J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12161
REVIEW ARTICLE
Pharmacology of topical prostaglandin F2a analogs and their place in the treatment of glaucoma in small animals T. MA SLANKA Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
Maslanka T. Pharmacology of topical prostaglandin F2a analogs and their place in the treatment of glaucoma in small animals. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12161. A distinguishing feature of the most common types of glaucoma is an increased intra-ocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to the progressive loss of retinal ganglion cells. Therefore, IOP-lowering medications are the mainstay of glaucoma therapy. Topical prostaglandin F2a analogs (PGAs) are a relatively new class of ocular hypotensive drugs, which have made a huge impact on the treatment of glaucoma in dogs. This study summarizes the current state of knowledge on the mechanism of action of these agents and their effect on IOP in dogs and cats. It also discusses potential harmful side effects of PGAs and presents contemporary opinions about their role and place in the medical management of glaucoma in small animals. (Paper received 25 October 2013; accepted for publication 4 August 2014) Tomasz Maslanka, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Street 13, 10-718 Olsztyn, Poland. E-mail: [email protected]
INTRODUCTION ‘Glaucoma’ is not the name of a single disease, but encompasses a group of ocular disorders; as these disorders have diverse features, the plural term ‘the glaucomas’ might be more appropriate (Casson et al., 2012). In all species, this group of disorders is unified in their final common pathway of characteristic optic nerve and retinal pathology, resulting in the loss of vision. Glaucoma is therefore widely considered to be a neurodegenerative disease (McLellan & Miller, 2011). The pathophysiological process of glaucomatous optic neuropathy is not fully understood, but it is likely to be a multifactorial event. An increase in intra-ocular pressure (IOP) is the principal risk factor for glaucoma, and the primary goal of treatment is to reduce IOP to values that will halt the death of retinal ganglion cells (Smith et al., 2010). It seems that topical application of prostaglandin F2a analogs (PGAs), ocular hypotensive drugs, is currently the most common practice in the treatment of glaucoma in humans. Undoubtedly, the introduction of these drugs into clinical practice has had a profound impact on the way glaucoma is now treated. The impact of these analogs may have been as profound as the effect of b-blockers introduced into glaucoma treatment in the 1970s (Cracknell & Grierson, 2009). The first commercially available PGA, unoprostone isopropyl, appeared in glaucoma treatment in Japan in 1994. This agent is no longer in use because of its limited efficacy and twice-daily administration regime. The second medication of this group was latanoprost marketed in 1996, © 2014 John Wiley & Sons Ltd
followed by travoprost and bimatoprost in 2001 and tafluprost in 2011.
MECHANISM OF ACTION In clinical and animal studies, it has been well established that PGAs reduce IOP by enhancing the uveoscleral outflow, although there are indications suggesting that another mechanism involved in the induction of this effect could consist of an increase of the trabecular outflow. These drugs do not affect aqueous humor (AH) production (Lim et al., 2008). The earliest evidence indicating that PGF2a reduces IOP by increasing the uveoscleral outflow was determined independently by two research teams, namely Crawford and Kaufman (1987) and Nilsson et al. (1989). They demonstrated that pretreatment with pilocarpine abolished the effect of endogenous PGF2a on IOP and uveoscleral outflow in monkeys. The IOP reduction can be explained as it is known that pilocarpine contracts the ciliary muscle and closes up the intramuscular spaces (Cracknell & Grierson, 2009). The claim that PGF2a and its analogs decrease IOP by increasing the uveoscleral outflow seems undisputable because this increase has been demonstrated repeatedly in studies on humans (Toris et al., 1993; Brubaker, 2001), monkeys (Nilsson et al., 1989), dogs (Gum et al., 1991), and rabbits (Poyer et al., 1992), but the exact mechanism of action has not been thoroughly investigated yet. 1
2 T. Maslanka
It is known that the induction of this effect is mediated by the prostaglandin F2a receptor (FP receptor) and that it is connected with a more intensive uveoscleral outflow. The participation of the FP receptor in the action produced by these drugs is implied by the results reported by Crowston et al. (2004), who showed that administration of latanoprost had no effect on IOP in FP-receptor-deficient (FPKO) mice. This finding was confirmed experimentally by Ota et al. (2005), who also concluded that administration of PGAs (latanoprost, travoprost, bimatoprost, and unoprostone) had no effect on IOP in FPKO mice. There are indications suggesting that indirect stimulation of the E-prostanoid 3 (EP3) receptor might be additionally involved in the mechanism of action of these drugs. The research by Ota et al. (2007) proves that tafluprost lowers IOP through the FP receptor in mice, but some of the IOP reduction induced by the drug may be through the EP3 receptor, which is stimulated by endogenous PG produced by FP stimulation. In general, it is believed that PGAs reduce the hydraulic resistance in the uveoscleral outflow as a result of the enhanced fluid permeability of the ciliary muscle interstitial spaces, but the mechanism which mediates this effect has not been unequivocally and completely explained. The contemporary state