Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium

Liquid suppository systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and mucoadhesive to the rectal tissues without leakage after the dose. However, a liquid suppository system containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a liquid suppository system using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers and sodium chloride were investigated. The mixtures of P 407 (15%) and P 188 (15-20%) existed as a liquid at room temperature, but gelled at physiological temperature. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. Furthermore, the poloxamer gels with less than 1.0% of sodium chloride, in which the drug was not precipitated, were inserted into the rectum of rabbits without difficulty and leakage, and retained in the rectum of rats for at least 6 h. Our results suggested that a thermosensitive liquid suppository system with sodium chloride and poloxamers was a more physically stable and convenient rectal dosage form for diclofenac sodium.     

Inhibition of γ-irradiation induced adhesion molecules and NO production by alginate in human endothelial cells

Inflammation is a frequent radiation-induced reaction following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with gamma-irradiation (gammaIR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell surface has been known to be associated with inflammation, interfering with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that high mannuronic acid-containing alginate (HMA) inhibits gammaIR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose dependent manner. HMA also inhibited gammaIR induced production of Nitric oxide (NO). These data suggest that HMA has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.     

Difference in the thermotolerance of mouse mammary carcinoma cells in vivo and in vitro

The kinetics of thermotolerance development were compared for cells in the SCK mammary carcinoma of A/J mice, and the same cells cultured in vitro. Tumors in the legs of mice or cells in culture flasks were conditioned with heat in a water bath at 43 degrees C for 30 min and the cells were left in the tumors or the culture flasks for various lengths of time after heat conditioning. The magnitude of thermotolerance was determined by preparing single cells and subjecting them to a test heating in a controlled environment in vitro at 43 degrees C, and the survival of the cells was determined by measuring the colony-forming ability in vitro. Thermotolerance in tumors reached its maximum 12 h after heat conditioning, at which time the survival response was characterized by Do (the duration of heating required for exponential cell inactivation to 1/e) of 116 min. This changed to a Do of 170 min when the cells in tumors were incubated in culture medium of neutral pH during the development of thermotolerance. In contrast, the thermotolerance of cells cultured in vitro was fully developed within 8 h, at which time the Do was 306 min. The kinetics of thermotolerance development, therefore, varied significantly between the cells of the same origin but grown in vivo or in vitro. Killing of tumor cells in vivo caused by the heat-conditioning dose was about three times greater than that for tumor cells in vitro, but the greater damage did not result in a greater development of thermotolerance. The above results indicate that the development of thermotolerance in tumors is suppressed by the influence of intratumor environment.     

Iris-sutured posterior chamber intraocular lens implantation during penetrating keratoplasty

PURPOSE: To evaluate the clinical indications and postoperative results of iris-sutured posterior chamber intraocular lens implants performed during penetrating keratoplasty. METHODS: Medical records were retrospectively reviewed for preoperative indications and postoperative results of 342 consecutive patients (366 eyes) who underwent iris suturing of a posterior chamber intraocular lens implant during penetrating keratoplasty over a 9-year period. RESULTS: Mean follow-up was 36 months. The principal indications for corneal transplantation were pseudophakic and aphakic bullous keratopathy. Mean postoperative best spectacle-corrected visual acuity was better than preoperatively at all measured time points (P < 0.0001) and improved from 20/474 preoperatively to 20/85 at 1 year. Nine eyes (7.7%) with known preoperative glaucoma required escalation of therapy by medication or surgery to control the intraocular pressure. Seventy-two eyes (29%) without known preoperative glaucoma required treatment of elevated intraocular pressure. Seventy-nine eyes (28%) without known preoperative cystoid macular edema were additionally diagnosed. Mean endothelial cell counts declined throughout the study time frame. Corneal donor rejection episodes occurred in 36 (9.8%) eyes, with the majority having a single episode. Overall, 27 (7.4%) eyes had known graft failure at last follow-up. Two eyes (0.5%) were enucleated following wound disruption. CONCLUSIONS: These long-term results of iris-sutured posterior chamber intraocular lens implants performed during penetrating keratoplasty suggest acceptable visual acuity, graft survival, and complication rates. They are similar to published retrospective and prospective results of flexible open-loop anterior chamber and transsclerally-sutured posterior chamber intraocular lens implants placed during penetrating keratoplasty.     

