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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 325 records · Page 18Linked to original sources
PubMed1978

Comparative responses of tracheal spirals and parenchymal strips to histamine and carbachol in vitro.

The responses of isolated guinea pig tracheal spirals and parenchymal strips to histamine and carbachol were compared. The parenchymal strip, a 1.5 x 1.5 x 20-mm strip cut from the periphery of the lung, constricted at a lower dose and had a larger maximal response to histamine than to carbachol. In contrast, the response of the tracheal spiral to equimolar doses of histamine or carbachol was the same. The responsiveness of both muscle strips to histamine was decreased by treatment with the H1 receptor antagonist mepyramine (0.1 micrometer), and the response to carbachol was blocked by treatment with atropine (0.1 micrometer). Indomethacin (3 micrometer), cimetidine (1 micrometer), propranolol (10 micrometer), and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (4 micrometer) did not alter the differential response of the two strips to histamine and carbachol. The differential response of parenchymal strips with many, few, or no conducting airways and blood vessels was identical, suggesting that the contractile element is alveolar duct smooth muscle or alveolar contractile elements. This differential pharmacologic response in vitro is consistent with the in vivo observation that histamine causes more peripheral airway constriction than does acetylcholine.

Acetylcholine↗
PubMed1977

Canine pulmonary response to aerosol histamine: direct versus vagal effects.

Histamine, a potent bronchoconstrictor, has been shown to produce bronchoconstriction both directly and by a vagal reflex. To define the relative roles of direct and reflex effects, we studied the pulmonary response of dogs exposed to increasing doses of aerosol histamine before and after vagal blockade or vagotomy. In addition, the relative contributions of aerodynamically large and small airways to the overall response were determined by the measurement of pulmonary resistance on sulfur hexafluoride-oxygen and helium-oxygen mixtures. Histamine aerosol caused a similar dose-dependent increase in resistance of aerodynamically large and small airways and fall in dynamic compliance. The dose-response relationships were not consistently altered by either vagal blockade or vagotomy. The following variables were found not to alter the experimental results: anesthesia, type of aerosol generator, control of breathing during aerosol exposure, spontaneous breathing vs. controlled ventilation after aerosol exposure, cold block of vagi vs. vagotomy. We conclude that 1) histamine aerosol in dogs causes a local dose-dependent constriction of bronchial smooth muscle, and 2) the vagus nerve played a relatively minor role in the pulmonary response to aerosol histamine in these experiments.

Aerosols↗
PubMed1976

Validation of an automated determination of pulmonary resistance by electrical subtraction.

An analog computer to determine dynamic pulmonary compliance (C) and pulmonary resistance (R) on a breath-by-breath basis was tested in guinea pigs and dogs. C was determined by dividing volume by transpulmonary pressure at instants of zero flow. R was determined by the method of electrical subtraction at predetermined flows. In both species the computer outputs and the results of direct analysis were in close agreement. In guinea pigs, the device reliably followed the rapid three- to fourfold changes in C and R resulting from histamine infusion. In unanesthetized dogs, the dispersion and mean values of C and R were similar by the two methods.

Airway Resistance↗
PubMed1976

Distribution of pulmonary resistance: effects of gas density, viscosity, and flow rate.

Theoretical predictions of the distribution of inspiratory viscous pressure loss were made for canine and human pulmonary airways for gases with varying density and viscosity at different pulmonary flow rates. We predicted that in canine or human airways when tracheal flow was turbulent, most of the total calculated pressure loss would be in the first few branchings of the bronchial tree; however when tracheal flow was nearly laminar inspiratory pressure loss would be spread more uniformly along the airways. To test these predictions an airway catheter was used to partition total pulmonary resistance (RL) in five anesthetized dogs. On air the catheter was positioned such that the mean resistance mouthward of the catheter tip (Rc) at a flow of 0.5 1/s was 63% of RL. At the same catheter position Rc was 87% of RL when the dogs were breathing a mixture of 80% sulfur hexafluoride-20% oxygen and resistance was determined at 1.0 1/s. Rc was 50% of RL when the dogs were breathing a mixture of 80% helium-20% oxygen and resistance was determined at 0.25 1/s. Thus altering gas physical properties and flow rates changed the distribution of pulmonary resistance as predicted.