of knowledge enables us to distinguish two basic ways in which PGAs may intensify the AH penetration between the ciliary muscle bundles: a) widening of the intermuscular spaces within the ciliary muscle (Toris et al., 2008); postulated mechanisms whereby PGAs may induce this effect: a) relaxation of the ciliary muscle (Poyer et al., 1995) and b) changes in the shape of ciliary muscle cells as a result of alterations in actin and vinculin localization within the cells (Stjernschantz et al., 1998). b) reduction in the volume of the extracellular matrix (ECM) filling spaces between the ciliary muscle bundles. The early effect of PGAs on the uveoscleral outflow may be connected to the widening of intermuscular spaces within the ciliary muscle as a result of its relaxation (Alm & Nilsson, 2009), but it is the remodeling of the ECM within the ciliary muscle which seems to be the major mechanism responsible for the long-term intensification of this outflow. This concept relies on the research results, demonstrating that a treatment with PGF2a or latanoprost leads to the following changes in the ciliary muscle: a) reduction of main ECM components, that is collagen (I, III, IV, and VI), fibronectin, laminin, and hyaluronan (Lindsey et al., 1997; Ocklind, 1998; Sagara et al., 1999). b) upregulation of several types of matrix metalloproteinases (MMPs) (Weinreb et al., 1997; Ocklind, 1998; Weinreb & Lindsey, 2002), that is proteolytic enzymes that degrade the extracellular matrix and are essential for tissue remodeling. c) presence of empty spaces between the ciliary muscle bundles (L€ utjen-Drecoll & Tamm, 1988). Based on the above data, the following sequence of events induced by PGAs in the ciliary muscle can be suggested: (i)
upregulation of some types of MMPs; (ii) increased degradation of ECM; (iii) depletion of ECM filling spaces between the ciliary muscle bundles; (iv) enlargement of the empty spaces between the ciliary muscle bundles; (v) decrease in the hydraulic resistance in the uveoscleral outflow; and (vi) IOP reduction. In support of the rearrangement of the ciliary muscle as the main factor, it was found that withdrawing latanoprost after 12month treatment caused a very slow recovery of the IOP, with a small but significant effect remaining after 2 weeks (Linden et al., 1997; Alm & Nilsson, 2009). Thus, the current state of knowledge implicates that this is the main mechanism behind the long-term ocular hypotensive effect of the discussed drugs, but the same mechanism is rather unlikely to be responsible for a rapidly occurring therapeutic effect of latanoprost in emergency therapy for primary angle closure glaucoma (PACG) in dogs. It is well known that in response to stimulation, most MMPs are synthesized in specific types of cells with a delay of several hours; MMP genes are generally considered to be ‘late-activated’ genes, as their transcripts are usually induced over a time course of several hours (Sampieri et al., 2008). Moreover, all MMPs are produced in a latent form (proMMP) requiring activation for catalytic activity, a process that is usually accomplished by the proteolytic removal of the propeptide domain (Murphy & Willenbrock, 1995). Doubtless, a reduction of IOP in response to the MMP-induced remodeling of the ECM within the ciliary muscle is not an instant process, but it takes time to develop and manifest itself, while it is known that 0.005% latanoprost can rapidly alleviate an attack of acute PACG in dogs and decrease IOP from as high as 80 mmHg to within normal limits in 1–2 h (Miller et al., 2003). Concluding, latanoprost must activate some other mechanism through which it evokes a rapid therapeutic effect in these patients. It has been demonstrated that PGF2a raised the permeability of human sclera, which was accompanied by increased expression of MMPs (Kim et al., 2001; Weinreb, 2001). This provides the ground to suggest that an increase in the AH transscleral outflow may participate in producing the PGA-induced enhancement of uveoscleral outflow. However, this is still a hypothetical issue. Some books and papers report that irrespective of its effect on the uveoscleral outflow, PGAs additionally decrease IOP by increasing the conventional outflow, an effect which might originate from certain changes within the trabecular meshwork (TM) and Schlemm canal. Although there are some indications (Richter et al., 2003; Oh et al., 2006; Bahler et al., 2008) permitting this thesis, it appears that a categorical claim in its favor lacks a firm empirical base. Richter et al. (2003) demonstrated that long-term treatment with different prostaglandins and a prostamide leads to some morphologic changes in the TM of monkeys. In their opinion, the presence of the said changes suggests that these agents may increase the conventional outflow. Oh et al. (2006) demonstrated that the transcription of the genes for MMP-1, -3, -17, and -24 in cultures of human TM cells was elevated by latanoprost treatment (Oh et al., 2006). Outflow model studies and outflow facility studies © 2014 John Wiley & Sons Ltd
Prostaglandin F2a analogues 3
