Regression of taxane-related cystoid macular edema after topical dorzolamide treatment: two case reports.

BACKGROUND: Cystoid macular edema is a rare, vision-threatening side effect of the taxane family of anticancer agents. There is no established treatment or standard treatment protocol for taxane-related cystoid macular edema. Here, we report two cases of taxane-related cystoid macular edema that were treated with topical dorzolamide. CASE PRESENTATION: In case 1, a 72-year-old Japanese woman with bilateral geographic choroiditis reported for a follow-up visit with a complaint of blurred vision in both eyes for 2 months after starting nanoparticle albumin-bound paclitaxel chemotherapy for multiple metastases of her breast cancer. Her best-corrected visual acuity had dropped from 1.2 to 0.9 in the right eye and from 1.0 to 0.4 in the left eye. Fundus examination showed no newly active geographic choroiditis lesion, but optical coherence tomography exhibited cystoid macular edema. We suspected taxane-related cystoid macular edema and terminated nanoparticle albumin-bound paclitaxel, and started topical dorzolamide treatment. Cystoid macular edema nearly resolved within 6 weeks in the right eye and within 10 weeks in the left eye after starting topical dorzolamide treatment. The resolution of cystoid macular edema without leaving a chorioretinal scar after discontinuation of paclitaxel confirmed our initial diagnosis of taxane-related cystoid macular edema. A few inconspicuous cystoid spaces persisted at the parafovea for a year after dorzolamide treatment ended, but regressed after restarting dorzolamide treatment without any side effects. Best-corrected visual acuity improved to 1.2 in the right eye and 1.0 in the left eye. In case 2, a 70-year-old Japanese man, who received nanoparticle albumin-bound paclitaxel for pancreatic cancer with multiple metastases, developed bilateral cystoid macular edema. Best-corrected visual acuity was 0.3 bilaterally. Cystoid macular edema resolved within 5 weeks after stopping nanoparticle albumin-bound paclitaxel and starting topical dorzolamide treatment confirming the diagnosis of taxane-related cystoid macular edema. Nine weeks later, best-corrected visual acuity improved to 0.8 in the right eye and 1.0 in the left eye. CONCLUSIONS: Cystoid macular edema in each case resolved within a few months without any side effects using topical dorzolamide and terminating taxane-based chemotherapy. Topical dorzolamide appears to be a safe and effective treatment option for patients with taxane-related cystoid macular edema whose quality of life is threatened by visual disturbances.

Effect of Rho Kinase Inhibitor Ripasudil (K-115) on Isolated Porcine Retinal Arterioles.

Purpose: To investigate the vasorelaxation effect of ripasudil (K-115), a novel Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, on isolated retinal arterioles. We determined whether the actions of ripasudil on the retinal microvascular diameter were dependent on the endothelium and/or potassium channels in the smooth muscle, with the goals of uncovering the signaling mechanisms required for this vasomotor activity and inhibiting the action of endothelin-1 (ET-1). Methods: In this in vitro study, we isolated porcine retinal arterioles, which were cannulated and pressurized without flow. We recorded diametric changes using videomicroscopic techniques. Results: In a dose-dependent (10 nM-30 µM) manner, retinal arterioles were relaxed in response to ripasudil [maximum % resting diameter, 160.3% ± 7.7% (mean ± standard error of the mean)]. The ripasudil-induced vasorelaxation was unaffected by endothelium removal, using nonselective potassium channel blocker tetraethylammonium, Ca2+-activated large-conductance potassium channel blocker iberiotoxin, voltage-gated potassium channel blocker 4-AP, ATP-sensitive potassium channel blocker glibenclamide, and inward rectifier potassium channel blocker BaCl2. Ripasudil prevented ET-1-caused vasoconstriction of the retinal arterioles regardless of the presence of endothelium to a similar extent. Conclusion: The ROCK inhibitor ripasudil elicits endothelium-independent relaxation and inhibits the action of ET-1 on the retinal arterioles. Determining the relaxation properties of ripasudil on the retinal microvasculature will likely support the development of potential therapies for glaucoma.

Thrombin-Induced Responses via Protease-Activated Receptor 1 Blocked by the Endothelium on Isolated Porcine Retinal Arterioles.

