Effect of prostaglandin analogs: Latanoprost, bimatoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human trabecular meshwork endothelial cells.

Bimatoprost, latanoprost, and unoprostone are prostaglandin F2α analogs (PGAs) and are used to lower intraocular pressure. We investigated the free acid effects of these three prostaglandin analogs: bimatoprost, latanoprost, and unoprostone on human matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in the trabecular meshwork (TM) cells. Immunoblot results show that all three PGAs generally increased MMPs-1,9 and TIMPs-4. Additionally, bimatoprost and latanoprost both increased MMP-3 and TIMP-2, while unoprostone had an indeterminate effect on both. Zymography results show that all three PGAs except unoprostone increased intermediate MMP-1 activity while bimatoprost and latanoprost increased MMP-9 activity. Together, these data suggest that the balance between MMPs and TIMPs correlate to the relative intraocular pressure lowering effectiveness observed in clinical studies of these PGAs.

Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma.

PURPOSE: We developed polycaprolactone (PCL) implants that achieve zero-order release of a proprietary ocular hypotensive agent (DE-117) over 6 months. METHODS: The release rates of DE-117-loaded PCL devices were tuned based on an established predictive model and confirmed by in vitro release studies. Devices containing DE-117 and empty devices were implanted intracamerally in normotensive rabbits for up to 8 weeks' duration. Devices were retrieved after rabbits were euthanized and evaluated for tissue adherence. The drug remaining in each device was analyzed by high performance liquid chromatography. Drug distribution in ocular tissues was measured by liquid chromatography coupled with a tandem mass spectrometry (LC/MS/MS). RESULTS: In vitro release of DE-117 showed zero-order release with a release rate of 0.5 µg/day over 6 months. Implantation in rabbit eyes demonstrated that the devices were well tolerated in the intracameral space. Quantification of DE-117 and hDE-117 (the hydrolyzed active form of DE-117) in ocular tissues (cornea, iris-ciliary body, aqueous humor, and vitreous humor) indicated sustained release of DE-117 and its conversion to hDE-117 when released from the device. Analysis of drug remaining in the device found that concentration of hDE-117 was below the limit of detection, indicating the encapsulated drug was protected from hydrolysis in the device. CONCLUSIONS: Proof-of-concept PCL drug delivery devices containing DE-117 show promise as a long-term glaucoma treatment based on their zero-order drug release profile in vitro, biocompatibility in vivo, and effective distribution of released drug in relevant ocular tissues.

Ocular Pharmacology.

Medications are a common treatment for glaucoma. Pharmacologic agents include sympathomimetics, beta-blockers, miotics (direct acting and cholinesterase inhibitors), carbonic anhydrase inhibitors, and prostaglandin agonists. Other agents include hyperosmotic agents and nonsteroidal anti-inflammatory drugs. Members of the ophthalmic health-care team, with heightened attention to patient safety, prescribe, administer, monitor side effects, and educate patients on glaucoma medications.

Observations on Prostaglandin Orbitopathy.

PURPOSE: To present the various orbital soft-tissue changes that can result from the use of topical prostaglandin analogs. METHODS: A case series of patients seen in a referral oculoplastic practice with presumed prostaglandin orbitopathy. RESULTS: Thirty-five patients were found to have a variety of disorders, including deepening of the superior sulci (24/35), hypertrichosis (32/35), periocular erythema (24/35), and meibomian gland dysfunction (18/35). Marginal eyelid thinning with posterior migration of the lash line was commonly present (34/35). Increased eyelid margin tension with horizontal eyelid shortening (32/35) was often associated with lateral canthal deformity or displacement (15/35). Lower eyelid retraction (18/35) seemed to contribute to ptosis in some patients, secondary to apparent tethering at the lateral canthus. Functional conditions resulting from the above structural abnormalities included tractional ptosis (n = 4), cicatricial entropion (n = 3), cicatricial ectropion (n = 2), trichiasis (n = 2), eyelid subluxation (n = 1), and chalazia (n = 1). CONCLUSIONS: While topical prostaglandin analogs are well-tolerated by many patients with glaucoma, some individuals using these medications develop structural changes of the orbital soft tissue resulting in a variety of cosmetic and functional eyelid disorders. The eyelid margins can thin, causing posterior migration of the lashes. Increased horizontal tension of the eyelids may result in acquired blepharophimosis and upper or lower eyelid malposition. These orbital changes may be partially reversible in some patients. When possible, it is reasonable to withhold the prostaglandin and allow a period of observation before proceeding with surgical correction.

Synthesis and in vitro cytotoxicity of cross-conjugated prostaglandin A and J series and their hydroxy derivatives.

The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 µM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM.

Traceless stereoinduction for the enantiopure synthesis of substituted-2-cyclopentenones.