strongly indicated that ECM turnover is essential in regulating outflow resistance in the TM (Oh et al., 2006). In light of the above, the results determined by Oh et al. (2006) suggest that latanoprost may increase the conventional outflow through the remodeling of the ECM of TM. The quoted results were not confirmed by the research performed by Bahler et al. (2008), who did not demonstrate any effect of latanoprost on MMPs activity, but showed that the drug increased the outflow facility in perfusion organ culture of human anterior segments and reduced IOP. These authors indicate that PGAs may increase the conventional outflow independently from MMPs. They also draw attention to the fact that prostaglandins cause disassembly of actin stress fibers and inhibition of phosphorylation of paxillin and other focal adhesion proteins (Bulin et al., 2005). These cytoskeletal and focal adhesion changes may loosen the attachment of the Schlemm canal cells, causing focal cell loss. The Schlemm canal cells would be less able to resist the perfusion pressure gradient between IOP and the lower pressure in the Schlemm canal (Bahler et al., 2008). The fact that the histological findings demonstrated by Bahler et al. (2008), such as focal loss of the Schlemm canal cells and loss of the underlying extracellular matrix in the juxtacanalicular region, were consistent with these changes might suggest that latanoprost increased the trabecular outflow (Bahler et al., 2008). Thus, the findings cited above suggest that PGAs may increase the conventional outflow by inducing changes within the TM and the Schlemm canal. On the other hand, the results determined by Tsai et al. (2012) suggest that latanoprost may inhibit this type of outflow in dogs. They found that topical 0.005% latanoprost increases episcleral venous pressure in dogs and hence may increase resistance to the AH outflow via the TM (Tsai et al., 2012). As the medication produces no such effect in humans and mice, these authors postulate that the observed response may be unique to dogs and suggest that dogs may not fully mimic human AH dynamics with topical 0.005% latanoprost. Topical administration of PGAs [bimatoprost (Gelatt & MacKay, 2002), latanoprost (Gelatt & MacKay, 2001), or travoprost (Gelatt & MacKay, 2004)] in dogs causes a moderate to marked miosis, but it has not been demonstrated that the administration of PGF2a (Erkilicß et al., 1996) and its analogs [latanoprost (Dinslage et al., 2000), unoprostone (Zarnowski et al., 2001)] had a marked influence on the pupil size in the human eye. Also in cats, topical application of PGAs [latanoprost (Studer et al., 2000), bimatoprost (Regnier et al., 2006)] induced miosis. The results determined by Yoshitomi and Ito (1988) suggest that PGF2a induces the contraction of the canine iris sphincter muscle directly rather than through the release of adrenergic or cholinergic neurotransmitters. Thus, the canine and feline, but not human iris sphincter muscle, appear sensitive to PGAs. The cause of this differentiation in the sensitivity to the contracting activity of PGAs is unknown, but it does not originate from the lack of FP receptors in the human sphincter muscle, whose presence has been documented in this muscle (Davis & Sharif, 1999). It is well known that the therapeutic action of parasympathomimetics in patients with angle closure glaucoma is © 2014 John Wiley & Sons Ltd
connected with the induction of miosis. Thus, as PGAs induce the miotic action in small animals, it is natural to ask the question whether these drugs—similarly to parasympathomimetics—can widen or open the drainage angle and the ciliary cleft in patients with angle closure? If they did, then this would actually mean that a rapidly occurring effect and high clinical efficacy of latanoprost in dogs with an acute attack of PACG could at least partly originate from improving/giving access of AH to the trabecular and uveoscleral outflow pathways. This hypothesis is supported by the results of the research carried out by Miller et al. (2002, 2003), in which at attempt was made to determine changes occurring under the effect of latanoprost within the anterior segment of the eye of healthy (2002) and PACG-stricken dogs (2003). These studies demonstrated that in normotensive dogs, latanoprost increased the surface area of the ciliary cleft, thereby potentially improving outflow via the conventional route. Whether this increase in the surface area is the result of contraction or relaxation of the ciliary musculature, or miosis, remains to be elucidated (Miller et al., 2002). Miller et al. (2003) have concluded that the ability of latanoprost to rapidly alleviate an acute attack of PACG in dogs appears to be associated with its ability to induce miosis. Miller et al. (2002) indicated that the ocular hypotensive effect of latanoprost in dogs appears to be more complex than simply improving uveoscleral outflow, which may also occur. Together, their results suggest that latanoprost may rapidly lower IOP in dogs with an acute attack of PACG, by inducing miosis, which breaks the pupillary block, and by opening the collapsed ciliary cleft. Some recently published research results seem to somewhat question the aforementioned findings alongside the resultant theses or conclusions. Tsai et al. (2013) demonstrated that a single topical dose of latanoprost (0.005%) in normal female Beagle dogs resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. A limitation of this study is the fact that these investigators used normotensive Beagle dogs only. Therefore, the results may not be generally applicable to glaucomatous dogs, especially in patients with acute attack of PACG. It should be noticed that pilocarpine and other miotics may shallow the anterior chamber in some patients (Hung et al., 1995), which does not change the fact that these drugs increase the angle width in patients with narrow angles (Kobayashi et al., 1999). The determination of the mechanism of action which underlines the rapid and effective output of the administration of latanoprost in dogs with an acute attack of PACG requires complex investigations on changes appearing under the effect of this medicine within the anterior segment of eyes of patients suffering from this ailment.
