Table 1 Research status of currently available candidate drugs for the prevention of cerebral vasospasm
Drug | Category | Effect | Therapeutic effect |
|---|---|---|---|
Nimodipine | L-type Ca2+ channel blockers | It inhibits cortical diffuse ischemia, enhances endogenous fibrinolytic activity, reduces the incidence of microthrombus, and improves microcirculation [6] | While there is currently no compelling evidence supporting nimodipine’s preventive effect on large artery spasms or any angiographic evidence of cerebral vasodilation [120], its significant improvement of neurological function outcomes and reduction in mortality rates following subarachnoid hemorrhage are well-established [121]. Thus, nimodipine is the preferred medication for preventing adverse prognostic outcomes resulting from DCI subsequent to aneurysmal subarachnoid hemorrhage [6] |
Nifedipine | L-type Ca2+ channel blockers | It exhibits regional selectivity for cerebral vascular smooth muscle [6] | It exerts a favourable effect on delayed cerebral ischemia and vascular spasm, but it does not improve mortality or disability rates. Furthermore, its efficacy is inferior compared to nimodipine [121] |
Fosinopril | Rho-associated protein kinase inhibitors | By increasing MLCP activity to reduce the sensitivity of vascular smooth muscle and pericytes to Ca2+, it can dilate blood vessels. Furthermore, it can inhibit the generation of free radicals in white blood cells, impede the migration of white blood cells, reduce blood viscosity, and enhance eNOS activity [6] | It exerts a favourable effect on delayed cerebral ischemia and vascular spasm, but it does not improve mortality or disability rates. In Japan, it is exclusively employed as a medication for the prevention of vasospasm [121] |
Magnesium sulphate | Voltage-gated Ca2+ channel blockers | It induces vasodilation by blocking voltage-dependent Ca2 + channels [8] | It exerts a favourable effect on delayed cerebral ischemia and vasospasm; however, it has not demonstrated improvements in mortality or disability rates. Notably, it is not a conventional medication [121] |
Xylometazoline | Phosphodiesterase type 3 inhibitors (PDE3 inhibitors) | By inhibiting PDE3 and increasing the concentration of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, it inactivates Ca2+-dependent myosin light chain kinase. Furthermore, it elevates NO levels in endothelial cells, thereby relaxing blood vessels [6, 122] | Xylometazoline has been shown to improve neurological outcomes and reduce mortality rates in patients with aneurysmal subarachnoid hemorrhage. Its efficacy, except for its impact on mortality rates, is comparable to that of nimodipine. However, there are currently no definitive guidelines or recommendations either endorsing or discouraging the utilisation of xylometazoline [121] |
Milrinone | Phosphodiesterase type 3 inhibitors (PDE3 inhibitors) | Phosphodiesterase type 3 inhibitors elevate intracellular cAMP levels and exert a vasodilatory effect on blood vessels [8] | In experimental SAH models, milrinone has demonstrated the capacity to prevent CVS without inducing systemic hemodynamic alterations. However, currently, randomised trials evaluating the efficacy of milrinone for the treatment of CVS in patients with SAH are lacking. Moreover, there is an absence of definitive guidelines or recommendations regarding the utilisation of milrinone [38] |
Statins | HMG-CoA reductase inhibitors | They upregulate eNOS expression, leading to NO generation. This action serves to inhibit vascular inflammation, oxidative stress, and cell apoptosis, ultimately contributing to EBI amelioration [38] | In clinical randomised controlled trials, statins have been demonstrated to improve delayed neurological dysfunction, CVS, and reduce mortality. However, currently, definitive guidelines or recommendations regarding the utilisation of statins are lacking [121, 123] |
Heparin | Glycosaminoglycan polymer | It is a highly sulphated glycosaminoglycan polymer with a high negative charge. It inhibits the activity of endothelin, diminishes the inflammatory response, and eliminates harmful oxygen-free radicals [6] | A recent meta-analysis showed that prolonged intravenous administration of heparin, exceeding 48 h, can reduce the incidence of cerebral infarction in patients with SAH while maintaining safety. However, there remains insufficient evidence to prove its effectiveness. Therefore, routine administration of heparin for the prevention of cerebral vasospasm is not recommended, except when indicated for the prevention of venous thromboembolism [6, 124] |
Eicosapentaenoic acid | Omega-3 polyunsaturated fatty acids | Eicosapentaenoic acid inhibits sphingosylphosphorylcholine-induced Rho kinase activation and reduces vascular smooth muscle contraction by inhibiting the translocation of Src family protein tyrosine kinases [6] | In experimental models, the intracerebroventricular injection of docosahexaenoic acid has been shown to reverse the vascular constriction induced by sphingosylphosphorylcholine in a canine model of subarachnoid hemorrhage. However, the clinical utilisation of eicosapentaenoic acid to mitigate cerebrovascular spasm in subarachnoid hemorrhage remains unexplored due to limited research on its effects [38] |
Crizotinib | Endothelin receptor antagonist | By inhibiting the vasoconstrictor peptide endothelin-1, it dilates blood vessels [8] | Beneficial effects have been observed for delayed cerebral ischemia and vasospasm; however, there is no evidence demonstrating its efficacy in reducing mortality or disability rates. Moreover, owing to significant adverse effects such as pulmonary enema, hypotension, cerebral ischemic anaemia, and hypotension, there are no definitive guidelines or recommendations supporting or opposing the utilisation of endothelin receptor antagonists [8, 121] |
Ipratropium | Free radical scavenger | It eliminates harmful free radicals [38] | A clinical study showed that intravenous injection of edaravone following surgical clipping of ruptured cerebral aneurysms significantly reduces the incidence of adverse outcomes induced by cerebral vasospasm [125]; however, currently, there is no robust evidence to corroborate its beneficial effects. Therefore, there are no definitive guidelines or recommendations for the utilisation of edaravone [38] |