The pseudoenantiomeric 4-O-Boc- and 4-OPMP-cyclopent-2-enones, readily available from hydroxymethylenefurane on multigram scale, are demonstrated to be exceptional building blocks for the synthesis of enantiopure 4-alkyl-5-(1'-hydroxyalkyl) substituted 2-cyclopentenones and derivatives thereof. The 4-OR substituent acts as a traceless stereoinducing element, conferring not only 1,2- but also 1,4-stereocontrol with excellent selectivity. The methodology developed here was applied for the rapid synthesis of natural products and biologically active 2-cyclopentenones such as TEI-9826, guaianes, and pseudoguaianolides.

O-Monoacyltartaric acid catalyzed enantioselective conjugate addition of a boronic acid to dienones: application to the synthesis of optically active cyclopentenones.

Enantioselective conjugate addition of styrylboronic acid to dienones was effectively catalyzed by an O-monoacyltartaric acid to afford monostyrylated products with good enantioselectivity. The RCM of the monostyrylated products using the Hoveyda-Grubbs II catalyst afforded optically active cyclopentenones, including a synthetic intermediate of the antitumor agent TEI-9826. The study shows that a diene additive such as 1,6-heptadiene or diallyl ether was essential for the RCM.

Iridium-catalyzed enantioselective allylic substitution of unstabilized enolates derived from α,ß-unsaturated ketones.

We report Ir-catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,ß-unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62-94% yield with 90-98% ee and >20:1 branched-to-linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI-9826.

Effect of ketorolac add-on treatment on intra-ocular pressure in glaucoma patients receiving prostaglandin analogues.

BACKGROUND/AIMS: While topical ocular hypotensive agents cause secretion of endogenous prostaglandin (PG), systemic and topical non-steroidal anti-inflammatory agents inhibit its production; thus, they may interfere with therapeutic efficacy. This study aimed to investigate the effect of add-on treatment with ketorolac on intra-ocular pressure (IOP)-lowering effects of three different PG analogues. METHODS: This study included 30 adult bilateral glaucoma patients who had been receiving PG analogues for primary open-angle glaucoma (n = 25) or pseudoexfoliation glaucoma (n = 5). Ketorolac tromethamine 0.5% and placebo drops were administered to the right and left eyes of the patients, respectively, 4 times a day for 1 week. IOP measurements were performed at baseline, within the first 4 h after application, on days 1, 3 and 7, and 1 and 7 days after discontinuation of the treatment. RESULTS: Eyes receiving ketorolac had significantly lower IOP throughout the treatment period (p < 0.001). Patients who were on latanoprost, travoprost and bimatoprost did not differ with regard to the change in IOP (p = 0.780). After discontinuation, pressures became similar on day 1 (p = 0.796) and day 7 (p = 0.314). CONCLUSION: In glaucoma patients, ketorolac significantly enhances the IOP-lowering effects of latanoprost, travoprost and bimatoprost.

Eficácia de dinoprostone e misoprostol para indução do trabalho de parto em nulíparas / Efficacy of dinoprostone and misoprostol for labor induction in nulliparous women

OBJETIVO: verificar a eficácia e a segurança de dinoprostone e misoprostol para indução do parto vaginal, com ou sem o uso de ocitocina em nulíparas. MÉTODOS: realizou-se estudo retrospectivo, observacional, envolvendo 238 pacientes que foram submetidas à indução do parto de janeiro de 2008 a fevereiro de 2010 com uso de misoprostol 25 mcg via vaginal ou pessário contendo 10 mg de dinoprostone. Desse grupo, foram selecionadas 184 pacientes, que apresentavam as seguintes características: nulíparas, gestação entre 37 e 42 semanas, feto único, apresentação cefálica, membranas íntegras e índice de Bishop < 3. Os resultados obstétricos e neonatais foram analisados e comparados entre ambos os grupos. A análise estatística foi realizada com o teste t, Chi quadrado e exato de Fisher, adotando-se como nível de significância valores p<0,05. RESULTADOS: a taxa de parto vaginal não foi estatisticamente diferente em pacientes que utilizaram misoprostol e dinoprostone (43,2 versus 50 por cento, p=0,35), respectivamente. O amadurecimento do colo foi superior no grupo com misoprostol (87,3 versus 75,6 por cento, p=0,04). Foi necessária a utilização da ocitocina em 58,8 por cento no grupo com misoprostol e 57,3 por cento no grupo com dinoprostone após o amadurecimento do colo. Falha de indução foi a principal indicação do parto cesárea em ambos os grupos, sem diferença estatística significante. Eventos adversos maternos e fetais, como taquissistolia e índices de Apgar foram similares. CONCLUSÃO: dinoprostone e misoprostol são eficazes para indução do parto vaginal, embora seja necessária a associação com ocitocina, apresentando perfil de segurança semelhante, sendo misoprostol mais eficiente no amadurecimento do colo uterino.