EFFECT ON IOP Among the PGAs that are known today, latanoprost is the most thoroughly examined medication in terms of its effect of on IOP in small animals. Studer et al. (2000) demonstrated
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that latanoprost produced a mean decline in IOP of 3 mmHg or about 25% in healthy dogs. Subsequent studies have confirmed that latanoprost significantly reduces IOP in normotensive canine eyes (Smith et al., 2010; Sarchahi et al., 2012). IOP-lowering action of this drug was also demonstrated in Beagles with inherited primary open-angle glaucoma. Gelatt and MacKay (2001) showed that 0.005% latanoprost significantly lowers IOP in the glaucomatous Beagles when instilled once daily (in the evening, morning) or twice daily. The twice-daily instillation of latanoprost resulted in less-daily IOP fluctuations. The reduction of IOP ranged from about 20 mmHg (45%) to 27 mmHg (60%) (Gelatt & MacKay, 2001). Willis (2004) observed a dramatic reduction of IOP in dogs with acute and chronic glaucoma within 20 min of administering latanoprost. As mentioned above, Miller et al. (2003) noted that 0.005% latanoprost can rapidly alleviate an attack of acute PACG in dogs and decrease IOP from as high as 80 mmHg to within normal limits in 1–2 h. Another study demonstrated that other PGAs, that is bimatoprost (Gelatt & MacKay, 2002), travoprost (Gelatt & MacKay, 2004), and unoprostone (Gelatt et al., 2004), also produce a significant decrease in IOP in glaucomatous Beagle. All the evidence indicates that the PGAs currently used in therapy do not produce an ocular hypotensive effect in the feline species; no effect of latanoprost (Studer et al., 2000), unoprostone (Bartoe et al., 2005), or bimatoprost (Bartoe et al., 2005; Regnier et al., 2006) on IOP of healthy cats has been determined. The lack of effect should not really be attributed to the fact that the uveoscleral outflow in cats only constitutes 3% of the total aqueous drainage (Bill, 1966) [whereas in dogs, it reaches 15% (Barrie et al., 1985)], because it has been demonstrated that topical application of PGF2a is able to significantly reduce IOP in cats. Most probably, the missing ocular hypotensive effect of PGAs in the feline species is due to the absence of the target sites for these agents. The biologically active metabolites of latanoprost, unoprostone, bimatoprost, and travoprost are highly selective FP receptor agonists, while feline ciliary muscle does not appear to express these receptors (Bhattacherjee et al., 1997). The IOP-lowering action of PGF2a in cats is mediated by EP1 receptors (Bhattacherjee et al., 1999), but these receptors (like EP2 receptors) are not involved in PGA-induced IOP reduction (Ota et al., 2006).
