UNOPROSTONE
- Unoprostone (UP) [Trade name: Rescula] belongs to the family of biologically active lipids known as Prostanoids.
- Unlike the prostaglandin analogues, which are 20-carbon derivatives of the eicosonoid prostaglandin F2α, UP is a 22-carbon derivative of docosahexaenoic acid.
- Docosahexaenoic acid is a naturally occurring omega-3 poly-unstaurated fatty acid endogenous to the central nervous system and retina.
- Docosahexaenoic acid is essential for the development and proper functioning of photoreceptor cells.
- It also protects the photoreceptor cells from apoptosis secondary to oxidative stress.
- UP has little or no affinity for the prostaglandin receptors, thus avoiding side effects attributed to prostanoid affinity for the prostaglandin F2α receptors.
- Unoprostone isopropyl is a synthetic docosanoid molecule.
- Its chemical name is: isopropyl (+)-(Z)-7-[(IR,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]-5-heptenoate.
- The chemical formula is: C25H44O5 .
- Unoprostone 0.15% (Rescula) is formulated as a sterile, isotonic, buffered aqueous solution of unoprostone isopropyl with a pH of 5.0-6.5 and preserved with 0.015% benzalkonium chloride.
- Unoprostone isopropyl is readily hydrolyzed by esterases to its active form, unoprostone free acid. Unlike Latanoprost, which is metabolized only by corneal esterases, UP undergoes additional metabolism once inside the eye by iris and ciliary body esterases. This pharmacokinetic profile is responsible for the shortened clinical efficacy of UP compared to Latanoprost.
- UP begins to reduce IOP after 30 minutes of ocular instillation.
- A clinically sustained effect is seen after atleast 2 weeks of twice-daily therapy.
- Mechanism of action:
- UP increases uveoscleral outflow.
- UP also stimulates Ca++ activated BK (Big Potassium) and CIC-2 type channels, leading to increased trabecular meshwork outflow.
- BK channels when activated cause cellular hyperpolarization. Endothelin-1 (ET-1) is known to induce trabecular meshwork contractility mediated via glutamate-associated increases in intracellular Ca++. Through BK channel activation, UP is believed to block this increase in intracellular Ca++ in trabecular meshwork cells and contribute to increased trabecular outflow and IOP reduction.
- Iberiotoxin, a specific inhibitor of BK channel activation was found to inhibit the hyperpolarization effect of UP.
- UP also acts on L-type Ca++ channel currents in the trabecular meshwork and reduces trabecular meshwork contractility independent of ET-1.
- UP has possible neuroprotective activity. ET-1 supposedly plays a role in apoptosis and ocular blood flow. The glutamate-associated hypercalcemia, which accompanies injury-induced retinal and ganglion cell apoptosis may be mediated by ET-1. This mediator (ET-1) is known to cause vasoconstriction of vascular smooth muscle. This action is blocked by UP, leading to increased ocular blood flow.
- UP also has possible neuromodulatory effect on RGC death.
- UP free acid and further metabolites have been reported to stimulate PGE2 release, which may play a role in IOP reduction (Takashi Ota, The effects of PGA on IOP in Prostanoid receptor deficient mice. Invest Ophthal Vis Sci.
2005 Nov;46(11):4159-63.)
- Efficacy: UP typically lowers IOP by 10-25% from baseline.
- Duration: Effect lasts for 2-5 hours, requiring twice daily instillation.
- In comparison, Latanoprost produces 25-30% IOP reduction and twice as much increase in pulsatile ocular blood flow.
- As adjunctive therapy to Timolol, UP was found to be as efficacious as brimonidine or dorzolamide.
- Side effects:
- Burning/stinging and ocular itching are more common with UP compared to Timolol but less as compared to Betoxolol.
- Adverse effects are mild-to-moderate and transient in nature.
- Iris pigmentation has been noted in 30% patients on UP, compared to 70% patients using Latanoprost.
- UP is also associated with lower incidence of abnormal lash growth, deepening of the upperlid sulcus and cystoid macular edema, compared to other prostanoids.
- UP does not affect heart rate or pulmonary function test parameters.
- Reference:
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