Garfield G. Mingo

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 α-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 μL). 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.

Antitussive Action of Antihistamines Is Independent of Sedative and Ventilation Activity in the Guinea Pig

We studied the oral actions of antihistamines from six chemical classes, namely: the ethanolamines (ENA, diphenhydramine and clemastine); ethylenediamines (EDA, pyrilamine and tripelennamine); piperidines (PPD, terfenadine and astemizole); piperazines (PPZ, hydroxyzine and cetirizine); phenothiazines (PTZ, promethazine), and the alkylamines (ALA, chlorpheniramine and bromopheniramine) on cough reflexes, pentobarbital-induced sedation and minute ventilation in the conscious guinea pig. Antihistamines of the ENA class had minimal effects on capsaicin-induced cough although both diphenhydramine (30 and 100 mg/kg p.o.) and clemastine (30 and 100 mg/kg p.o.) increased sedation time (ST). The PPZ class demonstrated both antitussive and sedating activity. The minimum effective oral antitussive dose (MED) of cetirizine and hydroxyzine was 30 and 10 mg/kg, respectively. The EDA did not exhibit antitussive activity. Tripelennamine (10, 30 and 100 mg/kg p.o.) but not pyrilamine enhanced ST. The MED for the PTZ, promethazine, was 10 mg/kg, and at 100 mg/kg promethazine increased ST. The ALA group displayed antitussive activity but only chlorpheniramine (10 mg/kg p.o.) had any effects on ST. The MED for chlorpheniramine and bromopheniramine was 3 and 10 mg/kg p.o., respectively. The PPD antihistamines, namely terfenadine and astemizole, inhibited cough (MED 30 and 10 mg/kg p.o.) without sedative effects. Of the antihistamines tested only promethazine (100 mg/kg p.o.) depressed ventilation responses; however, this dose of promethazine was associated with adverse behavioral effects. The present findings indicate that the antitussive actions of antihistamines are not directly related to histamine H1-receptor blockade because several antihistamines did not antagonize capsaicin-induced cough. In addition, the antitussive actions of antihistamines are independent of their sedative or ventilation effects.

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

Nonselective adrenergic α-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.

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 α-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.

Respiratory effects of baclofen and 3-aminopropylphosphinic acid in guinea-pigs.

1 The effects of the GABAB receptor agonists, baclofen and 3‐aminopropylphosphinic acid (3‐APPi) given by the subcutaneous or intracerebroventricular (i.c.v.) route were examined on minute ventilation (), tidal volume (VT) and respiratory rate (f) due to room air and carbon dioxide (CO2)‐enriched gas hyperventilation in conscious guinea‐pigs. 2 Baclofen (0.3–10 mg kg−1, s.c.) produced a dose‐dependent inhibition of and f due to room air and CO2 inhalation. The maximum inhibition of room air breathing was 85% ± 3 and f was 74% ± 3 at 10 mg kg−1, s.c. The maximum effects on CO2‐induced hyperventilation were 68% ± 9 and 51% ± 6, for and f respectively. Only the highest dose of baclofen studied (10 mg kg−1) produced a significant inhibition of VT due to room air breathing (46% ± 6) and CO2 breathing (38% ± 11). 3 3‐aPPi (0.3–100 mg kg−1, s.c.) did not affect , VT or f due to room air breathing or CO2 inhalation at any dose tested. Also, i.c.v. administration of 3‐aPPi (100 μg) did not affect ventilatory responses due to room air breathing or CO2 inhalation. 4 Pretreatment with the GABAB antagonist, CGP 35348 3‐aminopropyl‐(diethoxymethyl) phosphinic acid (3–30 mg kg−1, s.c.) blocked the respiratory depressant effects of baclofen (3 mg kg−1, s.c.) in a dose‐related fashion. 5 Intracerebroventricular (i.c.v.) administration of CGP 35348 (50 μg) blocked the respiratory depressant effects of baclofen. CGP 35348 given alone either i.c.v. or s.c. had no effects on respiration due to room air or CO2 inhalation. 6 Pretreatment with either the GABAA antagonist bicuculline (30 mg kg−1, s.c.) or the opioid antagonist, naloxone (1 mg kg−1, s.c.) had no effect on the respiratory depressant action of baclofen (3 mg kg−1, s.c). 7 These results show that baclofen inhibits ventilation due to room air breathing, and attenuates the hyperventilation response to CO2 inhalation. The peripherally acting GABAB agonist, 3‐APPi had no effect on ventilation. These findings demonstrate that the respiratory depressant effects of baclofen are due to activation of CNS GABAB receptors and indicates that only GABAB receptor agonists that penetrate into the CNS may cause respiratory depression.

Intranasal application of the α2-adrenoceptor agonist BHT-920 produces decongestion in the cat

The effect of α2-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 α2-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 α1-adrenergic agonist phenylephrine, and the nonselective α-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 α2-agonists may produce decongestant activity with an improved cardiovascular profile compared with current sympathomimetic drugs such as phenylephrine.

Evan's blue dye blocks capsaicin-induced cough and bronchospasm in the guinea pig

The influence of Evans blue dye on capsaicin-induced bronchoconstrictor and cough responses was investigated in the guinea pig. Evans blue (30 mg kg-1 i.v.) pretreatment shifted the bronchoconstrictor dose-response to capsaicin (0.3-100 micrograms kg-1 i.v.) to the right by 10-fold, but had no effect on the bronchospasm elicited by neurokinin A (0.3-10 micrograms kg-1 i.v.). Evans blue (0.3-30 mg kg-1 s.c.) also inhibited capsaicin-induced cough in a dose-dependent manner. Evans blue blocked capsaicin responses by the intravenous, subcutaneous, or inhaled routes of administration. We conclude bronchoconstrictor responses and cough in vivo.