CLINICAL USE There are no clinical trials on the efficacy and safety of use of PGAs in dogs. The recommendations found in literature about the application of latanoprost come from clinical observations made by veterinary doctors during treatment of glaucomatous dogs with this medication. Other PGAs may be equally or more effective than latanoprost, but have not been used as extensively as latanoprost (Martin, 2010). In the dog, latanoprost is mostly indicated for the treatment of primary glaucoma (Willis, 2004), but it can also be applicable in certain types of secondary glaucomas. According to the
recommendations contained in Slatter’s Fundamentals of Veterinary Ophthalmology, topical 0.005% latanoprost should be considered the first line drug in therapy of an acute attack of PACG in dogs (Miller, 2008). Also, Martin (2010) routinely uses this medication topically for emergency therapy in the dog, as it often reduces IOP within 15–30 min if it is successful. Martin (2010) and Willis (2004) indicate that topical latanoprost use may enable to avoid giving mannitol in dogs with an acute attack of glaucoma. However, long-term therapy for dogs with overt PACG remains elusive (Tsai et al., 2013). In one study (Focht et al., 2006), despite an initially positive response, only 11% of dogs maintained an IOP of
REVIEW ARTICLE
Pharmacology of topical prostaglandin F2a analogs and their place in the treatment of glaucoma in small animals T. MA SLANKA Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
Maslanka T. Pharmacology of topical prostaglandin F2a analogs and their place in the treatment of glaucoma in small animals. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12161. A distinguishing feature of the most common types of glaucoma is an increased intra-ocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to the progressive loss of retinal ganglion cells. Therefore, IOP-lowering medications are the mainstay of glaucoma therapy. Topical prostaglandin F2a analogs (PGAs) are a relatively new class of ocular hypotensive drugs, which have made a huge impact on the treatment of glaucoma in dogs. This study summarizes the current state of knowledge on the mechanism of action of these agents and their effect on IOP in dogs and cats. It also discusses potential harmful side effects of PGAs and presents contemporary opinions about their role and place in the medical management of glaucoma in small animals. (Paper received 25 October 2013; accepted for publication 4 August 2014) Tomasz Maslanka, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Street 13, 10-718 Olsztyn, Poland. E-mail: [email protected]
INTRODUCTION ‘Glaucoma’ is not the name of a single disease, but encompasses a group of ocular disorders; as these disorders have diverse features, the plural term ‘the glaucomas’ might be more appropriate (Casson et al., 2012). In all species, this group of disorders is unified in their final common pathway of characteristic optic nerve and retinal pathology, resulting in the loss of vision. Glaucoma is therefore widely considered to be a neurodegenerative disease (McLellan & Miller, 2011). The pathophysiological process of glaucomatous optic neuropathy is not fully understood, but it is likely to be a multifactorial event. An increase in intra-ocular pressure (IOP) is the principal risk factor for glaucoma, and the primary goal of treatment is to reduce IOP to values that will halt the death of retinal ganglion cells (Smith et al., 2010). It seems that topical application of prostaglandin F2a analogs (PGAs), ocular hypotensive drugs, is currently the most common practice in the treatment of glaucoma in humans. Undoubtedly, the introduction of these drugs into clinical practice has had a profound impact on the way glaucoma is now treated. The impact of these analogs may have been as profound as the effect of b-blockers introduced into glaucoma treatment in the 1970s (Cracknell & Grierson, 2009). The first commercially available PGA, unoprostone isopropyl, appeared in glaucoma treatment in Japan in 1994. This agent is no longer in use because of its limited efficacy and twice-daily administration regime. The second medication of this group was latanoprost marketed in 1996, © 2014 John Wiley & Sons Ltd
followed by travoprost and bimatoprost in 2001 and tafluprost in 2011.
MECHANISM OF ACTION In clinical and animal studies, it has been well established that PGAs reduce IOP by enhancing the uveoscleral outflow, although there are indications suggesting that another mechanism involved in the induction of this effect could consist of an increase of the trabecular outflow. These drugs do not affect aqueous humor (AH) production (Lim et al., 2008). The earliest evidence indicating that PGF2a reduces IOP by increasing the uveoscleral outflow was determined independently by two research teams, namely Crawford and Kaufman (1987) and Nilsson et al. (1989). They demonstrated that pretreatment with pilocarpine abolished the effect of endogenous PGF2a on IOP and uveoscleral outflow in monkeys. The IOP reduction can be explained as it is known that pilocarpine contracts the ciliary muscle and closes up the intramuscular spaces (Cracknell & Grierson, 2009). The claim that PGF2a and its analogs decrease IOP by increasing the uveoscleral outflow seems undisputable because this increase has been demonstrated repeatedly in studies on humans (Toris et al., 1993; Brubaker, 2001), monkeys (Nilsson et al., 1989), dogs (Gum et al., 1991), and rabbits (Poyer et al., 1992), but the exact mechanism of action has not been thoroughly investigated yet. 1
2 T. Maslanka