Airway Resistance↗
PubMed1976

Localization of airway constriction using gases of varying density and viscosity.

The relationship between the major site of airway constriction and change in total pulmonary resistance while breathing gases of varying density and viscosity was studied in five anesthetized dogs pretreated with atropine. Using an airway catheter, central and peripheral components of pulmonary resistance were measured by forced oscillation. Total pulmonary resistance was measured at 0.5 1/s with lungs air-filled, at 0.25 1/s with the lungs filled with 80% helium-20% oxygen (RL-He), and at 1.0 1/s with 80% sulfur hexafluoride-20% oxygen (RL-SF6). Intravenous histamine infusion resulted in a predominantly peripheral resistance increase as determined by the airway catheter and a much larger percentage increase in RL-He than in RL-SF6. Tracheal banding produced a purely central resistance increase and a greater change in RL-SF6 than in FL-He. These results support theoretical predictions that the predominant site of airways constriction can be determined without on airway catheter by comparing relative changes in total pulmonary resistance using different flow regimes.

Airway Resistance↗
PubMed1976

Physiologic basis and interpretation of common indices of respiratory mechanical function.

Tests of pulmonary mechanical function may be used in determining the prominent site of pulmonary reaction to intervention. Responses may be localized from a knowledge of changes in lung resistance and compliance. A peripheral airway or parenchymal response is characterized by a decrease in lung compliance. A central airway reaction is characterized by an increase in pulmonary resistance. In mixed reactions both parameters may change. In this communication some of the physiologic determinants of pulmonary resistance and compliance are discussed and examples of localized responses given.

Airway Resistance↗
PubMed1975

Atropine modification of the pulmonary effects of chemical mediators in the guinea pig.

The actions of histamine, slow-reacting substance of anaphylaxis (SRS-A), Bradykinin, and prostaglandin F2alpha on pulmonary mechanics in the unanesthetized guinea pig were separated into direct and secondary cholinergic airway effects on the basis of alteration of their actions by atropine. The effects of SRS-A (500 and 3,000 units/kg) on compliance were not significantly altered by atropine, while the effects of bradykinin (3.0 and 30 mug/kg) on compliance were decreased only at 3.0 mug/kg by atropine. The effects of both of these agents on resistance were decreased by atropine, suggesting that SRS-A and bradykinin act directly on the peripheral airways and by secondary cholinergic mechanisms on both central and peripheral airways. The effects of histamine (3.0 mug/kg) on both compliance and resistance were abolished by atropine, suggesting an action mainly via cholinergic pathways; while at a higher dose, 9.0 mug/kg, there was both a direct and a cholinergic action. The effects observed 20 sec after the administration of prostaglandin F2alpha (PGF2alpha) were not altered by atropine suggesting a direct action on airways, while both the compliance and resistance changes observed 3-8 min after PGF2alpha were abolished by atropine suggesting that the latter effects were mediated solely by cholinergic mechanisms

Airway Resistance↗
PubMed1975

Pulmonary response to antigen infusion in the sensitized guinea pig: modification by atropine.

Alterations in pulmonary conductance, dynamic compliance, respiratory frequency, minute volume, mean arterial pressure, pulse rate, relaxation volume-to-dry weight ratio, and wet-to-dry weight ratio resulting from antigen infusion in sensitized guinea pigs was examined with and without atropine treatment. In untreated animals 3 min after antigen infusion there were significant decreases in dynamic compliance and pulmonary conductance with an increase in relaxation volume-to-dry weight ratio while other parameters were not altered. In atropine-treated animals antigen infusion resulted in a decreased dynamic compliance and an increased relaxation volume-to-dry weight ratio but no significant change in pulmonary conductance. This suggests that the alterations in large and central airway tone resulting from antigen infusion are mediated predominantly by secondary cholinergic mechanisms while peripheral airway effects are mainly noncholinergic.

Animals↗
PubMed1974

Effects of intravenous administration of slow-reacting substance of anaphylaxis, histamine, bradykinin, and prostaglandin F2alpha on pulmonary mechanics in the guinea pig.