Loratadine and montelukast administered in combination produce decongestion in an experimental feline model of nasal congestion.

Background Histamine and leukotrienes act to exert numerous local and systemic effects that contribute to the pathophysiology of allergic rhinitis. The aim of these experiments was to evaluate the nasal decongestant effects of loratadine and montelukast alone and in combination in a feline model of nasal congestion. We also studied the decongestant actions of the alpha-agonist adrenergic agonist D-pseudoephedrine with and without desloratadine. Methods Acoustic rhinometry was used to determine nasal cavity dimensions after intranasal compound 48/80. Cats were given D-pseudoephedrine (0.3 mg/kg) alone or in combination with desloratadine (5 mg/kg) 1 hour before nasal provocation with compound 48/80 (1%, 75 microliters) to either the left or right nasal passageway. Using a similar design, the nasal decongestant effects of montelukast (1 mg/kg) and loratadine (10 mg/kg) were studied alone and in combination. Results The addition of desloratadine to D-pseudoephedrine did not improve decongestant efficacy compared with each drug given individually. In contrast, when montelukast (1 mg/kg) was given in combination with loratadine (10 mg/kg), the decongestant activity was greater than when these drugs were administered separately. Sixty minutes after compound 48/80 provocation the nasal cavity volume ratio (volume ratio of the compound 48/80 treated/untreated nasal passageway) for the control, montelukast alone, loratadine alone, and the montelukast plus loratadine–treated groups were 0.20 ± 0.03, 0.24 ± 0.01, 0.28 ± 0.03, and 0.50 ± 0.03. Conclusion Concomitant montelukast plus loratadine produces a greater degree of nasal decongestion compared with montelukast or loratadine alone in an experimental model of nasal congestion.

Alpha-2c-adrenergic receptors contribute to basal nasal patency in the anesthetized cat.

Background: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that α-adrenergic (both α1 and α2) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective α2c-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. Methods: Using acoustic rhinometry, we studied the activity of the selective α2c-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective α2-antagonist yohimbine and the nonselective α1-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. Results: JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective α1-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. Conclusions: The present set of experiments indicates that both α1- and α2-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, α2c-receptors may play a significant role in the sympathetic control of upper airway function.

Effects of an α2-Adrenoceptor Agonist in Nasal Mucosa

arteries and arterioles (resistance vessels), abundant arteriovenous anastomoses, and a subepithelial and periglandular capillary network (exchange vessels), which drain into collecting veins and large venous sinusoids (capacitance vessels). Although the nasal vasculature is under nervous and reflex control receiving innervation from sympathetic, parasympathetic and non-myelinated sensory nerves, the dominant motor supply is sympathetic. When stimulated, the sympathetic nerves release postganglionic transmitters, such as norepinephrine, that bind to a1and a2-adrenoceptors in the vasculature resulting in vasoconstriction. Nasal congestion, one of the symptoms of rhinitis, is induced by an increased blood flow leading to the filling of venous sinusoids with vascular congestion, swelling of the inferior turbinates and obstruction of nasal airflow. Adrenoceptor-agonists such as the selective a1-adrenoceptor agonist phenylephrine and the non-selective a-adrenoceptor agonist oxymetazoline constrict vessels and decrease the blood flow in the nasal mucosa. However, these agonists also have the potential to increase significantly the blood pressure leading to cardiovascular liabilities such as hypertension and stroke. In the present study, we evaluate the effects of the selective a2-adrenoceptor agonist BHT-920 in different in vitro nasal mucosal contractile bioassays [1], and we characterize the decongestant activity profile of the BHT-920 in a model of nasal congestion using acoustic rhinometry [2]. Nasal mucosae were removed from dog, pig and human and mucosal strips were placed in organ chambers filled with Krebs buffer, maintained at 37°C and aerated with 95% O2 – 5% CO2, and attached to force transducers for recording of isometric tension. Both a1and a2-adrenoceptor agonists dose-dependently contracted nasal mucosa in these different species indicating that a1and a2-adrenoceptors are present in nasal mucosae and modulate nasal mucosa vascular tone. Histological studies were performed in pig to identify the contribution of arteries and veins to the a1and a2adrenoceptor-mediated contractions. Tissues in organ baths were first challenged with 10 M phenylephrine or 10 M BHT-920. Then tissues were cut from the baths at the contraction peak and put into formalin. Formalin-fixed tissues were processed and paraffin embedded. Paraffin embedded tissues were sliced to 5mm and stained with H & E stain. We found that BHT-920 preferentially contracted the veins while phenylephrine induced contraction in both arteries and veins. In another set of experiments, pig nasal mucosa were embedded in low melt agarose, then cut into slices placed in tissue culture dish and incubated at 37°C overnight with 95% O2 – 5% CO2. Tissues were challenged with the non-selective aadrenoceptor agonist epinephrine, phenylephrine or BHT920. Tissue image was recorded and vascular size area analysis performed with Image J Software. Real time vessel contraction was evaluated as a percent of area decrease. We found that a2-adrenoceptor agonist preferentially contract veins while a1-adrenoceptor-agonist appears to preferentially act on the arteries of pig nasal mucosa. Histology study also demonstrated that sinusoids in pig nasal mucosa comprise the largest volume of blood. The decongestant activities of the a1-adrenoceptor agonist phenylephrine and the a2-adrenoceptor agonist BHT-920 against nasal congestion were evaluated by using the acoustic rhinometry technique in cat. Non-invasive measurements of nasal cross-sectional area and nasal volume made were performed. Area-distance curves provided estimates of crossSHORT COMMUNICATION