Table 4.
Effects of various antimalarial drugs on rabbit heart ventricular wedge preparations in comparison with those of dofetilidea
| Drug and concn | QT (ms) at: |
Tp-e (ms) at 2,000 ms | Endo APD90 (ms) at 2,000 ms | QRS (ms) at 2,000 ms | TdP risk score | |
|---|---|---|---|---|---|---|
| 2,000 ms | 1,000 ms | |||||
| DHA | ||||||
| Control | 314.8 ± 12.7 | 275.2 ± 7.7 | 59.0 ± 4.0 | 257.7 ± 14.2 | 37.6 ± 2.2 | 0.0 ± 0.0 |
| 1 μM | 315.8 ± 14.5 | 273.4 ± 7.6 | 58.8 ± 4.1 | 257.0 ± 14.2 | 37.4 ± 2.2 | 0.0 ± 0.0 |
| 3 μM | 315.0 ± 14.8 | 276.8 ± 7.9 | 58.6 ± 4.1 | 260 ± 14.5 | 37.4 ± 2.2 | 0 0.0 ± 0.0 |
| 10 μM | 317.2 ± 12.3 | 271.2 ± 8.3 | 57.6 ± 3.8 | 260.2 ± 14.4 | 37.4 ± 2.4 | −0.2 ± 0.2 |
| 30 μM | 307.0 ± 8.7 | 268.8 ± 5.4 | 56.6 ± 3.3 | 257.9 ± 13.1 | 37.6 ± 2.5 | −0.4 ± 0.2 |
| 100 μM | 300.6 ± 7.6** | 266.8 ± 5.4** | 51.6 ± 2.1* | 251.5 ± 9.1 | 37.6 ± 2.2 | −1.2 ± 0.4** |
| PQP | ||||||
| Control | 299.2 ± 10.3 | 270.8 ± 6.8 | 57.2 ± 3.9 | 260.2 ± 13.5 | 39.4 ± 2.4 | 0.0 ± 0.0 |
| 0.03 μM | 304.6 ± 11.4 | 271.0 ± 8.3 | 57.8 ± 4.0 | 267.0 ± 13.5 | 39.8 ± 2.3 | 0.0 ± 0.0 |
| 0.1 μM | 313.2 ± 10.9* | 276.2 ± 6.8 | 60.2 ± 3.4 | 275 ± 12.4* | 39.8 ± 2.3 | 0.0 ± 0.0 |
| 0.3 μM | 313.6 ± 9.6* | 277.4 ± 7.1** | 62.8 ± 2.6* | 281.4 ± 16.0** | 40.0 ± 2.2 | 0.2 ± 0.2 |
| 1 μM | 326.6 ± 12.7* | 282.6 ± 6.8** | 68.6 ± 2.9* | 287.6 ± 13.3** | 39.8 ± 2.3 | 1.0 ± 0.4 |
| 3 μM | 335.2 ± 12.8** | 283.8 ± 6.9*** | 75.0 ± 3.6* | 290.7 ± 17.2*** | 39.4 ± 2.4 | 1.8 ± 0.3* |
| DHA (2.4 μM) + PQP | ||||||
| Control | 318 ± 15 | 279 ± 8 | 55.4 ± 4.3 | 272 ± 16 | 38.0 ± 1.8 | 0.0 ± 0.0 |
| 0.03 μM | 328 ± 13* | 286 ± 8 | 56.2 ± 4.2 | 277 ± 15 | 38.2 ± 1.5 | 0.0 ± 0.0 |
| 0.1 μM | 330 ± 12 * | 287 ± 7 | 57.2 ± 4.4 | 281 ± 16 | 38.0 ± 1.7 | 0.0 ± 0.0 |
| 0.3 μM | 336 ± 14** | 288 ± 8 | 58.8 ± 4.8 | 283 ± 16 | 38.2 ± 1.9 | 0.0 ± 0.0 |
| 1 μM | 338 ± 14** | 289 ± 7 | 60.0 ± 4.9 | 287 ± 15 | 38 ± 1.7 | 0.0 ± 0.0 |
| 3 μM | 347 ± 19*** | 295 ± 8* | 61.8 ± 3.6*** | 293 ± 17 | 38.2 ± 2.0 | 0.4 ± 0.2 |
| 10 μM | 334 ± 21*** | 286 ± 9 | 0.3 ± 5.6*** | 283 + 21 | 38.5 ± 2.2 | 0.4 ± 0.4 |
| DHA (7.2 μM) + PQP | ||||||
| Control | 290.6 ± 13.7 | 266.2 ± 9.3 | 54.8 ± 6.4 | 252.4 ± 15.3 | 36.6 ± 1.6 | 0.0 ± 0.0 |
| 0.03 μM | 293.6 ± 15.5 | 266.2 ± 9.2 | 55.6 ± 6.5 | 254.7 ± 15.3 | 37.0 ± 1.7 | 0.0 ± 0.0 |
| 0.1 μM | 293.8 ± 13.2 | 266.4 ± 8.9 | 55.4 ± 6.2 | 253.0 ± 13.8 | 37.0 ± 1.8 | 0.0 ± 0.0 |
| 0.3 μM | 294.8 ± 14.5 | 267.4 ± 8.2 | 57.0 ± 6.0 | 251.3 ± 14.8 | 37.0 ± 1.8 | 0.0 ± 0.0 |
| 1 μM | 304.6 ± 15.6** | 269.8 ± 8.3 | 58.2 ± 6.1 | 259.8 ± 14.4 | 36.8 ± 1.5 | 0.0 ± 0.0 |
| 3 μM | 306.2 ± 13.7*** | 276.4 ± 7.4* | 57.0 ± 7.0 | 262.4 ± 14.1 | 36.4 ± 1.3 | 0.0 ± 0.0 |
