Table 1.
In-vivo impact of the combination of IL-6, HCQ, AZM, and TCZ on guinea pig ECG.
| HR (bpm) | PR (ms) | QRS (ms) | QTc (ms) | |
|---|---|---|---|---|
| A. Basal | 243 ± 13.0 | 67 ± 1.9 | 13 ± 0.4 | 192 ± 6.3 |
| IL-6 (184 μg/kg) | 218 ± 11.7* | 79 ± 2.7* | 14 ± 1.2 | 204 ± 5.3* |
| IL-6 (184 μg/kg) + AZM (1) + HCQ (0.5) | 206 ± 8.7* | 87 ± 3.4* | 16 ± 1.2* | 223 ± 10.4* |
| IL-6 (184 μg/kg) + AZM (1) + HCQ (1) | 173 ± 7.4*,**,*** | 93 ± 4.3*,** | 19 ± 1.2* | 242 ± 11.2*,** |
| IL-6 (184 μg/kg) + AZM (1) + HCQ (2) | 146 ± 13.7*,**,***,**** | 108 ± 8.5*,**,***,**** | 56 ± 6.7*,**,***,**** | 270 ± 15.3*,**,***,**** |
| B. Basal | 250 ± 6.1 | 67 ± 1.5 | 14 ± 1.5 | 188 ± 7.2 |
| AZM (1) + HCQ (0.5) | 255 ± 7.5 | 73 ± 1.5* | 16 ± 2.0 | 200 ± 6.7 |
| C. Basal | 283 ± 22.3 | 52 ± 2.4 | 17 ± 1.4 | 186 ± 8.4 |
| Tocilizumab (10 mg/kg) | 284 ± 24.0 | 53 ± 1.4 | 17 ± 1.8 | 181 ± 11.3 |
| Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) | 290 ± 23.0 | 54.7 ± 1.8 | 18 ± 1.5 | 181 ± 11.6 |
| Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) + AZM (1) + HCQ (0.5) | 288 ± 17.4 | 54 ± 1.5 | 19 ± 1.4 | 195 ± 11.8**,*** |
| Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) + AZM (1) + HCQ (1) | 281 ± 18.2 | 56 ± 1.7 | 19 ± 1.5 | 208 ± 10.3**,*** |
| Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) + AZM (1) + HCQ (2) | 257 ± 14.4**,***,****,***** | 59 ± 1.8*,**,***,****,***** | 22 ± 1.9*,**,***,****,***** | 224 ± 8.3*,**,***,****,***** |
All values are expressed as mean ± SE, n = 6 guinea pigs for (A), n = 6 guinea pigs for (B) and n = 6 guinea pigs for (C). In panel (A), paired t-test was used to compare data before (basal) and after the drugs; each guinea pig is used as its own control. One-way repeated measures analysis of variance was used to compare data between the treatments with IL-6 alone and the combination with AZM and HCQ for HR, PR, QRS and QTc in the same group of guinea pigs. *p < 0.05 versus Basal; **p < 0.05 versus IL-6 (184 μg/kg); ***p < 0.05 versus IL-6 (184 μg/kg) + AZM (1) + HCQ (0.5);
****p < 0.05 versus IL-6 (184 μg/kg) + AZM (1) + HCQ (1). In panel (B), the paired t-test was used to compare data from AZM (1) + HCQ (0.5) for HR, PR, QRS and QRS with basal conditions. *p < 0.05 versus Basal. In panel (C), paired t-test was used to compare data before (basal) and after the drugs; each guinea pig is used as its own control. One-way repeated measures analysis of variance was used to compare data between the treatments with Tocilizumab alone and in combination with IL-6, AZM and HCQ for HR, PR, QRS and QTc in the same group of guinea pigs. *p < 0.05 versus Basal; **p < 0.05 versus Tocilizumab (10 mg/kg); ***p < 0.05 versus Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg); ****p < 0.05 versus Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) + AZM (1) + HCQ (0.5); *****p < 0.05 versus Tocilizumab (10 mg/kg) + IL-6 (184 μg/kg) + AZM (1) + HCQ (1). The numbers in parenthesis indicate the corresponding multiple(s) of clinically relevant dose (CRD). QTc = QT/RR1/3. HR heart rate, IL-6 Interleukin-6, AZM azithromycin, HCQ Hydroxychloroquine and TCZ Tocilizumab. AZM (1) = 38.2 mg/kg; HCQ (0.5) = 22.9 mg/kg; HCQ (1) = 45.8 mg/kg; HCQ (2) = 91.6 mg/kg.