Heart rate (HR), blood pressure (BP), and MAPD at rest and during pacing with S2 = 200 ms Refer to Table 1 for exact cumulative doses during the infusion protocol and the free fraction of each drug in guinea pig plasma. Baseline data are represented as raw values. Data for doses 1 through 4 are represented as mean change from baseline. The vehicle reference for moxifloxacin and telithromycin is SBE-CD; the vehicle reference for erythromycin is sterile water.
Treatment | Baseline | Dose 1 | Dose 2 | Dose 3 | Dose 4 |
|---|---|---|---|---|---|
| Vehicle (SBE-CD) (n = 6) | |||||
| HR (beats/min) | 240 ± 7 | –11 ± 2 | –16 ± 2 | –22 ± 3 | –23 ± 1 |
| BP (mm Hg) | 46 ± 2 | 2 ± 1 | 0 ± 1 | –2 ± 1 | –2 ± 1 |
| MAPD90(rest) (ms) | 135 ± 3 | 10 ± 1 | 15 ± 1 | 19 ± 2 | 20 ± 2 |
| MAPD50(rest) (ms) | 113 ± 3 | 11 ± 1 | 17 ± 1 | 21 ± 1 | 23 ± 2 |
| MAPD90(200) (ms) | 123 ± 2 | 5 ± 1 | 9 ± 1 | 10 ± 1 | 11 ± 1 |
| MAPD50(200) (ms) | 102 ± 2 | 7 ± 1 | 10 ± 1 | 12 ± 1 | 13 ± 2 |
| Vehicle (sterile water) (n = 7) | |||||
| HR (beats/min) | 232 ± 6 | –7 ± 2 | –14 ± 5 | –20 ± 5 | –25 ± 6 |
| BP (mm Hg) | 40 ± 2 | 4 ± 2 | 2 ± 2 | 3 ± 2 | 4 ± 2 |
| MAPD90(rest) (ms) | 143 ± 3 | 9 ± 3 | 8 ± 2 | 17 ± 2 | 22 ± 3 |
| MAPD50(rest) (ms) | 117 ± 3 | 9 ± 3 | 10 ± 3 | 20 ± 2 | 27 ± 3 |
| MAPD90(200) (ms) | 127 ± 1 | 4 ± 1 | 6 ± 1 | 8 ± 1 | 11 ± 1 |
| MAPD50(200) (ms) | 103 ± 2 | 5 ± 1 | 8 ± 2 | 12 ± 2 | 17 ± 2 |
| Moxifloxacin (n = 6) | |||||
| HR (beats/min) | 245 ± 7 | –11 ± 4 | –14 ± 1 | –26 ± 3 | –67 ± 7* |
| BP (mm Hg) | 51 ± 2 | 1 ± 1 | –1 ± 1 | –3 ± 2 | –13 ± 3* |
| MAPD90(rest) (ms) | 138 ± 3 | 9 ± 1 | 14 ± 1 | 24 ± 1 | 59 ± 3* |
| MAPD50(rest) (ms) | 115 ± 2 | 11 ± 2 | 16 ± 2 | 24 ± 3 | 54 ± 4* |
| MAPD90(200) (ms) | 124 ± 1 | 6 ± 1 | 8 ± 1 | 13 ± 1 | 23 ± 2* |
| MAPD50(200) (ms) | 103 ± 2 | 7 ± 1 | 9 ± 2 | 14 ± 2 | 22 ± 3* |
| Free drug (μM) | 0.8 ± 0.1 | 3.1 ± 0.4 | 10.0 ± 1.3 | 41.0 ± 8.1 | |
| Erythromycin (n = 8) | |||||
| HR (beats/min) | 239 ± 6 | –8 ± 2 | –17 ± 4 | –38 ± 9 | –83 ± 9* |
| BP (mm Hg) | 44 ± 3 | 2 ± 1 | –1 ± 3 | –12 ± 3* | –26 ± 3* |
| MAPD90(rest) (ms) | 145 ± 3 | 5 ± 2 | 13 ± 3 | 29 ± 4 | 71 ± 8* |
| MAPD50(rest) (ms) | 125 ± 4 | 6 ± 2 | 13 ± 3 | 27 ± 4 | 48 ± 9* |
| MAPD90(200) (ms) | 133 ± 2 | 3 ± 1 | 7 ± 1 | 14 ± 2* | 22 ± 2* |
| MAPD50(200) (ms) | 115 ± 3 | 4 ± 1 | 7 ± 2 | 12 ± 2 | 8 ± 3* |
| Free drug (μM) | 0.8 ± 0.1 | 3.0 ± 0.2 | 13.9 ± 1.0 | 58.3 ± 4.9 | |
| Telithromycin (n = 7) | |||||
| HR (beats/min) | 231 ± 7 | –4 ± 4 | –12 ± 5 | –7 ± 4* | –20 ± 6 |
| BP (mm Hg) | 47 ± 3 | 6 ± 2 | 2 ± 1 | –1 ± 2 | –16 ± 4* |
| MAPD90(rest) (ms) | 144 ± 3 | 7 ± 2 | 8 ± 3 | 8 ± 4* | 14 ± 5* |
| MAPD50(rest) (ms) | 119 ± 2 | 13 ± 3 | 14 ± 3 | 11 ± 5 | 11 ± 4* |
| MAPD90(200) (ms) | 130 ± 1 | 7 ± 2 | 8 ± 2 | 4 ± 2 | 3 ± 2* |
| MAPD50(200) (ms) | 107 ± 1 | 11 ± 2 | 12 ± 2 | 8 ± 3 | 2 ± 2* |
| Free drug (μM) |
| 0.1 ± 0.01 | 0.4 ± 0.03 | 2.3 ± 0.4 | 7.9 ± 0.6 |
↵* Denotes significant difference from predose baseline compared with respective vehicle difference from predose baseline at each dose level within a given treatment, P < 0.05