PURPOSE: Thrombin, a serine protease, causes organ-specific responses to vessels. However, the mechanism by which thrombin affects the retinal microcirculation remains unclear. We examined the effects of thrombin on the retinal microvasculature and signaling mechanisms. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized (55 cmH2O) without flow in this in vitro study. Videomicroscopy techniques recorded changes in diameter in the retinal arterioles in response to thrombin at concentrations ranging from 0.001 to 20 mU/ml. RESULTS: Extraluminal administration of thrombin induced concentration-dependent vascular responses, that is, vasoconstriction at low concentrations less than 5 mU/ml and vasorelaxation with high concentrations greater than 5 mU/ml. However, intraluminal administration of thrombin (5 mU/m) did not constrict the retinal arterioles; in denuded vessels, intraluminal administration constricted the retinal arterioles. Thrombin-induced vasoconstriction was significantly (p < 0.01) suppressed by pretreatment with a protein kinase C (PKC) inhibitor and a protease-activated receptor (PAR)-1 inhibitor but not by PAR-2 and PAR-4 inhibitors or denudation. A rho kinase (ROCK) inhibitor also suppressed thrombin-induced vasoconstriction (5 mU/ml) compared with sodium nitroprusside. Endothelial denudation and pretreatment with an endothelial nitric oxide (NO) synthase inhibitor suppressed vasorelaxation caused by a high concentration of thrombin. CONCLUSIONS: A low concentration of thrombin causes vasoconstriction of smooth muscles via PAR-1, PKC, and ROCK, and a high concentration of thrombin possibly causes vasorelaxation of the retinal arterioles via nitric oxide synthase activation in the endothelium. The vascular endothelium might block signaling of thrombin-induced vasoconstriction in the retinal arterioles when administered intraluminally.

Benzo(e)pyrene Inhibits Endothelium-Dependent NO-Mediated Dilation of Retinal Arterioles via Superoxide Production and Endoplasmic Reticulum Stress.

Purpose: To investigate whether benzo(e)pyrene (B(e)P), a toxicant in cigarette smoke, affects the endothelium-dependent nitric oxide (NO)-induced vasodilation of the retinal arterioles, and whether oxidative stress, distinct protein kinase signaling pathways, and endoplasmic reticulum (ER) stress are associated with the B(e)P-induced effect on the retinal arterioles. Methods: In this in vitro study, porcine retinal arterioles were isolated, cannulated, and pressurized without flow. These vessels were treated with intraluminal administration of B(e)P or B(e)P plus blockers for 180 minutes. Diametric changes to agonists were recorded by videomicroscopy. Results: Intraluminal treatment with 100 µM B(e)P for 180 minutes significantly reduced the arteriolar vasodilation caused by the endothelium-dependent NO-mediated agonists bradykinin and A23187 but not that caused by endothelium-independent NO donor sodium nitroprusside. The adverse effects of B(e)P on the vasodilatory action of bradykinin were prevented by the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) inhibitor apocynin, the c-Jun N-terminal kinase (JNK) inhibitor SP600125, the p38 mitogen-activated protein kinase inhibitor SB203580, genistein, resveratrol (RSV), and the ER stress inhibitor 4-phenylbutyrate (4-PBA). The xanthine oxidase inhibitor allopurinol did not alter the effect of B(e)P on the vasodilatory action induced by bradykinin. Conclusions: B(e)P decreases the endothelium-dependent NO-induced vasodilation in the retinal arterioles through the production of superoxide from NADPH oxidase, which is linked to JNK and p38 kinase. The results suggested that ER stress is instrumental in B(e)P-induced endothelial dysfunction and that genistein and RSV might preserve endothelial function.

Effect of the External Lubrication Method for a Rotary Tablet Press on the Adhesion of the Film Coating Layer.

External lubrication is a useful method which reduces the adhesion of powder to punches and dies by spraying lubricants during the tableting process. However, no information is available on whether the tablets prepared using an external lubrication system can be applicable for a film coating process. In this study, we evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method, compared with those prepared using internal lubrication method. We also evaluated wettability, roughness and lubricant distribution state on the tablet surface before film coating, and investigated the relationship between peeling of the film coating layer and these tablet surface properties. Increasing lubrication through the external lubrication method decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. On the other hand, increasing lubrication through the internal lubrication method, decreased both wettability of the tablet surface and the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed using an X-ray fluorescent analyzer and lubricant agglomerates were observed in the case of the internal lubrication method. However, the lubricant was uniformly dispersed in the external lubrication samples. These results indicate that the distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant.

Histamine-Induced Dilation of Isolated Porcine Retinal Arterioles: Role of Endothelium-Derived Hyperpolarizing Factor.

