Lineage of drug discovery research on fluorinated pyrimidines: chronicle of the achievements accomplished by Professor Setsuro Fujii.

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing.

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity.

The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.

INTRODUCTION: This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues. METHODS: A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews. RESULTS: BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation. CONCLUSION: As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy. TRIAL REGISTRATION NUMBER: jRCTs051190125.

Patients with glaucoma who require further reduction in intraocular pressure while undergoing monotherapy with prostaglandin analogue ophthalmic solution have been prescribed two enhanced treatment options: 0.1% brimonidine/0.5% timolol fixed combination ophthalmic solution (BTFC) and 1% dorzolamide/0.5% timolol fixed combination ophthalmic solution (DTFC). The Aibeta Crossover Study Group in Japan compared the efficacy and tolerability of fixed combinations of BTFC versus DTFC when an additional fixed combination ophthalmic solution was prescribed in patients with open-angle glaucoma or ocular hypertension who had been treated with prostaglandin analogue monotherapy. We recruited 110 patients previously treated with prostaglandin analogue monotherapy at 20 clinical centers in Japan, then randomly assigned them to two alternative treatment groups: the BTFC to DTFC group or the DTFC to BTFC group, as an adjunctive therapy to prostaglandin analogues for total of 16 weeks. We compared the reduction in intraocular pressure, occurrence of side effects, eye discomfort after instillation, and patient preference between BTFC versus DTFC instillations. The intraocular pressure reduction of BTFC instillation was comparable to that of DTFC instillation, showing non-inferiority to DTFC (3.55 mmHg vs. 3.60 mmHg; P < 0.0001, mixed-effects model). Both eye drops caused few side effects; however, patients felt greater eye discomfort with DTFC than with BTFC (P < 0.0001). Because of less eye irritation, more patients preferred BTFC (P < 0.0001) over DTFC. We can recommend using BTFC for patients who feel eye discomfort with DTFC­prostaglandin analogue combination therapy.

[Fundus photoplanimetry of the optic nerve head in the Sakurae Study].

PURPOSE: To explore the fundus photoplanimetric distribution of the optic nerve head in a population-based health survey conducted in Sakurae area, in Shimane, Japan(the Sakurae Study). METHODS: After the exclusion of poor quality images from the 1660 right eye-fundus photos obtained from the Sakurae Study in 1991, 1583 photos were digitized, and then were planimetrically analyzed using a newly developed computer software, CDSketch. The parameters calculated included vertical and horizontal cup-to-disc (C/D) ratios, superior and inferior rim-to-disc (R/D) ratios, disc and cup vertical-to-horizontal (V/H) ratios, and disc-macular distance-to-disc diameter (DM/DD) ratio. RESULTS: For the vertical and horizontal C/D, superior and inferior R/D, disc and cup V/H, and DM/DD ratios, mean values were calculated to be 0.58, 0.59, 0.20, 0.18, 1.11, 1.09, 2.60, respectively, and median values were calculated to be 0.58, 0.59, 0.19, 0.18, 1.11, 1.09, 2.57, respectively; no parameter showed any remarkably skewed distribution. The vertical C/D ratio was positively correlated with the cup V/H ratio, but was not correlated with the disc V/ H ratio. The vertical and horizontal C/D, and the disc and cup V/H ratios were negatively correlated with the DM/DD ratio. CONCLUSIONS: The distributions of the various optic nerve head parameters and their correlations in the Sakurae Study are reported. Both mean and median values of the vertical C/D ratio were approximately 0.6 in this study population. These values were larger than the previously reported C/D ratios obtained by direct ophthalmoscopic observations and/or by subjective methods.

The Efficacy, Safety, and Satisfaction Associated with Switching from Brinzolamide or Brimonidine to Brinzolamide/Brimonidine in Open-Angle Glaucoma Patients.

