Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression.

Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.

Evaluation of the preserving efficacy of lubricant eye drops with a novel preservative system.

Products provided in multidose containers must be adequately preserved in order to prevent contamination during repeated use. The aim of this study was to evaluate the ability of a lubricant eye drop formulation without traditional preservatives to control and prevent contamination under extreme microbial conditions. Bottles of a new lubricant eye drop with a novel preservative system (SYSTANE FREE Lubricant Eye Drops, Alcon Laboratories, Inc., Fort Worth, TX) were stored at elevated (40 degrees C) and room temperature (25 degrees C) for up to 1 year. The formulation was inoculated with microorganisms to contain high levels (approximately 1x10(6) colony forming units [cfu]/mL) of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus niger. The inoculated samples were stored at 20-25 degrees C during testing. Three types of tests were conducted: (1) tests with 1 inoculation, (2) tests with 2 inoculations over 28-day test periods, and (3) tests with 6 inoculations over a 6-month test period. Additionally, a comparison of the preservative efficacy of the SYSTANE FREE formulation to marketed products, including sodium perborate, stabilized oxychloro complex, and polyhexamethylene biguanide eye drops, was performed. In all studies, the number of survivors was determined using standard microbiological dilution pour-plate techniques. The results consistently showed that the SYSTANE FREE formulation meets preservative efficacy standards equally well, or better, than, marketed eye drop products. Even with multiple inoculations, the formulation repeatedly showed no recovery of the organisms. Though the SYSTANE FREE formulation contains no traditional preservatives, its unique blend of ions and buffers was capable of preventing contamination of the contents even after exposure to extreme conditions.

Contribution of regimen steps to disinfection of hydrophilic contact lenses.

The effect of regimen steps on overall performance of contact lens disinfection processes was evaluated. Hydrophilic lenses were inoculated with Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans, or Fusarium solani. Contributions of regimen steps and rinse volumes to disinfection abilities of OPTI-FREE EXPRESS, Solo-care Plus (Ciba Vision), Complete (Allergan), and ReNu MultiPlus (Bausch & Lomb) multi-purpose solutions were examined. Numbers of surviving microorganisms were determined. Results showed that the number and timing of regimen steps was directly related to performance of products. OPTI-FREE EXPRESS solution showed fewer survivors than did other products. Minimizing regimen steps could adversely affect product efficacy.

Anatomy of a regimen: consideration of multipurpose solutions during non-compliant use.

Consumers are often non-compliant with instructions for contact lens care products. This study explores the antimicrobial capacity of multipurpose solutions using variable use conditions. Opti-Free Express (Alcon) Multi-Purpose Disinfecting Solution with Polyquad (Alcon) and Aldox (Alcon) antimicrobial system and products containing PHMB (ReNu MultiPlus, Solo-care, and Complete multipurpose solutions) were evaluated. Products were challenged with Fusarium solani, Candida albicans, Serratia marcescens, Pseudomonas aeruginosa, and Staphylococcus aureus. The antimicrobial activity and effectiveness of regimen steps, rinse volume, stored lenses and organic soil were evaluated. The results show that products using similar regimens can show different disinfection abilities. Opti-Free Express Multi-Purpose Disinfecting Solution retained effectiveness using variable and non-compliant conditions.