Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor.

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min(-1) kg(-1) in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 l kg(-1) in mice. Oral bioavailability ranged from 13% in monkeys to 53% in dogs. Predicted human clearance using allometry was 0.096-0.649 ml min(-1) kg(-1) and the predicted volume of distribution was 0.766 l kg(-1). Protein binding was extensive with an unbound fraction less than or equal to 6%, and the blood-to-plasma partition ratio ranged from 0.6 to 0.8 in all species tested. GDC-0449 was metabolically stable in mouse, rat, dog and human hepatocytes and had a more rapid turnover in monkey hepatocytes. Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 microM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 microM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 microM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells. Overall, GDC-0449 has an attractive preclinical profile and is currently in Phase II clinical trials.

Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug.

Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min(-1) kg(-1), respectively. In mass balance studies using [(14)C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose. In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9. In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9. In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.

Re-evaluating selection criteria for local anaesthesia in day surgery.

Day surgery is an increasing element of surgical practice, particularly in plastic surgery. A large proportion of work is undertaken using local anaesthesia in the elderly who have associated co-morbidity. At present no national guidelines exist for the use of local anaesthesia in day surgery. This study aimed to examine the relationship between patient selection and complications, in order to identify those who should be excluded from local anaesthetic day surgery treatment. A retrospective analysis of patients undergoing local anaesthetic plastic surgical procedures over a 10-month period identified 328 operative episodes. There were 37 complications, two of which required admission 5 days post surgery for treatment of wound infection. The remaining complications were treated on an outpatient basis. An increased level of complication was seen in males with elevated systolic blood pressure and with the use of full thickness skin grafts in reconstruction. Age, smoking, ASA grade, and medication that altered coagulation (aspirin, warfarin and steroids) were not associated with increased complication levels. We conclude that local anaesthetic plastic surgical procedures are associated with a very low level of risk, and are suitable for those patients traditionally regarded as unsuitable for general anaesthetic day surgery.

Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin.

Inhibition of wound contraction by topical anti microbial agents has been described. The purpose of this study was to further investigate that phenomenon and to explore the effect that other agents such as Aloe vera might have on this process. Full-thickness excised wounds were created on the dorsum of Sprague-Dawley rats under anaesthesia. The wounds were treated with topical agents three times daily for fourteen days, then observed until healed. Groups were: saline control, placebo (aqueous cream) control, silver sulphadiazine (SSD) cream 1%, SSD 0.5%, SSD 1% with Aloe vera, SSD 1% with nystatin, nystatin. Wound surface areas were measured each three days. Time to 50% and 90% healing was compared using ANOVA. Wound half-life and healing times were shortest in the SSD/Aloe vera and nystatin groups (P<0.05) and longest in the 1% SSD and saline control groups. The placebo group (aqueous cream) healed in a significantly shorter time (P<0.05) than the control (saline) group. Wound contraction was delayed by saline and SSD. Nystatin and Aloe vera, when added to SSD, reversed that effect. These data suggest that a dry wound (saline) heals slowly. Infection control without delay of wound healing is most appealing and clinical trials are planned.