Respiratory safety pharmacology: concurrent validation of volume, rate, time, flow and ratio variables in conscious male Sprague-Dawley rats.

This study compares basic respiratory variables (rate, tidal and minute volumes) with time-, flow- and ratio-derived parameters obtained using head-out plethysmography in rats following administration of reference drugs (isotonic saline, 2.0 mL/kg, IV; albuterol, 400 µg/kg, inhalation; methacholine, 136 µg/kg, IV; and remifentanil, 14 µg/kg, IV) to identify respiratory variables with superior sensitivity. Paired t-tests by block-period, and analysis of covariance (ANCOVA) with baseline as covariate and a posteriori pair-wise comparisons using Dunnett's test were used. Variations in respiratory parameters observed over time justify the use of a control group in any respiratory safety pharmacology study for inter-groups comparison. Handling-, and slumbering-, induced perturbations were minimal. The system was sensitive and specific to detect changes in respiratory variables related to pharmacologically-induced bronchodilation, bronchoconstriction and central respiratory depression. The standard variables (respiratory rate, tidal and minute volumes) confirmed to be the cornerstone of respiratory safety pharmacology to detect pharmacological changes. Flow-derived parameters appeared as highly valuable complement for interpretation of respiratory response, whereas time- and ratio-derived parameters presented limited added value during interpretation.

Respiratory safety pharmacology: positive control drug responses in Sprague-Dawley rats, Beagle dogs and cynomolgus monkeys.

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.

Validation of respiratory safety pharmacology models: conscious and anesthetized beagle dogs.

INTRODUCTION: 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. DISCUSSION: 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.

Comparison of three anesthetic protocols for intraduodenal drug administration using endoscopy in rhesus monkeys (Macaca mulatta).

The purpose of this study was to evaluate 3 anesthetic protocols for intraduodenal drug administration by endoscopy in rhesus monkeys (Macaca mulatta). Anesthesia was induced using intramuscular ketamine and midazolam, isoflurane (inhalant gas), or intravenous propofol in male and female rhesus monkeys. A noninvasive dosing line was placed in the duodenum by use of endoscopy, and 50% dextrose (3 ml/kg) was administered. Blood pressure, heart rate, body temperature, and reflexes (corneal, palpebral, pharyngeal) and myorelaxation (mandibular reflex and reaction to limb manipulation) were evaluated every 5 min. To estimate intestinal absorption, glycemia was evaluated prior to dextrose administration and at 2, 5, 10, 15, 20, 30, 45, and 60 min after dosing. All 3 protocols resulted in successful induction of anesthesia. Recovery from isoflurane and propofol was significantly faster than from ketamine-midazolam. Duration of the recovery period after isoflurane was less variable than with propofol, but isoflurane produced greater hypothermia. Isoflurane and propofol resulted in predictable glucose absorption after intraduodenal dextrose administration, whereas ketamine-midazolam led to an inconsistent increase in glycemia.