It is known that the induction of this effect is mediated by the prostaglandin F2a receptor (FP receptor) and that it is connected with a more intensive uveoscleral outflow. The participation of the FP receptor in the action produced by these drugs is implied by the results reported by Crowston et al. (2004), who showed that administration of latanoprost had no effect on IOP in FP-receptor-deficient (FPKO) mice. This finding was confirmed experimentally by Ota et al. (2005), who also concluded that administration of PGAs (latanoprost, travoprost, bimatoprost, and unoprostone) had no effect on IOP in FPKO mice. There are indications suggesting that indirect stimulation of the E-prostanoid 3 (EP3) receptor might be additionally involved in the mechanism of action of these drugs. The research by Ota et al. (2007) proves that tafluprost lowers IOP through the FP receptor in mice, but some of the IOP reduction induced by the drug may be through the EP3 receptor, which is stimulated by endogenous PG produced by FP stimulation. In general, it is believed that PGAs reduce the hydraulic resistance in the uveoscleral outflow as a result of the enhanced fluid permeability of the ciliary muscle interstitial spaces, but the mechanism which mediates this effect has not been unequivocally and completely explained. The contemporary state of knowledge enables us to distinguish two basic ways in which PGAs may intensify the AH penetration between the ciliary muscle bundles: a) widening of the intermuscular spaces within the ciliary muscle (Toris et al., 2008); postulated mechanisms whereby PGAs may induce this effect: a) relaxation of the ciliary muscle (Poyer et al., 1995) and b) changes in the shape of ciliary muscle cells as a result of alterations in actin and vinculin localization within the cells (Stjernschantz et al., 1998). b) reduction in the volume of the extracellular matrix (ECM) filling spaces between the ciliary muscle bundles. The early effect of PGAs on the uveoscleral outflow may be connected to the widening of intermuscular spaces within the ciliary muscle as a result of its relaxation (Alm & Nilsson, 2009), but it is the remodeling of the ECM within the ciliary muscle which seems to be the major mechanism responsible for the long-term intensification of this outflow. This concept relies on the research results, demonstrating that a treatment with PGF2a or latanoprost leads to the following changes in the ciliary muscle: a) reduction of main ECM components, that is collagen (I, III, IV, and VI), fibronectin, laminin, and hyaluronan (Lindsey et al., 1997; Ocklind, 1998; Sagara et al., 1999). b) upregulation of several types of matrix metalloproteinases (MMPs) (Weinreb et al., 1997; Ocklind, 1998; Weinreb & Lindsey, 2002), that is proteolytic enzymes that degrade the extracellular matrix and are essential for tissue remodeling. c) presence of empty spaces between the ciliary muscle bundles (L€ utjen-Drecoll & Tamm, 1988). Based on the above data, the following sequence of events induced by PGAs in the ciliary muscle can be suggested: (i)
upregulation of some types of MMPs; (ii) increased degradation of ECM; (iii) depletion of ECM filling spaces between the ciliary muscle bundles; (iv) enlargement of the empty spaces between the ciliary muscle bundles; (v) decrease in the hydraulic resistance in the uveoscleral outflow; and (vi) IOP reduction. In support of the rearrangement of the ciliary muscle as the main factor, it was found that withdrawing latanoprost after 12month treatment caused a very slow recovery of the IOP, with a small but significant effect remaining after 2 weeks (Linden et al., 1997; Alm & Nilsson, 2009). Thus, the current state of knowledge implicates that this is the main mechanism behind the long-term ocular hypotensive effect of the discussed drugs, but the same mechanism is rather unlikely to be responsible for a rapidly occurring therapeutic effect of latanoprost in emergency therapy for primary angle closure glaucoma (PACG) in dogs. It is well known that in response to stimulation, most MMPs are synthesized in specific types of cells with a delay of several hours; MMP genes are generally considered to be ‘late-activated’ genes, as their transcripts are usually induced over a time course of several hours (Sampieri et al., 2008). Moreover, all MMPs are produced in a latent form (proMMP) requiring activation for catalytic activity, a process that is usually accomplished by the proteolytic removal of the propeptide domain (Murphy & Willenbrock, 1995). Doubtless, a reduction of IOP in response to the MMP-induced remodeling of the ECM within the ciliary muscle is not an instant process, but it takes time to develop and manifest itself, while it is known that 0.005% latanoprost can rapidly alleviate an attack of acute PACG in dogs and decrease IOP from as high as 80 mmHg to within normal limits in 1–2 h (Miller et al., 2003). Concluding, latanoprost must activate some other mechanism through which it evokes a rapid therapeutic effect in these patients. It has been demonstrated that PGF2a raised the permeability of human sclera, which was accompanied by increased expression of MMPs (Kim et al., 2001; Weinreb, 2001). This provides the ground to suggest that an increase in the AH transscleral outflow may participate in producing the PGA-induced enhancement of uveoscleral outflow. However, this is still a hypothetical issue. Some books and papers report that irrespective of its effect on the uveoscleral outflow, PGAs additionally decrease IOP by increasing the conventional outflow, an effect which might originate from certain changes within the trabecular meshwork (TM) and Schlemm canal. Although there are some indications (Richter et al., 2003; Oh et al., 2006; Bahler et al., 2008) permitting this thesis, it appears that a categorical claim in its favor lacks a firm empirical base. Richter et al. (2003) demonstrated that long-term treatment with different prostaglandins and a prostamide leads to some morphologic changes in the TM of monkeys. In their opinion, the presence of the said changes suggests that these agents may increase the conventional outflow. Oh et al. (2006) demonstrated that the transcription of the genes for MMP-1, -3, -17, and -24 in cultures of human TM cells was elevated by latanoprost treatment (Oh et al., 2006). Outflow model studies and outflow facility studies © 2014 John Wiley & Sons Ltd
Prostaglandin F2a analogues 3