The effects of intravenous administration of a purified preparation of slow-reacting substance of anaphylaxis (SRS-A), histamine, bradykinin, and prostaglandin F(2alpha) (PGF(2alpha)) on the mechanics of respiration were assessed in the unanesthetized guinea pig. Geometrically increasing doses of SRS-A resulted in graded decreases in average pulmonary compliance, with only modest increases in average pulmonary resistance. A dose with apparent maximal effects. 3,000 U/kg, resulted in a decrease of 49+/-7% of compliance below control values, with an increase in resistance of 24+/-8% above control. Intravenous administration of geometrically increasing amounts of histamine, bradykinin, and prostaglandin F(2alpha) also resulted in decreased compliance; but in each case this was accompanied by a marked increase in respiratory resistance. A decrease of compliance of approximately 50%, induced by intravenous histamine, bradykinin, or PGF(2alpha), was accompanied by an increase of 60-140% in resistance. Thus, intravenously administered SRS-A alters pulmonary mechanics with a more peripheral effect than any of the other agents tested.

Airway Resistance↗
PubMedDate not supplied

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Administration, Inhalation↗
PubMedDate not supplied

Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Administration, Inhalation↗
PubMedDate not supplied

Mutations in the human 5-lipoxygenase gene.

Our data demonstrate the presence of a naturally occurring family of alleles in the core promoter of the 5-LO gene, which is characterized by the deletion or addition of consensus Sp1 (-GGGCGG) and Egr-1 (-GCGGGGGCG-) binding motifs. Each of the variant alleles can bind Sp1 and Egr-1 protein, as indicated by EMSA and supershift analysis with nuclear extracts. In addition, preliminary data from CAT reporter assays indicate that these alleles are less effective than the wild-type allele in initiating 5-LO gene expression. Whether patients harboring the various alleles identified herein have different capacities to transcribe the 5-LO gene and the importance of such potential regulation to the clinical expression of 5-LO have yet to be determined.

5' Untranslated Regions↗
PubMedDate not supplied

The biology of 5-lipoxygenase: function, structure, and regulatory mechanisms.

5-Lipoxygenase (5-LO) catalyzes the two-step conversion of arachidonic acid to leukotriene A4 (LTA4). The first step consists of the oxidation of arachidonic acid to the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), and the second step is the dehydration of 5-HPETE to form LTA4. These events are the first committed reactions leading to the synthesis of all leukotrienes and play a critical role in controlling leukotriene production. 5-LO has evolved many complex structural features and regulatory mechanisms to allow it to fulfill this highly specialized role. The biology of 5-LO is reviewed here with an emphasis on enzymatic function, protein and gene structure, essential cofactors, and the many regulatory mechanisms controlling its expression.

Adenosine Triphosphate↗
PubMedDate not supplied

Asthma therapy with agents preventing leukotriene synthesis or action.

Elucidation of the biochemistry of leukotriene production and the pharmacology of its actions has led to the development of a number of therapeutic agents shown to be of value in the treatment of asthma. These agents either prevent the synthesis of the leukotrienes, by preventing the action of the 5-lipoxygenase-activating protein or the catalytic action of the 5-lipoxygenase, or by inhibiting the action of leukotrienes at the CysLT1 receptor. Numerous clinical trials in exercise-induced asthma, allergen-induced asthma, aspirin-induced asthma, and spontaneously occurring asthmatic episodes have indicated that these agents are safe and effective asthma treatments.

Acetates↗
PubMedDate not supplied

Genetic determinants of 5-lipoxygenase transcription.

BACKGROUND: 5 Lipoxygenase (5-LO) is a critical enzyme in the production of the leukotrienes. We have identified a series of mutations in the 5-LO gene that modify gene transcription. These mutations consist of addition of an Sp-1 binding motif (-GGGCGG-) or deletion of one or two Sp-1 binding motifs in the 5-LO core promoter. METHODS: Mutant forms of the 5-LO core promoter were placed in a chloramphenicol acetyl transferase (CAT) reporter construct using either HeLa or SL-2 cells. RESULTS: In HeLa cells all of the mutant forms are less effective in driving CAT reporter activity than the wild-type promoter. In SL-2 cells the construct containing the addition mutation was more effective in driving CAT reporter activity, while the constructs containing the deletion mutations were less effective. CONCLUSIONS: These data indicate that naturally occurring mutations in the 5-LO core promoter modify gene transcription in vitro.

Arachidonate 5-Lipoxygenase↗