Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL^?1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter. There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.     

Clinical trial: the efficacy and safety of oral PF‐03491390, a pancaspase inhibitor – a randomized placebo‐controlled study in patients with chronic hepatitis C

Aliment Pharmacol Ther 31 , 969–978

Summary

Background Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF‐03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases. Aim To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. Methods Double‐blind, randomized, placebo‐controlled, parallel‐dose study in 204 patients treated with placebo or PF‐03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly. Results Significant reductions in serum AST and ALT were observed within 1 week of initiating PF‐03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF‐03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue. Conclusion PF‐03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks.     

"Ulcerative Appendicitis" Occurring as a Skip Lesion in Chronic Ulcerative Colitis

A 39-year old white female with a 19-year history of chronic ulcerative colitis was admitted to the hospital with fulminating disease and toxic megacolon requiring total colectomy.
The appendicial changes were most unusual. The pathological changes were typical of those seen in ulcerative colitis, namely, mucosal ulceration and crypt abscess formation ("ulcerative appendicitis"). Furthermore, these changes occurred as a skip lesion since the cecum and ascending colon were both free of disease.     

Antigenic variation in Giardia lamblia: cellular and humoral immune response in a mouse model

Neonatal mice (CR:NIH:S) were infected with a cloned human isolate of Giardia lamblia (GS/M-83-H7) and the surface antigens of the intestinal trophozoites, as well as the cellular and humoral immune responses, were analysed during the course of infection. Infections in mice peaked 2-3 weeks after inoculation and were self-cured by day 42 post-infection (p.i.). The proportion of trophozoites expressing the Mr 72,000 surface antigen of the initial inoculum had decreased by day 12 and approached zero by day 22 p.i., similar to infections in humans. The predominant parasite-specific humoral response was an IgM- and IgG-isotype directed to the original Mr 72,000 surface antigen as well as other antigens. T-lymphocytes (predominantly LY4(CD4)+) isolated from Peyer's patches 12 days p.i. and later showed a significant proliferative response to Giardia lamblia antigens. Spleen and lymph node cells showed no lymphoproliferative response. T-cell blot analysis revealed the presence of dominant T-cell epitopes in the areas of Mr 200,000-75,000 and less than 50,000 polypeptides. No response was demonstrated in the Mr 72,000 region (migration site of the major surface antigen), suggesting T-cell dependent mechanisms are most likely not responsible for the surface antigen switch which occurred during the course of infection. This model infection can be used to study the role of immunological mechanisms in Giardia lamblia variant antigen switching and in the control of infections.     

Decreased fracture incidence after 1 year of pamidronate treatment in children with spastic quadriplegic cerebral palsy

Aim The aim of this study was to assess the rate of fracture before and after a 1‐year course of intravenous pamidronate in children with spastic quadriplegic cerebral palsy (CP) who had previously experienced fractures. Method Twenty‐five children (nine males, 16 females) with quadriplegic CP in Gross Motor Function Classification System (GMFCS) level IV or V who were treated with intravenous pamidronate for approximately 1 year were identified. All participants had previously experienced at least one non‐traumatic fracture. Each received 15 doses of pamidronate over a mean of 13.6 months. Post‐treatment observation ranged from 1 to 10 years 6 months (mean 4y 1mo). The fracture rate before and after commencement of treatment was calculated using the person‐years method. Results The participants had experienced a total of 86 fractures before treatment began, occurring over 280.6 person‐years, giving a fracture rate of 30.6% per year. During the post‐treatment observation period, totalling 107.5 person‐years, 8 of the 25 children experienced a total of 14 fractures. This fracture rate of 13.0% per year is a statistically significant decrease (p=0.02). Interpretation Pamidronate treatment lowered the rate of fracture, and a 1‐year course appears to provide a protective effect after treatment ends. For the majority of participants, this effect lasted 4 years or longer. However, a subset of children suffered a fracture soon after the drug was discontinued. In these children, a longer course of treatment appears to have been necessary.     

In-vitro and In-vivo Studies of the Diclofenac Sodium Controlled-release Matrix Tablets

Controlled release matrix tablets for diclofenac sodium were developed in this study. Five matrix-tablet formulations were prepared by granulating two viscosity grades of HPMC (hydroxylpropylmethylcellulose) in varying ratios with water in the planetary mixer. The in-vitro dissolution tests indicate that all five matrix formulations prolong the release of diclofenac sodium. The main factors controlling drug release were the HPMC viscosity grade and the amount of HPMC used. The larger the amount of high viscosity grade HPMC used, the slower the resultant release rate of diclofenac sodium. There was no significant degradation of diclofenac sodium or change in drug release rate in any of the five formulations during a three-month period of stability testing. The sustained release ability of four formulations was further demonstrated in an in-vivo study in six healthy subjects. There were in-vitro/in-vivo correlations between C_max, AUC_0–14, and the time for 50 or 80% drug to be released.