Validation of respiratory safety pharmacology models: conscious and anesthetized beagle dogs.
BACKGROUND
Installation, operation and performance qualifications were performed on a test system for respiratory monitoring.


METHODS
For performance qualification, conscious dogs received saline (0.2 mL/kg, iv, n=12), albuterol (100 microg/kg, inhalation, n=5), methacholine (2.0 and 8.0 microg/kg, iv, n=8) and remifentanil (4.0 microg/kg, iv, n=7). Following anesthesia with propofol infusion, dogs received saline (iv, n=15), albuterol (100 microg/kg, inhalation, n=8), methacholine (8.0 microg/kg, iv, n=8), remifentanil (4.0 microg/kg, iv, n=7), and cholecystokinine tetrapeptide (CCK-4) (10 microg/kg, iv, n=7) and were exposed to hypoxic gas mixture (10% oxygen) (n=12).


RESULTS
Saline had no significant respiratory effect. Albuterol increased tidal volume (TV) (+28%, p<0.05) and minute ventilation (MV) (+96%, p<0.01) in conscious dogs. In anesthetized dogs, MV was significantly increased (+23%, p<0.05) but the difference was not statistically significant for TV and respiratory rate (RR). Methacholine at 2.0 microg/kg increased MV (+45%, p<0.01) in conscious animals while 8.0 microg/kg increased RR (+66%, p<0.01), TV (+24%, p<0.05) and MV (+88%, p<0.05). In anesthetized dogs, methacholine increased RR (+51%, p<0.05), MV (+34%, p<0.05), lung elastance (+36.9%, p<0.01), and resistance (+45.8%, p<0.01). Remifentanil decreased MV in conscious dogs (-68%, p<0.01) while transient apnea was observed in all anesthetized dogs. CCK-4 increased RR (+328%, p<0.01) and MV (+127%, p<0.05) and decreased TV (-58%, p<0.01). Exposure to hypoxic gas mixture increased MV and RR (p<0.01). Baseline MV was lower (p<0.05) in anesthetized than in conscious dogs.


CONCLUSIONS
Arterial blood gas values, particularly SaO(2), presented a limited sensitivity to detect any ventilation disturbance, but allowed confirmation of both ventilatory compensatory phenomenon (when present) and initial pharmacologic drug effect. These results also highlight the greater sensitivity of the conscious model when compared to anesthetized dogs.
Authier
Simon
S
LAB Research Inc., 445 Armand Frappier, Laval, Canada. authiers@labresearch.com
Legaspi
Margarita
M
Gauvin
Dominique
D
Chaurand
Fernando
F
Fournier
Sebastien
S
Troncy
Eric
E
D000420:Albuterol / Q000494:pharmacology; D000758:Anesthesia / Q000009:adverse effects*; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D000077208:Remifentanil; D015203:Reproducibility of Results; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000139:chemically induced*; D013758:Tetragastrin / Q000494:pharmacology; D013997:Time Factors
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D006993:Hypnotics and Sedatives; D010880:Piperidines; D013758:Tetragastrin; D016210:Methacholine Chloride; D000077208:Remifentanil; D000420:Albuterol