PURPOSE: Although endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles has been well described, the role of endothelium-derived hyperpolarizing factor (EDHF) in the retinal arteriolar response remains unclear. In the current study, we examined the contribution of EDHF to the retinal arteriolar dilation to the inflammatory agent histamine and investigated the signaling mechanisms underlying this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow for functional study by using video microscopic techniques. The immunohistochemical staining was performed to determine histamine receptor subtypes. RESULTS: Histamine (0.1-30 µM) produced concentration-dependent dilation of retinal arterioles in a manner sensitive to H1- and H2-receptor antagonists chlorpheniramine and famotidine, respectively. Histamine-induced vasodilation was almost abolished after endothelial removal. In the intact vessels, vasodilation to histamine was partially inhibited by the inhibitors of cyclooxygenase (indomethacin), NO synthase (NG-nitro-L-arginine methyl ester, L-NAME), or Ca2+ -activated K+ (KCa) channels (apamin plus charybdotoxin). Combination of the above inhibitors abolished histamine-induced vasodilation. Residual vasodilation in the presence of indomethacin and L-NAME was further reduced by the cytochrome P450 enzyme inhibitor sulfaphenazole but not by the gap junction inhibitor carbenoxolone or the hydrogen peroxide scavenger catalase. Immunohistochemical signals for H1- and H2-receptor expression were found only in the endothelium. CONCLUSIONS: The endothelium plays an essential role in the dilation of porcine retinal arterioles to histamine via H1- and H2-receptor activation. The EDHF derived from cytochrome P450 contributed in part to this vasodilation via KCa channel activation, in addition to the endothelial release of NO and prostanoids.

Beraprost sodium, a stable prostacyclin analogue, elicits dilation of isolated porcine retinal arterioles: roles of eNOS and potassium channels.

PURPOSE: Prostacyclin (PGI2) is usually described as an endoEDRFsthelium-derived relaxing factor, but the vasoreactivity to PGI2 in the retinal arterioles and the underlying mechanisms are not fully understood. We examined the effects of PGI2 on the retinal microcirculation using beraprost sodium (BPS), a stable PGI2 analogue, and the signaling mechanisms involved in this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to BPS. RESULTS: Beraprost sodium elicited dose-dependent (0.1 pM-0.1 µM) vasodilation of the retinal arterioles that was abolished by the PGI2 receptor (IP) antagonist CAY10441. Beraprost sodium-induced vasodilation decreased by 50% after the endothelium was removed and was inhibited by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) comparable with denudation. Inhibition of soluble guanylyl cyclase by 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and blockage of protein kinase A (PKA) by Rp-8-Br-cAMPS were comparable to L-NAME. Beraprost sodium-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor, tetraethylammonium, and the adenosine triphosphate-sensitive potassium (KATP) channel blocker, glibenclamide. Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ. CONCLUSIONS: Beraprost sodium, a stable PGI2 analogue, causes vasodilation of the retinal arterioles mediated via the IP receptor. The current findings suggest that BPS elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle, respectively.

Role of Ca2+ -dependent and Ca2+ -sensitive mechanisms in sphingosine 1-phosphate-induced constriction of isolated porcine retinal arterioles in vitro.

Although sphingosine 1-phosphate (S1P), a bioactive lipid derived from activated platelets, has a variety of physiologic effects on vessels, no reports have described the effect of S1P on the retinal circulation. We examined the effect and underlying mechanism of the vasomotor action of S1P on porcine retinal arterioles. The porcine retinal arterioles were isolated, cannulated, and pressurized without flow for in vitro study. S1P-induced diameter changes were recorded using videomicroscopic techniques. S1P elicited concentration-dependent (1 nM-10 µM) vasoconstriction of the retinal arterioles that was abolished by the S1P receptor 2 (S1PR2) antagonist JTE-013. S1P-induced vasoconstriction was abolished by the Rho kinase (ROCK) inhibitor H-1152 and was inhibited partly by the protein kinase C (PKC) inhibitor Gö-6983. The inhibition of phospholipase C by U73122 and L-type voltage-operated calcium channels (L-VOCCs) by nifedipine inhibited S1P-induced vasoconstriction; a combination of both inhibitors abolished S1P-induced vasoconstriction. Furthermore, inhibition of myosin light chain kinase (MLCK) by ML-9 significantly blocked S1P-induced vasoconstriction; further coadministration of ML-9 with H-1152 or Gö-6983 abolished S1P-induced vasoconstriction. The current data suggest that S1P elicits vasoconstriction of the retinal arterioles via S1PR2 in vascular smooth muscle cells and this vasoconstriction may be mediated by the Ca2+ -sensitive pathway via activation of PKC leading to activation of ROCK and the Ca2+ -dependent pathway via activation of L-VOCCs resulting in activation of MLCK.

Dilation of porcine retinal arterioles to cilostazol: roles of eNOS phosphorylation via cAMP/protein kinase A and AMP-activated protein kinase and potassium channels.