PURPOSE: to determine the efficacy and safety of dinoprostone and misoprostol for the induction of vaginal childbirth, with or without the use of oxytocin in nulliparous women. METHODS: in this retrospective observational study, 238 patients were subjected to the induction of delivery from January 2008 to February 2010 with the use of misoprostol 25 mcg by the vaginal route or a pessary containing 10 mg of dinoprostone. A total of 184 patients were selected, with the following characteristics: nulliparous, gestational age of 37-42 weeks, singleton pregnancies, cephalic presentation, intact membranes, and Bishop score < 3. Obstetric and neonatal data were analyzed and compared between groups. The Student t-test, chi-square test and Fisher's exact test were used for statistical analysis, with the level of significance set at p<0.05. RESULTS: the rate of vaginal childbirth did not differ significantly in patients who used misoprostol and dinoprostone (43.2 percent versus 50 percent; p = 0.35, respectively). The ripening of cervix was higher in the group treated with misoprostol (87.3 percent versus 75.6 percent, p=0.04). The use of oxytocin was necessary in 58.8 percent of the misoprostol group and 57.3 percent in the dinoprostone group after the ripening of cervix. Failed induction was the primary indication of caesarean section delivery in both groups, with no significant difference between them. Fetal and maternal adverse events, such as tachysystole and Apgar scores were similar. CONCLUSION: dinoprostone and misoprostol are both effective for vaginal childbirth induction, although they need to be combined with oxytocin. They showed a similar safety profile, with misoprostol being more efficient regarding cervical ripening.

Predicting response to glaucoma therapy in one eye based on response in the fellow eye: the monocular trial.

OBJECTIVE: To evaluate whether the change in intraocular pressure (IOP) observed in one eye after starting a glaucoma medication regimen is predictive of the change in IOP due to the same medication in the fellow eye. METHODS: A retrospective medical record review of 22 patients with primary open-angle glaucoma (POAG) and 27 glaucoma suspects who underwent monocular drug trials before the drug was added to the second eye. The absolute change in IOP from baseline and the relative change (change in treated eye minus change in fellow eye) in the first eye treated were compared with the second eye after binocular treatment. RESULTS: The absolute and relative decreases in IOP of the first eye were poorly correlated with those of the second eye in patients with POAG (r(2) < 0.001; P = .97 and r(2) = 0.040; P = .38, respectively). However, they were well correlated in glaucoma suspects (r(2) = 0.348; P = .001 and r(2) = 0.396; P < .001, respectively). CONCLUSIONS: The change in IOP of one eye due to a medication may be predictive of the subsequent response of the fellow eye to the same medication in glaucoma suspects, but not in patients with POAG. Using the fellow eye as a control may confer a more accurate portrayal of the true therapeutic effects of a medicine, although further study is needed to support both of these findings.

Preparation of 2,4-disubstituted cyclopentenones by enantioselective iridium-catalyzed allylic alkylation: synthesis of 2'-methylcarbovir and TEI-9826.

A broadly applicable synthesis of chiral 2- or 2,4-substituted cyclopent-2-enones has been developed by combining asymmetric iridium-catalyzed allylic alkylation reactions and ruthenium-catalyzed ring-closing metathesis. Enantiomeric excesses (ee values) in the range of 95-99 % ee have been achieved. This method offers a straightforward access to biologically active prostaglandins of the PGA type. As an example, an enantioselective synthesis of the prostaglandin-analogue 13,14-dihydro-15-deoxy-Delta(7)-prostaglandin-A1-methyl ester (TEI-9826) has been carried out. Furthermore, the carbonucleoside 2'-methylcarbovir has been prepared from O-protected 4-hydroxymethyl-2-methyl-cyclopent-2-enone by Pd-catalyzed allylic amination.

Enantioselective synthesis of 12-amino alkylidenecyclopentenone prostaglandins.

An enantioselective synthesis of new 12-amino alkylidenecyclopentenone prostaglandins is reported. The key step of the synthesis involved a [3.3] sigmatropic rearrangement of an asymmetric allylic cyanate to elaborate an asymmetric 5-amino-1,6-diene which was further transformed into cyclopentenone by successive ring-closing metathesis reaction catalyzed by the Grubbs reagent and one-pot oxidation. A palladium-catalyzed cross-coupling reaction on a 5-iodo-1,5-diene allowed the synthesis of prostanoids with variable Rw side chains. These new compounds exhibit high cytotoxic activities.