strongly indicated that ECM turnover is essential in regulating outflow resistance in the TM (Oh et al., 2006). In light of the above, the results determined by Oh et al. (2006) suggest that latanoprost may increase the conventional outflow through the remodeling of the ECM of TM. The quoted results were not confirmed by the research performed by Bahler et al. (2008), who did not demonstrate any effect of latanoprost on MMPs activity, but showed that the drug increased the outflow facility in perfusion organ culture of human anterior segments and reduced IOP. These authors indicate that PGAs may increase the conventional outflow independently from MMPs. They also draw attention to the fact that prostaglandins cause disassembly of actin stress fibers and inhibition of phosphorylation of paxillin and other focal adhesion proteins (Bulin et al., 2005). These cytoskeletal and focal adhesion changes may loosen the attachment of the Schlemm canal cells, causing focal cell loss. The Schlemm canal cells would be less able to resist the perfusion pressure gradient between IOP and the lower pressure in the Schlemm canal (Bahler et al., 2008). The fact that the histological findings demonstrated by Bahler et al. (2008), such as focal loss of the Schlemm canal cells and loss of the underlying extracellular matrix in the juxtacanalicular region, were consistent with these changes might suggest that latanoprost increased the trabecular outflow (Bahler et al., 2008). Thus, the findings cited above suggest that PGAs may increase the conventional outflow by inducing changes within the TM and the Schlemm canal. On the other hand, the results determined by Tsai et al. (2012) suggest that latanoprost may inhibit this type of outflow in dogs. They found that topical 0.005% latanoprost increases episcleral venous pressure in dogs and hence may increase resistance to the AH outflow via the TM (Tsai et al., 2012). As the medication produces no such effect in humans and mice, these authors postulate that the observed response may be unique to dogs and suggest that dogs may not fully mimic human AH dynamics with topical 0.005% latanoprost. Topical administration of PGAs [bimatoprost (Gelatt & MacKay, 2002), latanoprost (Gelatt & MacKay, 2001), or travoprost (Gelatt & MacKay, 2004)] in dogs causes a moderate to marked miosis, but it has not been demonstrated that the administration of PGF2a (Erkilicß et al., 1996) and its analogs [latanoprost (Dinslage et al., 2000), unoprostone (Zarnowski et al., 2001)] had a marked influence on the pupil size in the human eye. Also in cats, topical application of PGAs [latanoprost (Studer et al., 2000), bimatoprost (Regnier et al., 2006)] induced miosis. The results determined by Yoshitomi and Ito (1988) suggest that PGF2a induces the contraction of the canine iris sphincter muscle directly rather than through the release of adrenergic or cholinergic neurotransmitters. Thus, the canine and feline, but not human iris sphincter muscle, appear sensitive to PGAs. The cause of this differentiation in the sensitivity to the contracting activity of PGAs is unknown, but it does not originate from the lack of FP receptors in the human sphincter muscle, whose presence has been documented in this muscle (Davis & Sharif, 1999). It is well known that the therapeutic action of parasympathomimetics in patients with angle closure glaucoma is © 2014 John Wiley & Sons Ltd
connected with the induction of miosis. Thus, as PGAs induce the miotic action in small animals, it is natural to ask the question whether these drugs—similarly to parasympathomimetics—can widen or open the drainage angle and the ciliary cleft in patients with angle closure? If they did, then this would actually mean that a rapidly occurring effect and high clinical efficacy of latanoprost in dogs with an acute attack of PACG could at least partly originate from improving/giving access of AH to the trabecular and uveoscleral outflow pathways. This hypothesis is supported by the results of the research carried out by Miller et al. (2002, 2003), in which at attempt was made to determine changes occurring under the effect of latanoprost within the anterior segment of the eye of healthy (2002) and PACG-stricken dogs (2003). These studies demonstrated that in normotensive dogs, latanoprost increased the surface area of the ciliary cleft, thereby potentially improving outflow via the conventional route. Whether this increase in the surface area is the result of contraction or relaxation of the ciliary musculature, or miosis, remains to be elucidated (Miller et al., 2002). Miller et al. (2003) have concluded that the ability of latanoprost to rapidly alleviate an acute attack of PACG in dogs appears to be associated with its ability to induce miosis. Miller et al. (2002) indicated that the ocular hypotensive effect of latanoprost in dogs appears to be more complex than simply improving uveoscleral outflow, which may also occur. Together, their results suggest that latanoprost may rapidly lower IOP in dogs with an acute attack of PACG, by inducing miosis, which breaks the pupillary block, and by opening the collapsed ciliary cleft. Some recently published research results seem to somewhat question the aforementioned findings alongside the resultant theses or conclusions. Tsai et al. (2013) demonstrated that a single topical dose of latanoprost (0.005%) in normal female Beagle dogs resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. A limitation of this study is the fact that these investigators used normotensive Beagle dogs only. Therefore, the results may not be generally applicable to glaucomatous dogs, especially in patients with acute attack of PACG. It should be noticed that pilocarpine and other miotics may shallow the anterior chamber in some patients (Hung et al., 1995), which does not change the fact that these drugs increase the angle width in patients with narrow angles (Kobayashi et al., 1999). The determination of the mechanism of action which underlines the rapid and effective output of the administration of latanoprost in dogs with an acute attack of PACG requires complex investigations on changes appearing under the effect of this medicine within the anterior segment of eyes of patients suffering from this ailment.