PURPOSE: Cilostazol, a selective inhibitor of phosphodiesterase 3, has antiplatelet aggregation and peripheral vasodilation effects. We examined the effects of cilostazol on the retinal microvascular diameter to determine its dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to cilostazol. RESULTS: The retinal arterioles dilated in response to cilostazol in a dose-dependent (100 pM-10 µM) manner; the dilation decreased by 60% after endothelial removal. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited cilostazol-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase and blockade of protein kinase A (PKA) were comparable to L-NAME. Compound C, an AMP-activated protein kinase (AMPK) inhibitor, partially inhibited cilostazol-induced vasodilation, which exhibited a weaker inhibitory effect on cilostazol-induced vasodilation than blockade of PKA. The large-conductance Ca²âº-activated K channel (BK(Ca) channel) blocker, iberiotoxin, also inhibited cilostazol-induced vasodilation. The residual vasodilation decreased further with co-administration of L-NAME and iberiotoxin. CONCLUSIONS: Cilostazol elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO release and BK(Ca) channel activation, respectively. Endothelial nitric oxide synthase (eNOS) phosphorylation via the cAMP/PKA and AMPK pathways and consequent activation of the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway might play an important role in cilostazol-induced vasodilation of the retinal arterioles.

Fenofibrate, an anti-dyslipidemia drug, elicits the dilation of isolated porcine retinal arterioles: role of nitric oxide and AMP-activated protein kinase.

PURPOSE: Although recent clinical trials have demonstrated that fenofibrate is effective for treating diabetic retinopathy, the mechanism of this beneficial effect remains unclear. In the current study, we examined the effect of the vasomotor action of fenofibrate on porcine retinal arterioles. METHODS: Porcine retinal arterioles (internal diameter, 60-90 µm) were isolated, cannulated, and pressurized (55 cmH(2)O) without flow in vitro. Video-microscopic techniques recorded the diameter responses to fenofibrate. RESULTS: The retinal arterioles dilated in a dose-dependent manner in response to fenofibrate (10 nM to 30 µM). This vasodilation significantly decreased after the endothelium was removed. N(ω)-nitro-L-arginine methyl ester (a nitric oxide [NO] synthase inhibitor), 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (a soluble guanylyl cyclase inhibitor), wortmannin (a phosphatidylinositol [PI] 3-kinase inhibitor), and compound C (an AMP-activated protein kinase inhibitor) attenuated the effect of fenofibrate-induced vasodilation to an extent comparable to that produced by denudation. Pretreatment with GW6471, a peroxisome proliferator-activated receptor-α blocker, did not significantly inhibit fenofibrate-induced vasodilation. CONCLUSIONS: Fenofibrate primarily elicited endothelium-dependent dilation of the retinal arterioles. The current findings suggested that fenofibrate-induced endothelium-dependent vasodilation is mediated by the release of NO, which probably mediates dilation via activation of guanylyl cyclase, the PI3-kinase pathway, and the AMP-activated protein kinase pathway. Understanding the vasodilatory effect of fenofibrate on the retinal microvasculature may improve potential therapy for diabetic retinopathy.

The effect of backbone structure on polycation comb-type copolymer/DNA interactions and the molecular assembly of DNA.

A series of comb-type copolymers comprised of various polycation backbones and dextran (Dex) side chains were prepared to study the DNA/copolymer interaction. While the cationic copolymers with a lower degree of dextran grafts maintained an ability to condense DNA molecules into a globule form those with a higher degree of dextran grafting interacted with DNA without inducing DNA condensation. The structural differences in cationic backbones diversely influenced DNA hybridization as evaluated by circular dichroism (CD) spectrometry and UV-melting analyses. The copolymer having a polyallylamine (PAA) backbone induced B-->A-type transformation of DNA duplex, whereas the copolymers having either alpha-poly(l-lysine) (alpha PLL) or epsilon-poly(l-lysine) (epsilon PLL) backbone induced B-->C-type transformation. The PAA copolymer is the first example of the artificial polymer that induces B-->A-type transformation under physiologically relevant condition. UV-melting analyses of DNA strands indicated that the alpha PLL copolymers showed the highest stabilization efficacy toward poly(dA).poly(dT) duplex and poly(dA).2poly(dT) triplex without affecting reversibility of inter DNA association. Melting temperatures (T(m)) of the triplex increased from 38 degrees Celsius to 99 degrees Celsius by the addition of the alpha PLL copolymer with an appropriate grafting degree. While the PAA copolymers had higher density of cationic groups along the backbone than alpha PLL copolymers, these copolymers moderately increased T(m) of the DNA triplex. The PAA copolymer caused considerable hysteresis in thermal melting/reassociation processes. Note that the PLL copolymers increased T(m) of the DNA triplex and not the duplex, suggesting their potential as a triplex selective stabilizer. Chemical structures of the cationic backbones of the copolymers were characteristically affected on the copolymer/DNA interaction even if their backbones were surrounded by abundant side chains (> wt%) of dextran. The study suggested that tailor-made design of "functional polycounterion" is a strategy to engineer molecular assembling of DNA.