We evaluated switching from brinzolamide 1% or brimonidine 0.1% to a fixed-combination of brinzolamide 1% and brimonidine 0.1%, and then determined the efficacy, safety, and satisfaction associated with these changes in glaucoma patients. This prospective, nonrandomized study evaluated a total of 31 enrolled glaucoma patients who underwent treatment with at least brinzolamide 1% or brimonidine 0.1%. Patients were administered a brinzolamide/brimonidine fixed-combination ophthalmic suspension (BBFC) after being switched from their original brinzolamide 1% or brimonidine 0.1% therapy. All other intraocular pressure (IOP)-lowering medications currently being used were continued. IOP, superficial punctate keratopathy (SPK), and conjunctival hyperemia data obtained at baseline and then at 4 and 12 weeks were evaluated. To assess the changes in treatment satisfaction, this study utilized the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). There was a significant decrease in the mean baseline IOP from 15.7 ± 4.9 mmHg to 13.6 ± 4.4 (p = 0.001) and 13.5 ± 3.9 mmHg (p = 0.002) at 4 and 12 weeks, respectively. Evaluation of the incidence of conjunctival hyperemia or SPK score showed there were no significant changes noted at any time point. The TSQM-9 score demonstrated there was a significant increase for effectiveness after switching from brinzolamide 1% or brimonidine 0.1% to BBFC. After switching from brinzolamide 1% or brimonidine 0.1% to BBFC, there was a significant decrease in the IOP. Patients were aware of the effectiveness of switching from brinzolamide 1% or brimonidine 0.1% to BBFC.

Investigation of the association between SLC1A3 gene polymorphisms and normal tension glaucoma.

PURPOSE: To investigate whether the solute carrier family 1, member 3 (SLC1A3) gene, which encodes the glutamate aspartate transporter, is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: Two hundred and ninety-five Japanese patients with NTG and 518 Japanese healthy controls were recruited. Patients exhibiting comparatively early NTG onset were selected because early onset suggests that genetic factors may show stronger involvement. We genotyped 5 single-nucleotide polymorphisms (SNPs) in SLC1A3 and assessed the allelic and genotypic diversity among cases and controls. RESULTS: There were no statistically significant differences in the frequency of SLC1A3 alleles and genotypes between cases and controls. CONCLUSIONS: Our study showed no association between SLC1A3 and NTG, suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis.

The Efficacy, Safety and Satisfaction Associated with Switching from Brinzolamide 1% and Brimonidine 0.1% to a Fixed Combination of Brinzolamide 1% and Brimonidine 0.1% in Glaucoma Patients.

We evaluated glaucoma patients for the efficacy, safety and satisfaction associated with switching from brinzolamide 1% and brimonidine 0.1% to a fixed combination of brinzolamide 1% and brimonidine 0.1%. A total of 22 glaucoma patients were enrolled and completed this prospective, nonrandomized study that evaluated patients who underwent treatment with at least brinzolamide 1% and brimonidine 0.1%. Patients on brinzolamide 1% and brimonidine 0.1% were switched to a brinzolamide/brimonidine fixed-combination ophthalmic suspension (BBFC). Evaluations of intraocular pressure (IOP), superficial punctate keratopathy (SPK) and conjunctival hyperemia were conducted at baseline and at 4 and 12 weeks. The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) was utilized to assess the change in treatment satisfaction. At baseline and at 4 and 12 weeks, the IOP was 15.0 ± 4.1, 14.8 ± 4.1 and 14.8 ± 4.1 mmHg, respectively. There were no significant differences observed at any of the time points. However, the SPK score significantly decreased at 12 weeks, even though no significant differences were observed for the conjunctival hyperemia incidence at any of the time points. After switching from brinzolamide 1% and brimonidine 0.1% to BBFC, there was a significant increase in the TSQM-9 score for convenience and global satisfaction. Both an improvement in the degree of SPK and an increase in treatment satisfaction occurred after switching from brinzolamide 1% and brimonidine 0.1% to BBFC, even though there were sustained IOP values throughout the 12-week evaluation period.

Genotyping HLA-DRB1 and HLA-DQB1 alleles in Japanese patients with normal tension glaucoma.

PURPOSE: Normal tension glaucoma (NTG) is a subtype of glaucoma in which intraocular pressure is within the statistically normal range. NTG may be associated with an immune disorder. The aim of this study was to determine whether specific alleles in the human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 genes correlated with NTG in Japanese patients. METHODS: We genotyped the HLA-DRB1 and HLA-DQB1 alleles in 113 Japanese patients with NTG and in 184 healthy Japanese control subjects using the polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) Luminex method. We assessed the allelic diversity in patients and controls. RESULTS: There were no statistically significant differences in the allele frequency of HLADRB1 and HLA-DQB1 between NTG patients and control subjects, and no HLA-DRB1-HLA-DQB1 haplotypes demonstrated any significant association with NTG. CONCLUSIONS: Our findings suggest that HLA-DRB1 and HLA-DQB1 polymorphisms have no significant effect on the development of NTG in Japanese patients.

