Table 1.
Pharmacosensitivity profile of DLP spasms and associated comorbidities
| Drug | Mechanism of action | Acute effect (latency to onset) | Sustained effect with repeat dosing | Tolerability | |
|---|---|---|---|---|---|
| Treatment period | Effect | ||||
| A. For model characterization | |||||
| ACTH 1–24 (Synacthene) [34] | Multiple ACTH signaling effects | No effect | PN4-12 | No effect on spasms | No side effects |
| Vigabatrin [34] | GABA aminotransferase inhibitor | Effective with delay (within 18–24 hours) | PN4-11 | 1 day | High mortality (sedation, poor feeding) |
| Phenytoin [45] | Sodium channel blocker | No effect | Not tested | Not tested | No side effects |
| B. Experimental drugs | |||||
| CPP-115 (vigabatrin analog) [35]§ | GABA aminotransferase inhibitor, high affinity | Effective (within the first hour) | PN4-12 | 2–3 days | No side effects |
| Rapamycin [36] | mTOR inhibitor (mTORC1 preferential) | Effective (within the first 2 hours) | PN4-6 | Suppresses spasms without rebound. Partial improvement of learning (PN16–19) | Transient deceleration of weight growth |
| Carisbamate [45]§ | Unknown (effect on spasms not via sodium channel blockade) | Effective (within the first hour) | PN4, PN6-7 | Not tested | No side effects |
| NAX 5055 (galanin analog) [38] | Galanin receptor 1 agonist | No effect | Not tested | Not tested | No side effects |
| VX-765 (this study) | Caspase 1 inhibitor | No consistent effect | Not tested | Not tested | No side effects |
| CGP35348 (this study) | GABAB receptor inhibitor | No effect | Not tested | Not tested | No side effects |
| 17β-estradiol (this study) | Estrogen signaling | No acute effect on PN3 | PN3–10 | No effect on spasms | No side effects |
§
Indicates drugs that have been designated by the Foods and Drug Administration orphan drugs for IS in the USA.