EFFECT ON IOP Among the PGAs that are known today, latanoprost is the most thoroughly examined medication in terms of its effect of on IOP in small animals. Studer et al. (2000) demonstrated
4 T. Maslanka
that latanoprost produced a mean decline in IOP of 3 mmHg or about 25% in healthy dogs. Subsequent studies have confirmed that latanoprost significantly reduces IOP in normotensive canine eyes (Smith et al., 2010; Sarchahi et al., 2012). IOP-lowering action of this drug was also demonstrated in Beagles with inherited primary open-angle glaucoma. Gelatt and MacKay (2001) showed that 0.005% latanoprost significantly lowers IOP in the glaucomatous Beagles when instilled once daily (in the evening, morning) or twice daily. The twice-daily instillation of latanoprost resulted in less-daily IOP fluctuations. The reduction of IOP ranged from about 20 mmHg (45%) to 27 mmHg (60%) (Gelatt & MacKay, 2001). Willis (2004) observed a dramatic reduction of IOP in dogs with acute and chronic glaucoma within 20 min of administering latanoprost. As mentioned above, Miller et al. (2003) noted that 0.005% latanoprost can rapidly alleviate an attack of acute PACG in dogs and decrease IOP from as high as 80 mmHg to within normal limits in 1–2 h. Another study demonstrated that other PGAs, that is bimatoprost (Gelatt & MacKay, 2002), travoprost (Gelatt & MacKay, 2004), and unoprostone (Gelatt et al., 2004), also produce a significant decrease in IOP in glaucomatous Beagle. All the evidence indicates that the PGAs currently used in therapy do not produce an ocular hypotensive effect in the feline species; no effect of latanoprost (Studer et al., 2000), unoprostone (Bartoe et al., 2005), or bimatoprost (Bartoe et al., 2005; Regnier et al., 2006) on IOP of healthy cats has been determined. The lack of effect should not really be attributed to the fact that the uveoscleral outflow in cats only constitutes 3% of the total aqueous drainage (Bill, 1966) [whereas in dogs, it reaches 15% (Barrie et al., 1985)], because it has been demonstrated that topical application of PGF2a is able to significantly reduce IOP in cats. Most probably, the missing ocular hypotensive effect of PGAs in the feline species is due to the absence of the target sites for these agents. The biologically active metabolites of latanoprost, unoprostone, bimatoprost, and travoprost are highly selective FP receptor agonists, while feline ciliary muscle does not appear to express these receptors (Bhattacherjee et al., 1997). The IOP-lowering action of PGF2a in cats is mediated by EP1 receptors (Bhattacherjee et al., 1999), but these receptors (like EP2 receptors) are not involved in PGA-induced IOP reduction (Ota et al., 2006).
CLINICAL USE There are no clinical trials on the efficacy and safety of use of PGAs in dogs. The recommendations found in literature about the application of latanoprost come from clinical observations made by veterinary doctors during treatment of glaucomatous dogs with this medication. Other PGAs may be equally or more effective than latanoprost, but have not been used as extensively as latanoprost (Martin, 2010). In the dog, latanoprost is mostly indicated for the treatment of primary glaucoma (Willis, 2004), but it can also be applicable in certain types of secondary glaucomas. According to the
recommendations contained in Slatter’s Fundamentals of Veterinary Ophthalmology, topical 0.005% latanoprost should be considered the first line drug in therapy of an acute attack of PACG in dogs (Miller, 2008). Also, Martin (2010) routinely uses this medication topically for emergency therapy in the dog, as it often reduces IOP within 15–30 min if it is successful. Martin (2010) and Willis (2004) indicate that topical latanoprost use may enable to avoid giving mannitol in dogs with an acute attack of glaucoma. However, long-term therapy for dogs with overt PACG remains elusive (Tsai et al., 2013). In one study (Focht et al., 2006), despite an initially positive response, only 11% of dogs maintained an IOP of