Analysis of microsatellite polymorphisms within the GLC1F locus in Japanese patients with normal tension glaucoma.

PURPOSE: To investigate whether the GLC1F locus is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: We recruited 242 unrelated Japanese subjects, including, 141 NTG patients and 101 healthy controls. The patients exhibiting a comparatively early onset were selected as they suggest that genetic factors may show stronger involvement. Genotyping and assessment of allelic diversity was performed on 11 highly polymorphic microsatellite markers in and around the GLC1F locus. RESULTS: Individuals carrying the 163 allele of D7S1277i had a statistically significant increased risk of NTG (p=0.0013, pc=0.016, OR=2.47, 95%CI=1.42-4.30). None of the other markers identified significant loci (pc>0.05) after Bonferroni's correction. CONCLUSIONS: These findings suggested that the genes in the GLC1F locus may be associated with the pathogenesis of NTG.

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

Association of toll-like receptor 2 gene polymorphisms with normal tension glaucoma.

PURPOSE: Toll-like receptor 2 (TLR2) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands, and interacts with heat-shock proteins, which are reportedly involved in normal tension glaucoma (NTG). We investigated whether TLR2 polymorphisms are associated with NTG. METHODS: 200 Japanese patients with NTG and 128 healthy Japanese controls were recruited. We genotyped five single-nucleotide polymorphisms (SNPs) in the TLR2 gene and assessed the allele and haplotype diversities between cases and controls for all SNPs. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the NTG cases were detected, compared with the controls. CONCLUSIONS: Our study showed no evidence for an association between TLR2 polymorphisms and NTG. TLR2 polymorphisms may not play an important role in NTG pathogenesis in the Japanese population.

Aromatic substitution reaction of 2-chloropyridines catalyzed by microsomal glutathione S-transferase 1.

We investigated the substitution reaction of a series of 2-chloropyridine derivatives catalyzed by rat liver microsomal glutathione S-transferase 1. Various 2-chloropyridine derivatives were metabolized to the corresponding substituted glutathione conjugates via displacement of chlorine atom with glutathione. The reaction was affected by the electron-withdrawing strength and position of the substituents. Molecular orbital calculations on the change in Gibbs free energy between the initial and transition states verified the presence of a Meisenheimer complex and its influence on the reaction rate.

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

Induction by latanoprost of collagen gel contraction mediated by human tenon fibroblasts: role of intracellular signaling molecules.

PURPOSE: The outcome of glaucoma filtration surgery is affected by subconjunctival wound healing. The effects of the antiglaucoma drug latanoprost on the contractility of human Tenon fibroblasts (HTFs) cultured in a three-dimensional collagen gel were investigated. METHODS: HTFs were cultured in a type I collagen gel with latanoprost or various inhibitors of intracellular signaling. Collagen gel contraction was evaluated by measurement of gel diameter, and collagen degradation was determined by measurement of the amount of hydroxyproline generated by acid-heat hydrolysis of culture supernatants. Phosphorylation of mitogen-activated protein kinases (MAPKs), focal adhesion kinase (FAK), and myosin light chain (MLC) was assessed by immunoblot analysis, and the formation of actin stress fibers was examined by laser confocal microscopy. RESULTS: HTF-mediated collagen gel contraction was stimulated by latanoprost in a concentration- and time-dependent manner. Latanoprost had no effect on collagen degradation by HTFs. Latanoprost induced phosphorylation of MAPKs (ERK, p38, and JNK) and FAK, as well as the formation of stress fibers in HTFs. Furthermore, latanoprost-induced collagen gel contraction was reduced by inhibitors of ERK (PD98059 and ERK inhibitor II), p38 (SB203580), JNK (JNK inhibitor II), Rho-associated kinase (Y27632), phospholipase C (U73122), and MLC kinase (ML-7). CONCLUSIONS: Latanoprost induced collagen gel contraction mediated by HTFs. This action of latanoprost appeared to depend on the formation of stress fibers and the activation of MAPKs, FAK, Rho-associated kinase, phospholipase C, and MLC kinase in HTFs. Latanoprost may therefore influence subconjunctival wound healing by affecting the contractility of Tenon fibroblasts.

Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.

Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.

Identification of a novel spiropiperidine opioid receptor-like 1 antagonist class by a focused library approach featuring 3D-pharmacophore similarity.

