Subchronic vaginal toxicity studies of Alcide Allay gel and liquid in guinea pigs

Alcide Allay, an antimicrobial preparation produced in gel and liquid forms, was evaluated for vaginal toxicity in guinea pigs. 1.0 g/kg Allay gel or placebo was administered intravaginally once per day over a 30 day period while 2.5 g/kg Allay liquid (containing either of two concentrations of sodium chlorite and lactic acid as active ingredients) or placebo was applied vaginally three times per day for 10 days. At the conclusion of the studies, hematology, blood and urine clinical chemistry tests and necropsies were performed. RBC, HGB, HCT, MCHC and direct bilirubin increased while CO2, SGPT and CPK decreased in blood after Allay liquid treatment. Creatinine, urea nitrogen and uric acid in urine were statistically reduced in the liquid groups. Hematology and clinical chemistry parameters were within the normal range of values reported in the literature for guinea pigs, indicating no clinical significance due to drug treatment. Significant differences in organ body/weight ratios were observed between controls and Allay gel and liquid groups. However, only the livers in the gel study and the vaginas in both studies were changed histologically.     

Immunosuppression in liver transplantation: beyond calcineurin inhibitors.

Although calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression in liver transplantation (LTX), their long-term toxicity significantly contributes to morbidity and mortality. The elucidation of mechanisms of alloimmunity and leukocyte migration have provided novel targets for immunosuppression development. The toxicities of these agents differ from that of the CNI and act additively or synergistically. CNI avoidance protocols in LTX have not been achieved routinely; however, pilot trials have begun to delineate the limitations and promises of such approaches. CNI-sparing protocols appear to be much more promising in balancing the early need for minimizing rejection while tapering doses and minimizing long-term toxicity.     

Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.     

Cost-effectiveness of cadaveric and living-donor liver transplantation

BACKGROUND: Cadaveric liver transplantation (5-year survival >80%) represents the standard of care for end-stage liver disease (ESLD). Because the demand for cadaveric organs exceeds their availability, living-donor liver transplantation has gained increasing acceptance. Our aim was to assess the marginal cost-effectiveness of cadaveric and living-donor orthotopic liver transplantation (OLT) in adults with ESLD. METHODS: Using a Markov model, outcomes and costs of ESLD treated (1) conservatively, (2) with cadaveric OLT alone, and (3) with cadaveric OLT or living-donor OLT were computed. The model was validated with published data. The case-based scenario consisted of data on all 15 ESLD patients currently on our waiting list (3 women, 12 men; median age, 48 years [range, 33-59 years]) and on the outcome of all OLT performed for ESLD at our institution since 1995 (n=51; actuarial 5-year survival 93%). Living-donor OLT was allowed in 15% during the first year of listing; fulminant hepatic failure and hepatocellular carcinoma were excluded. RESULTS: Cadaveric OLT gained on average 6.2 quality-adjusted life-years (QALYs) per patient compared with conservative treatment, living-donor OLT, an additional 1.3 QALYs compared with cadaveric OLT alone. Marginal cost-effectiveness of a program with cadaveric OLT alone and a program with cadaveric and living-donor OLT combined were similar (E 22,451 and E 23,530 per QALY gained). Results were sensitive to recipient age and postoperative survival rate. CONCLUSIONS: Offering living-donor OLT in addition to cadaveric OLT improves survival at costs comparable to accepted therapies in medicine. Cadaveric OLT and living-donor OLT are cost-effective.     

Living donor liver transplantation in patients with portal vein thrombosis: a survey and review of technical issues

BACKGROUND: Unlike cadaveric liver transplantation, current attitudes in living donor liver transplantation (LDLT) quote increased risk factors in the potential recipient such as retransplantation, multiple previous surgeries, or preexisting recipient portal vein thrombosis (PVT) as absolute or relative contraindications to this procedure. METHODS: An international survey was performed to examine the attitude of transplant teams relative to LDLT in the setting of preexisting PVT in the potential recipient. A questionnaire was sent to a total of 80 transplant centers performing LDLT in the United States, Europe, Canada, Japan, Southeast Asia, and Australia. RESULTS: A response was obtained from 47 transplant centers (59% response rate). This included 2146 LDLT procedures that combined both left and right lobe allografts. The incidence of acute preexisting recipient PVT was 18 (0.8%) and of chronic PVT was 26 (1.2%). Thrombectomy was performed in 28 (64%), a jump graft in 13 (29.5%), and a combination of both thrombectomy and a jump graft in 2 (4.5%) cases. With reference to the presence of preexisting PVT in the potential recipient, 5 centers considered this to be an absolute contraindication (10.7%), 24 centers as a relative contraindication (51%), and 18 as not being a contraindication (38.3%) to LDLT. CONCLUSIONS: The overall response to our questionnaire reflected a cautious attitude within the transplant community. Ethical criteria pertaining to risk undertaken by a healthy donor in situations of higher recipient morbidity risk does seem to impact on the decision to undertake LDLT in this group of patients.     

A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning

OBJECTIVE: To evaluate the protective effects of ischemic preconditioning in a prospective randomized study involving a large population of unselected patients and to identify factors affecting the protective effects. SUMMARY BACKGROUND DATA: Ischemic preconditioning is an effective protective strategy in several animal models. Protection has also been suggested in a small series of patients undergoing a hemihepatectomy with 30 minutes of inflow occlusion. Whether preconditioning confers protection in other types of liver resection and longer periods of ischemia is unknown. Therefore, we conducted a prospective randomized study to evaluate the impact of ischemic preconditioning in liver surgery. METHODS: A total of 100 unselected patients undergoing major liver resection (> bisegmentectomy) under inflow occlusion for at least 30 minutes were randomized during surgery to either receive or not receive an ischemic preconditioning protocol (10 minutes of ischemia followed by 10 minutes of reperfusion). Univariate and multivariate analyses were performed to identify independent factors affecting the protective effects of ischemic preconditioning. ATP contents in liver were measured as a possible mechanism of protection. RESULTS: Both groups (n = 50 in each) were comparable regarding age, gender, duration of inflow occlusion, and resected liver volumes. Postoperative serum transaminase levels were significantly lower in preconditioned than in control patients (median peak AST 364 U/L vs. 520 U/L, P = 0.028; ALT 406 vs. 519 U/L, P = 0.049). Regression multivariate analysis revealed an increased benefit of ischemic preconditioning in younger patients, in patients with longer duration of inflow occlusion (up to 60 minutes), and in cases of lower resected liver volume (<50%). Patients with steatosis were also particularly protected by ischemic preconditioning. ATP content in liver tissue was preserved by ischemic preconditioning in young but not older patients. CONCLUSIONS: This study establishes ischemic preconditioning as a protective strategy against hepatic ischemia in humans. The strategy is particularly effective in young patients requiring a prolonged period of inflow occlusion, and in the presence of steatosis, and is possibly related to preservation of ATP content in liver tissue. Other strategies are needed in older patients.