Factor IX concentrate versus prothrombin complex concentrate for the treatment of hemophilia B during surgery

Hemophilia B patients are usually treated for the prevention and control of bleeding episodes with a plasma derivative containing the four vitamin K-dependent clotting factors (PPSB). Prothrombin complex concentrate and the French PPSB concentrate are known to be thrombogenic when used in long-term treatment of surgical patients. The present study reports two cases of thrombotic episodes following surgery in PPSB-treated hemophilia B patients. Since 1986, there has been available a factor IX (FIX) concentrate depleted of the other vitamin K-dependent clotting factors and virally inactivated by the solvent-detergent method. This preparation has been used as replacement therapy in six patients with severe hemophilia B who were to undergo orthopedic surgery. The management of the patients before and after operation was without any thrombotic complication or undesirable side effects. The present study suggests that there is a need for an FIX preparation devoid of the other vitamin K-dependent clotting factors for long-term therapy of hemophilia B patients.     

Pharmacokinetics of DA-7218, a new oxazolidinone, and its active metabolite, DA-7157, after intravenous and oral administration of DA-7218 and DA-7157 to rats

DA-7218 (a prodrug of DA-7157), a new oxazolidinone, was hydrolysed via phosphatase to form its active metabolite, DA-7157, in rats. The pharmacokinetic parameters of DA-7218 and DA-7157 were evaluated after intravenous (5, 10 and 20 mg kg(-1)) and oral (20, 50 and 100 mg kg(-1)) administration of DA-7218 to rats. DA-7218 and DA-7157 exhibited dose-proportional pharmacokinetics after both intravenous and oral administration of DA-7218 to rats. The stability of DA-7218 and DA-7157, blood partition of DA-7157, and the plasma protein binding of DA-7157 were also evaluated. DA-7218 was unstable in rat blood, plasma, bile and liver homogenates, but DA-7157 was stable, suggesting that DA-7218 is hydrolysed via phosphatase. DA-7157 rapidly reached equilibrium between plasma and blood cells, and the mean equilibrium plasma-to-blood cells ratio was 3.18, indicating that binding of DA-7157 to blood cells was not considerable. The protein binding of DA-7157 in fresh rat plasma was 93.4%.     

Intraocular pressure alterations following intravitreal triamcinolone acetonide

AIMS: To determine the prevalence of intraocular pressure (IOP) alterations following intravitreal injection of triamcinolone acetonide (IVTA) and to assess possible risk factors of IOP elevation in eyes receiving single and/or repeat injections. METHODS: Retrospective, consecutive case series. 570 consecutive eyes of 536 patients who received a single IVTA injection (4 mg/0.1 ml) and a second set of 43 eyes of 40 patients who received a second injection. Retrospective review of all IVTA cases performed by three vitreoretinal surgeons over a 42 month period beginning in 2000. The main outcome measure was change in IOP defined as absolute value of IOP elevation (5 mm Hg or higher, 10 mm Hg or higher), and percentage of baseline (30% or higher increase from baseline IOP). RESULTS: Of the 528 eyes receiving single injections, 281 (53.2%) had an IOP elevation; 267 eyes (50.6%) experienced an elevation of IOP of at least 30%, and 245 (45.8%) and 75 (14.2%) eyes had an increase of 5 mm Hg or 10 mm Hg or more, respectively. Baseline IOP greater than 16 mm Hg is a risk factor for post-injection IOP elevation. Of the 43 eyes which received a second injection, 28 (65.1%) experienced an increase in IOP of at least 30% of baseline. Filtering surgery was required in five (0.094%) of the single and one (2.3%) of repeat injection eyes. CONCLUSIONS: Elevated IOP after IVTA is common and patients should be monitored beyond 6 months post-injection. Patients with a baseline IOP more than 16 mm Hg or receiving a second injection should be carefully monitored for an elevated IOP.     

Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature

PURPOSE OF REVIEW: The purpose of this article is to briefly review the literature of corticosteroid-induced ocular hypertension and glaucoma, its risk factors, the pathophysiology, and treatment options. In particular, literature pertaining to glaucoma in response to intravitreal triamcinolone acetonide will be reviewed. RECENT FINDINGS: Primary open-angle glaucoma, status as a glaucoma suspect, and a family history of glaucoma are risk factors for an ocular hypertensive response with the use of corticosteroid therapy. Recent studies suggest that younger age may also be a risk factor in patients treated via the intravitreal route with corticosteroids. The mechanism of elevated intraocular pressure is increased aqueous outflow resistance owing to an accumulation of extracellular matrix material in the trabecular meshwork. SUMMARY: Corticosteroid-induced ocular hypertension and glaucoma has been recognized for more than 50 years. Knowing the risk factors, prevalence, and pathophysiology can help the clinician prevent, monitor, and treat corticosteroid-induced ocular hypertension and glaucoma.