Avaliaçäo da resposta tecidual frente a diferentes materiais de fixaçäo em enxertos ósseos autógenos: análise microscópica morfológica / Evaluation of tissue response due to different fixation materials in autogenous bone grafts: microscopic morphological analysis

Os enxertos ósseos autógenos têm sido largamente empregados para a reconstruçäo de rebordos atróficos. A fixaçäo destes enxertos é fundamental no fenômeno de reparaçäo óssea, propiciando a incorporaçäo ao leito receptor e rápida revascularizaçäo. Placas e parafusos sintéticos reabsorvíveis têm sido desenvolvidos na tentativa de minimizar alguns pontos negativos dos materiais metálicos rotineiramente utilizados para esta finalidade. O presente estudo avaliou comparativamente as condiçöes ósseas locais de enxertos ósseos autógenos oriundos da regiäo mentoniana quando em contato com parafusos de ácido poliglicólico (PGA)/ácido poli (L-láctico) (PLA) e de titânio. Para esta avaliaçäo, participaram sete pacientes apresentando atrofias maxilar e mandibular severas, impossibilitando a reabilitaçäo com implantes osteointegráveis. Após quatro meses das cirurgias de enxerto, as áreas onde se localizavam os parafusos de teste foram biopsiadas com brocas trefinas, obtendo-se os espécimes a serem submetidos a procedimento histotécnico de rotina e corados em H.E. e Tricrômico de Mallory para avaliaçäo morfológica em microscopia óptica de luz. A partir desta análise observou-se, adjacente aos parafusos de titânio, tecido ósseo viável, com eventuais áreas recobertas por células de revestimento e ausência de reabsorçäo. Adjacente aos parafusos reabsorvíveis, o tecido ósseo também apresentou viabilidade morfológica, porém, com presença de extensa faixa de tecido conjuntivo fibroso interposto, e eventuais células gigantes. Estes resultados sugerem que ambos os métodos de fixaçäo proporcionaram condiçäo de reparo no local de enxertos, contudo, os parafusos reabsorvíveis induziram reaçäo inflamatória mais extensa que os de titânio, caracterizada por reaçäo tipo corpo estranho

Effect of the novel prostaglandin A1 derivative TEI-6363 on ROS17/2.8 cell differentiation in vitro.

The effect of TEI-6363 (5-[E-4-N,N-dimethylaminophenylmethylene]-4-hydroxy-2-[1-methyl imidazole-2-ilthio]-4-[4-phenylbutyl]-2-cyclopentenone), a chemically synthesized prostaglandin A1 derivative, on cell proliferation and osteoblastic differentiation was investigated concurrently. ROS17/2.8 cells (a rat osteosarcoma-derived cell line) were treated with TEI-6363 at two concentrations, 10(-7) and 10(-6) M, and viable cells were counted to assess cytotoxic effects and determine the growth curve. After 96 h of treatment, there was no evidence of any effect of TEI-6363 on cell viability at either concentration. However, a clear inhibitory effect on cell proliferation was observed after treatment with 10(-6) M TEI-6363 for 24 h or longer. A pulse-treatment experiment showed that TEI-6363 induced the inhibition of proliferating ROS17/2.8 cells 24 h after addition. The inhibition of proliferation was associated with G1-arrest demonstrated by flow cytometric analysis, and incorporation of [3H]thymidine by ROS17/2.8 cells was decreased. Osteoblastic differentiation (assessed on the basis of increased alkaline phosphatase activity and collagen synthesis) was induced by TEI-6363 treatment at 10(-6) M following G1-arrest and inhibition of cell proliferation. These results suggest that TEI-6363 arrested the cell cycle of ROS17/2.8 cells at the G1 phase and induced osteoblastic differentiation. These results did not appear to be dependent on a marked cytotoxic effect.

Anti-cancer-prostaglandin-induced cell-cycle arrest and its modulation by an inhibitor of the ATP-dependent glutathione S-conjugate export pump (GS-X pump).

The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Here we report that Delta7-PGA1 methyl ester, a synthetic anti-cancer PG, increased the level of mRNA for the cyclin-dependent kinase inhibitor p21 in human leukaemia HL-60 cells. The induction of p21 was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Since the p53 gene is deleted in HL-60 cells, the anti-cancer PG is suggested to inhibit cancer cell growth by inducing p21 via a p53-independent pathway. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta7-PGA1 methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anti-cancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump (ATP-dependent glutathione S-conjugate export pump) activity towards the glutathione S-conjugate of Delta7-PGA1 methyl ester (Km 110 nM). GIF-0019 ¿N-carbomethoxy-S-[5-(4-benzoylphenyl)pentyl]glutathione dimethyl ester¿, a specific inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta7-PGA1 methyl ester and induced G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anti-cancer PG.