A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library was designed based on 3D-pharmacophore similarity to known actives. A novel D-proline amide class was identified in this library and was found to possess potent ORL1 antagonistic activity.

Effects of antiglaucoma drugs on collagen gel contraction mediated by human corneal fibroblasts.

PURPOSE: Measurement of intraocular pressure is affected by the shape and thickness of the cornea, and corneal shape is thought to be maintained by contraction of corneal fibroblasts. The effects of the antiglaucoma drugs latanoprost, timolol maleate, and pilocarpine on the contraction of corneal fibroblasts cultured in a 3-dimensional collagen gel were investigated. The effects of these drugs on collagen degradation by corneal fibroblasts and their possible cytotoxicity were also examined. MATERIALS AND METHODS: Human corneal fibroblasts were cultured in a 3-dimensional gel of type I collagen and in the presence of various concentrations of latanoprost, timolol maleate, or pilocarpine for various times. Collagen gel contraction was evaluated by daily measurement of gel diameter. The extent of collagen degradation was determined by measurement of the amount of hydroxyproline generated by acid-heat hydrolysis of culture supernatants. The release of lactate dehydrogenase from corneal fibroblasts was determined as an index of drug cytotoxicity. RESULTS: Latanoprost stimulated collagen gel contraction mediated by corneal fibroblasts in a concentration- and time-dependent manner, whereas timolol maleate and pilocarpine had no such effect. None of the 3 drugs affected collagen degradation by corneal fibroblasts or exhibited cytotoxicity at concentrations as high as 100 muM. CONCLUSIONS: Among the antiglaucoma drugs examined, only latanoprost stimulated collagen gel contraction mediated by human corneal fibroblasts. This action of latanoprost might affect corneal shape and thereby influence measurement of intraocular pressure.

Aqueous humor dynamics associated with the phorbol ester-induced decrease in intraocular pressure in the rabbit.

PURPOSE: To determine the effects of injection of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) into the anterior chamber of the eye on intraocular pressure (IOP) and aqueous humor dynamics. METHODS: IOP was measured for 24 h after intracameral injection of PMA (3 to 50 pmol) in unanesthetized rabbits. Aqueous humor dynamics (aqueous flow, total outflow facility, and uveoscleral outflow) were determined approximately 6 h after injection of 50 pmol of PMA in animals pretreated with indomethacin. RESULTS: Intracameral injection of 50 pmol of PMA induced a biphasic effect on IOP, consisting of a transient increase apparent at 0.5 and 1 h and a sustained decrease apparent after 2 h. This effect of PMA was dose dependent. Whereas pretreatment with indomethacin attenuated the PMA-induced increase in IOP, the sustained decrease in IOP remained apparent in the pretreated rabbits. Intracameral injection of 4alpha-PMA, an inactive PMA analog, had no effect on IOP. PMA also significantly increased uveoscleral outflow, but it had no effect on aqueous flow or total outflow facility. CONCLUSION: Intracameral injection of PMA reduced IOP in the rabbits by increasing the rate of uveoscleral outflow. This IOP-lowering effect of PMA may be mediated by activation of PKC.

Additional reduction in intraocular pressure achieved with latanoprost in normal-tension glaucoma patients previously treated with unoprostone.

PURPOSE: To determine whether treatment with latanoprost eye drops is able to further reduce intraocular pressure (IOP) in normal-tension glaucoma (NTG) patients whose IOP has been well controlled with unoprostone. PATIENTS AND METHODS: A total of 34 eyes (34 individuals) with NTG that had been treated with 0.12% unoprostone eye drops twice daily for >or=3 months were switched to treatment once daily with eye drops containing 0.005% latanoprost. IOP was measured before and 1, 2, and 3 months after the switch to latanoprost. RESULTS: The mean IOP of all eyes was decreased significantly by 1.8, 2.9, and 2.3 mmHg at 1, 2, and 3 months after the switch from unoprostone to latanoprost treatment. The IOP of patients with an initial IOP of 12 mmHg was reduced by 11.0 or 19.9%, respectively, after 3 months on latanoprost. The IOP of 30 (88.2%) of the 34 eyes was further reduced by the switch from unoprostone to latanoprost. CONCLUSIONS: Latanoprost reduced the IOP of NTG patients who had already been treated with unoprostone, even though both drugs are prostaglandin-related. Switching to latanoprost might thus achieve a maximal decrease in IOP and thereby better prevent damage to the optic nerve and loss of visual field in NTG patients.