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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.
Medical Therapy for Glaucoma
Published in Neil T. Choplin, Carlo E. Traverso, Atlas of Glaucoma, 2014
Jennifer E. Williamson, Janet B. Serle
Several potential new targets for antiglaucoma drugs have also been identified in recent years. These include adenosine receptors, angiotensin II receptors, cannabinoid receptors, serotonin receptorsactin receptors and rho-associated protein kinase. It is anticipated that additional receptors will be identified that mediate ocular outflow and aqueous inflow, leading to development of new drugs that act at these receptors. One class of compounds, Rho kinase inhibitors (ROCK) appears promising in preclinical and early clinical trials. The topical Rho kinase inhibitor AR-12286 has been shown in recent clinical trials to produce significant clinical and statistical reductions in IOP in a dose-dependent manner. Mean IOP reductions were 4.4–6.8 mmHg from baseline at peak effect. The only adverse effect of note was transient conjunctival hyperemia.
5-(Sulfamoyl)thien-2-yl 1,3-oxazole inhibitors of carbonic anhydrase II with hydrophilic periphery
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Stanislav Kalinin, Alexander Kovalenko, Annika Valtari, Alessio Nocentini, Maxim Gureev, Arto Urtti, Mikhail Korsakov, Claudiu T. Supuran, Mikhail Krasavin
Glaucoma-related high intraocular pressure can be alleviated by the use of eye drops of prostaglandin analogues, beta blocking agents and carbonic anhydrase inhibitors (CAIs)1. The recent approval of rho kinase inhibitors and NO donors significantly expands the range of treatment options2,3. The clinically used topical CAIs for glaucoma treatment include dorzolamide (1) and brinzolamide (2), compounds that are (a) relatively lipophilic and (b) non-selective as inhibitors of a particular carbonic anhydrase isoform4. Acetazolamide (3) and methazolamide (4) are also used as anti-glaucoma agents (Figure 1), but they are oral medications which frequently cause adverse drug reactions5. Potent and selective inhibition of carbonic anhydrase II isoform (hCA II) is an important mechanism of action due to the critical importance of this enzyme in reduction of glaucoma-related intraocular pressure6.
Balancing treatments for patients with systemic hypertension and glaucoma
Published in Expert Opinion on Pharmacotherapy, 2020
Aakriti G. Shukla, Reza Razeghinejad, Jonathan S. Myers
Additionally, combination drugs that include a beta blocker and another agent have demonstrated variable effects on blood pressure. Combination drugs that include both a beta blocker and an alpha-2 agonist have not found to be significantly different in terms of ocular perfusion pressure and blood pressure from agents that included a beta blocker and a carbonic anhydrase inhibitor [38] or beta blocker and a prostaglandin[39]. Other studies have not agreed with these findings [40,41]. Furthermore, fixed combinations of beta-blocking agents and prostaglandins, in particular the latanoprost/carteolol fixed combination, have demonstrated similar IOP lowering effects, tolerability, and no significant adverse blood pressure and heart rate outcomes as compared to the use of these agents separately, but are not available in the United States[42]. Finally, the advent of novel agents such as rho kinase inhibitors and a combination of rho kinase inhibitor and prostaglandin analog offers alternative once daily dosed agents with relatively minimal systemic side effects[43].
Advances in small-molecule therapy for managing angina pectoris in the elderly
Published in Expert Opinion on Pharmacotherapy, 2019
Nida Waheed, Ahmad Mahmoud, Cecil A. Rambarat, Carl J. Pepine
Fasudil is a rho kinase inhibitor thought to improve myocardial oxygen supply through coronary micro and macrovascular vasodilation in addition to systemic vasodilation leading to improved myocardial perfusion with decreased afterload. Fasudil acts via the Rho/ROCK pathway which increases calcium sensitivity of vascular smooth muscle [86]. In a randomized trial among patients with stable angina, fasudil 80 mg three times/day led to decreased ischemic threshold during exercise testing and a trend toward increased exercise duration when compared with placebo [87]. In another trial, fasudil significantly increased oxygen saturation in the coronary sinus, supporting improved blood flow in addition to improvement in pacing-induced myocardial ischemia, ischemic ST-segment depression, and myocardial lactate production [88]. Although not directly studied among the elderly with angina, other studies have found fasudil to be safe among elderly patients [89,90]. Several other rho kinase inhibitors are under evaluation for ischemic heart disease.