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Therapeutics in pulmonary hypertension
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Maria F. Acosta, Don Hayes, Jeffrey R. Fineman, Jason X.-J. Yuan, Stephen M. Black, Heidi M. Mansour
Rho-kinase inhibitors: The small GTPases such as RhoA and its target, the Rho-kinase, have significant effects in the prevention of vasoconstriction and in the remodeling of the vascular vessels (47). As explained above, PH is characterized by an imbalance in vasoconstriction-vasodilation. This imbalance is caused by the overproduction and underproduction of vasoconstrictors and vasodilators, respectively. Some vasoconstrictors involved in the development of PH also mediate the Rho/Rho kinase pathway, and hence there is a downregulation of the eNOS and an exacerbation in the pulmonary vascular remodeling. Inhibitors of the Rho-kinase pathway can also contribute as an antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory agents for the treatment of PH (47). Some Rho-kinase inhibitors that are currently in trials include statins (simvastatin, pravastatin, atorvastatin, rosuvastatin) and fasudil.
Hard Shell Capsules in Clinical Trials
Published in Larry L. Augsburger, Stephen W. Hoag, Pharmaceutical Dosage Forms, 2017
Moji Christianah Adeyeye, Amusa Adebayo
Hard gelatin capsules have also been used to deliver drugs farther down into the intestinal region. Schellekens et al. [73] coated the capsule with a pH-responsive polymer (Eudragit S) and related the responsiveness to the swelling index of the disintegrant, particularly croscarmellose. Studies in humans showed that the coat was able to resist the acidic gastric conditions in the stomach and duodenum, delaying the delivery of the drug until the distal segments of the intestine was reached. A more sophisticated targeted drug delivery system using capsules was reported earlier by Hinderling et al. [74] in which the drug Fasudil was delivered at different GI sites using the InteliSite capsule. The authors achieved the delivery by remote control following activation by a magnetic signal.
Combination of constraint-induced movement therapy with fasudil amplifies neurogenesis after focal cerebral ischemia/reperfusion in rats
Published in International Journal of Neuroscience, 2022
Our findings are consistent with our previous result that compared with fasudil, CIMT promotes stronger nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion [6]. Furthermore, CIMT promoted post-stroke neurogenesis, at least in part, by overcoming Nogo-A–RhoA–ROCK signaling pathway [6]. However, the inhibition degree of CIMT on this pathway cannot be determined. In the present study, we found that CIMT appeared to be more effective in enhancing neurogenesis after focal cerebral ischemia/reperfusion in rats when combinating with fasudil. This suggests that although CIMT inhibits the Nogo-A–RhoA–ROCK pathway to some extent, the inhibition degree is not complete. Growing evidence indicates that brain plasticity may play a role through some of the mechanisms, including axonal and dendritic reorganization, neurogenesis or angiogenesis [4,13]. Fasudil stimulates axonal regrowth and enhances recovery after stroke by inhibiting Rho/ROCK pathway [14]. Nogo-A negatively regulates microvascular proliferation through intracellular activation of the RhoA/ROCK pathway in the early postnatal brain, and inhibition of RhoA/ROCK can significantly induce angiogenesis [15]. Therefore, the suppression of Nogo-A, angiogenesis, sprouting and pathfinding actions induced by blockade of Rho/ROCK pathway may contribute to the development of plasticity of CIMT.
5-Fluorouracil, capecitabine and vasospasm: a scoping review of pathogenesis, management options and future research considerations
Published in Acta Cardiologica, 2022
Eleftherios Teperikidis, Aristi Boulmpou, Panagiotis Charalampidis, Chalil Tsavousoglou, George Giannakoulas, Christodoulos E. Papadopoulos, Vassilios Vassilikos
Further available options for treating vasospastic angina include nicorandil and fasudil (Class IIa) [63]. Nicorandil is a dual nitrate and ATP-sensitive K channel agonist [66]. We ran a PubMed search using ‘fluorouracil and nicorandil’ which yielded 3 results, 2 of which were case reports where nicorandil was successfully used as part of a multi-drug regimen, including nitrates, in the treatment of 5-FU cardiotoxicities [67,68]. However, nicorandil is not widely available and therefore clinical experience is minor, whilst its use in routine clinical treatment is limited. Fasudil is an intracellular calcium antagonist and a Rho Kinase inhibitor that is approved in Japan and China for the treatment of cerebral vasospasm. Rho kinase is an important mediator of vasoconstriction [69]. Several other potential mechanisms for this molecule have been proposed. While its use in the treatment of vasospasm is classified as Class IIa, we ran a PubMed search using ‘fluorouracil and fasudil’ which yielded no results. Finally, ranolazine and trimetazidine, two broadly used regimens in the treatment of chronic stable angina, may be considered as therapeutic options in 5-FU vasospastic angina. While our search for ‘fluorouracil and ranolazine’ did not produce any results, we were able to locate 1 case report for ‘fluorouracil and trimetazidine’ [70]. In this report, trimetazidine was successfully administered along with CCB and nitrates in a capecitabine re-challenge attempt.
An overview of pharmacotherapy for cerebral vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage
Published in Expert Opinion on Pharmacotherapy, 2021
Tatsuya Maruhashi, Yukihito Higashi
The level of evidence for nimodipine is better than that for fasudil. Nimodipine has been shown to reduce the severity of neurological deficits in 4 randomized, double-blind, placebo-controlled trials conducted in different countries including the USA, France, UK, and Canada [76,79,174,175]. Several additional trials have also shown a beneficial effect of nimodipine on outcomes in patients with aneurysmal subarachnoid hemorrhage [176–178]. In contrast, the number of adequate and well-controlled clinical studies in which the effect of fasudil on outcomes in patients with aneurysmal subarachnoid hemorrhage was investigated is small[102]. Moreover, the efficacy of fasudil in non-Asian patients is unknown. Large randomized, double-blind, placebo-controlled trials are needed for further establishment of the beneficial effect of fasudil on aneurysmal subarachnoid hemorrhage. When nimodipine is available, nimodipine should be preferentially used as first-line treatment for the prevention of clinical deterioration due to DCI after aneurysmal subarachnoid hemorrhage. Although there is a possibility that combinations of nimodipine with fasudil and ciloztazol are more effective than is nimodipine therapy alone, the efficacy of those combination therapies is unknown.