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Biomedical subjects

J A Hey

Publications and source records attributed to J A Hey.

78 records · Page 5Linked to original sources
PubMedDate not supplied

A simple non-invasive method to measure the cough reflex in dogs.

INTRODUCTION: This study describes a method to measure the cough reflex in dogs that is simple to perform, requires no surgical intervention and can be used to profile efficacy and side-effect liabilities of antitussive drugs. METHODS: Experiments were performed in propofol-anesthetized dogs in which cardiopulmonary functions were non-invasively monitored before and after the induction of cough produced by spraying 0.75 ml of distilled water into the trachea. RESULTS: The magnitude of the cough response, measured by the frequency and amplitude was not different for individual dogs performed with repeated trials on different days. Treatment with the opioid antitussive drug, torbutrol (0.055-0.0055 mg/kg, s.c.) inhibited the cough frequency but not the amplitude induced by the water challenge. Furthermore, side effects of torbutrol were identified as mild respiratory depression and an anesthetic-sparing effect with propofol. DISCUSSION: This method offers many distinct advantages to evaluate efficacy of antitussive drugs including the fact that no surgery is required, it takes only 15-20 min to complete an experiment, and it can be used to simultaneously profile antitussive and side effect liabilities of drugs developed for the treatment of cough.

Animals↗
PubMedDate not supplied

Comparative oral and topical decongestant effects of phenylpropanolamine and d-pseudoephedrine.

Nonselective adrenergic alpha-agonists such as phenylpropanolamine and d-pseudoephedrine are widely used as decongestants to treat nasal congestion associated with a variety of nasal diseases. Although the activity of these drugs is well established in clinical studies, a direct comparison of their nasal decongestant effect as determined by changes in nasal cavity dimensions and nasal architecture has not been studied. Using acoustic rhinometry, we evaluated the effects of these drugs on nasal cavity volume, minimum cross-sectional area (Amin), and the distance from the nosepiece to the Amin (Dmin) in a feline, pharmacological model of nasal congestion. Administration of topical compound 48/80 (1%), a mast cell histamine liberator, into the left nasal passageway decreased nasal volume by 66%, reduced Amin by 51%, and increased Dmin by 116%. The congestive responses to compound 48/80 (1%) were reproducible through six weeks. In a subset of cats, the nasal cavity volume effect of repetitive exposure to compound 48/80, given once every two weeks for six weeks, was not different from the nasal responses after the initial exposure to compound 48/80. Pretreatment with oral phenylpropanolamine (10 mg/kg) or oral d-pseudoephedrine (10 mg/kg) attenuated the nasal effects of compound 48/80, but were associated with a pronounced increase in systolic blood pressure of +51 and +82 mmHg, respectively. A similar decongestant profile was observed with phenylpropanolamine (1%) and d-pseudoephedrine (1%) when given topically. Topical phenylpropanolamine (1%) and d-pseudoephedrine (1%) 45 minutes after dosing increased blood pressure +44 and +17 mmHg, respectively, over control animals. We conclude that oral and topical phenylpropanolamine and d-pseudoephedrine display equieffective nasal decongestant activity and produce similar cardiovascular profiles characterized by significant increases in blood pressure.

Administration, Oral↗
PubMedDate not supplied

Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion.

We studied the pharmacological actions of combined histamine H1/H3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in nasal cavity volume produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7 cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 microL). We conclude that combined H1/H3 histamine receptor blockade enhances the efficacy of an H1 antagonist by conferring decongestant activity to the H1 antihistamine. We propose that the decongestant activity of combined H1/H3 blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.

Airway Resistance↗
PubMedDate not supplied

Changes in nasal resistance and nasal geometry using pressure and acoustic rhinometry in a feline model of nasal congestion.

This is the first report describing the use and pharmacological characterization of nasal patency by both pressure rhinometry and acoustic rhinometry (AcR) in an experimental cat model of nasal congestion. In pressure rhinometry studies, aerosolized compound 48/80 (0.1-3.0%), a mast cell liberator, increased nasal airway resistance (NAR) 1.2 +/- 0.6, 5.8 +/- 0.5, 8.6 +/- 1.1 and 7.9 +/- 1.5 cmH2O.L/minute, respectively. Increases in NAR produced by compound 48/80 were associated with a 395% increase in histamine concentration found in the nasal lavage fluid. Pretreatment with the alpha-adrenoreceptor agonist, phenylpropanolamine (PPA; 0.1-3.0 mg/kg, i.v.), and the NO synthetase inhibitor, NG-nitro-L-arginine (L-NAME; 10 mg/kg, i.v.) attenuated the increases in NAR produced by compound 48/80. The histamine H1 antagonist chlorpheniramine (1.0 mg/kg, i.v.) and the H2 antagonist, ranitidine (1.0 mg/kg, i.v.) had no decongestant activity. Also without decongestant activity were the muscarinic antagonist atropine, the cyclooxygenase inhibitor indomethacin, and the 5-HT blocker methysergide. Aerosolized histamine (0.1-1.0%) also produced a dose dependent increase in NAR. In studies using acoustic rhinometry (AcR), intranasal application of compound 48/80 (0.1-1.0%) elicited pronounced decreases in nasal cavity volumes and minimum cross-sectional area (Amin). Pretreatment with PPA (3 mg/kg, i.v. or 10 mg/kg, p.o.) attenuated the decreases in nasal volume and Amin. The effects of topical intranasal histamine (0.1-1.0%) on nasal geometry were similar to compound 48/80. We conclude that the cat is a useful model for evaluating the pharmacological actions of potential nasal decongestants. Furthermore, we also conclude that AcR is a useful method for noninvasive assessment of nasal patency in a preclinical setting.

Acoustics↗
PubMedDate not supplied

Intranasal application of the alpha2-adrenoceptor agonist BHT-920 produces decongestion in the cat.

The effect of alpha2-selective adrenoreceptor activation on nasal cavity dimension in an experimental model of congestion has not been defined. Presently, we used acoustic rhinometry to evaluate the decongestant activity of BHT-920, a selective alpha2-adrenergic agonist against nasal congestion produced by intranasal compound 48/80. Administration of the mast cell liberator compound 48/80 (1%) into a nasal passageway decreased ipsilateral volume and minimum cross-sectional area by 73 +/- 4% and 42 +/- 6%, respectively. The congestant effect of compound 48/80 was blocked by topical BHT-920 (0.3 and 1%) in a dose related manner. In addition, the decrease in minimum cross-sectional area produced by compound 48/80 was attenuated after topical BHT-920 treatment. As a comparison we also evaluated the topical decongestant activity effects of the alpha1-adrenergic agonist phenylephrine, and the nonselective alpha-agonist oxymetazoline. Both phenylephrine (0.1-1.0%) and oxymetazoline (0.01-0.3%) produced decongestion. The blood pressure effects of these three drugs also were evaluated. At doses of 0.3 and 1.0%, BHT-920 did not produce hypertension. In contrast, oxymetaZoline (0.01-0.1%) produced a transient hypertension that peaked at 15 minutes and fully recovered 45 minutes after administration. The hypertensive effect of phenylephrine at 0.3 and 1.0% lasted over 60 minutes. The present findings indicate that selective alpha2-agonists may produce decongestant activity with an improved cardiovascular profile compared with current sympathomimetic drugs such as phenylephrine.

Administration, Intranasal↗