude that both SCG and NED protect against AMP-induced bronchoconstriction, NED being at least 2.3 (0.7-11.5)-fold more potent than SCG, and that they achieve this effect by a similar mechanism(s).

Adenosine Monophosphate↗