| Lumefantrine | ||||||
| Control | 280.4 ± 12.0 | 249.8 ± 11.0 | 50.2 ± 3.4 | 236.9 ± 19.0 | 36.0 ± 1.6 | 0.0 ± 0.0 |
| 0.3 μM | 292.0 ± 14.0 | 260.8 ± 11.2* | 51.2 ± 3.4 | 245.2 ± 21.5 | 36.0 ± 1.8 | 0.0 ± 0.0 |
| 1 μM | 295.0 ± 15.5 | 264.2 ± 10.6* | 51.6 ± 3.6 | 247.5 ± 21.2 | 36.0 ± 1.6 | 0.0 ± 0.0 |
| 3 μM | 297.2 ± 16.2* | 265.2 ± 10.8** | 52.0 ± 3.8 | 248.6 ± 22.2 | 35.8 ± 1.6 | 0.0 ± 0.0 |
| 10 μM | 311.8 ± 21.8* | 265.6 ± 11.3** | 54.2 ± 5.2 | 263.6 ± 25.4* | 36.2 ± 1.5 | 0.4 ± 0.4 |
| 30 μM | ND | ND | ND | ND | ND | ND |
| Artemether (0.18 μM) + lumefantrine | ||||||
| Control | 296.0 ± 10.3 | 277.6 ± 7.1 | 52.0 ± 4.0 | 258.3 ± 8.2 | 38.4 ± 3.1 | 0.0 ± 0.0 |
| 0.3 μM | 300.6 ± 10.7* | 283.0 ± 7.8* | 52.6 ± 4.1 | 259.8 ± 8.2 | 38.4 ± 3.1 | 0.0 ± 0.0 |
| 1 μM | 304.0 ± 11.0* | 282.6 ± 8.4 | 53.0 ± 4.6 | 265.0 ± 12.5 | 38.0 ± 3.2 | 0.0 ± 0.0 |
| 3 μM | 304.8 ± 10.5** | 282.2 ± 8.9 | 52.4 ± 4.5 | 261.2 ± 9.5 | 38.8 ± 3.3 | 0.2 ± 0.2 |
| 10 μM | 309.8 ± 9.9** | 282.4 ± 6.9 | 52.8 ± 5.1 | 266.7 ± 9.1 | 38.2 ± 3.0 | 0.4 ± 0.2 |
| 30 μM | ND | ND | ND | ND | ND | ND |
| Chloroquine | ||||||
| Control | 307.4 ± 7.9 | 280.2 ± 8.3 | 52.2 ± 3.4 | 278.7 ± 8.8 | 38.0 ± 2.8 | 0.0 ± 0.0 |
| 0.1 μM | 309.6 ± 7.6 | 281.2 ± 7.6 | 52.2 ± 4.1 | 281.0 ± 7.3 | 38.4 ± 2.8 | 0.0 ± 0.0 |
| 0.3 μM | 316.4 ± 11.0 | 286.4 ± 8.1 | 55.0 ± 4.0 | 290.9 ± 3.0 | 38.4 ± 2.9 | 0.0 ± 0.0 |
| 1 μM | 341.4 ± 10.5 | 299.6 ± 10.5 | 61.2 ± 3.8 | 314.5 ± 5.34 | 38.4 ± 2.9 | 0.8 ± 0.4 |
| 3 μM | 376.4 ± 18.7* | 318.8 ± 15.7* | 73.8 ± 7.1 * | 347.6 ± 16.2 | 41.6 ± 3.6 | 2.8 ± 1.0 |
| 10 μM | 477.0 ± 49.2* | 390.6 ± 20.9* | 106.6 + 19.2* | 445.1 ± 45.0* | 48.4 ± 4.2*** | 5.2 ± 1.3* |
| Dofetilide | ||||||
| Control | 289.2 ± 8.2 | 262.0 ± 2.8 | 51.2 ± 2.8 | 249.1 ± 13.2 | 41.6 ± 2.2 | 0.0 ± 0.0 |
| 0.3 nM | 330.8 ± 17.3 | 291.2 ± 13.2 | 65.2 ± 5.0 | 286.5 ± 26.9 | 41.6 ± 2.2 | 1.8 ± 0.9* |
| 1 nM | 353.8 ± 25.2 | 309.6 ± 17.7 | 76.6 ± 8.4 | 315.5 ± 34.9 | 41.8 ± 2.1 | 3.4 ± 0.7* |
| 3 nM | 432.0 ± 45.9** | 344.8 ± 24.6** | 103.6 ± 7.5** | 382.8 ± 51.6** | 41.8 ± 2.2 | 7.6 ± 1.0** |
| 10 nM | 547.8 ± 55.3** | 431.0 ± 16.3** | 170.4 ± 23.1** | 555.1 ± 59.3** | 41.8 ± 2.1 | 9.2 ± 0.8** |
| 30 nM | 647.4 ± 71.6*** | 464.8 ± 33.8*** | 170.4 ± 23.1*** | 574.0 ± 78.2*** | 41.6 ± 2.1 | 10.0 ± 0.0*** |
a
All values represent mean ± SEM of five preparations (except for 2.4 μM DHA plus 10 μM PQP, where only four preparations were used). Endo, endocardium;
*
, P < 0.05 versus control group;
**
, P < 0.02 versus control group;
***
, P < 0.01 versus control group; ND, no valid data available because the compound was not completely dissolved in the Tyroide's solution.