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.

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.

[Pharmaceutical and pharmacological development of antitumor prostaglandins].

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.