Effect of fumonisin B(1) on rat hepatic P450 system

The effects of the mycotoxin fumonisin B(1) (FB(1)) on the hepatic cytochrome P450 system were investigated in male rats dosed daily by oral gavage with 3 mg FB(1) per kg body weight for 9 consecutive days. FB(1) treatment resulted in a reduced weight gain. At the same time, CYP2E activity was increased, which is considered to mark the metabolic changes inherent to growth retardation in young rats. Treatment with FB(1) also resulted in a selective inhibition of CYP2C11 and to a lesser extent, CYP1A2 in liver microsomes obtained from treated animals, whereas it did not affect significantly the activity of CYP2A1/2A2, CYP2B1/2B2, CYP3A1/3A2 and CYP4A. The significant inhibition of CYP2C11 is considered to reflect a suppressed activity of protein kinase activity resulting from the inhibition of sphingolipid biosynthesis caused by FB(1).     

Prognosis of diabetic patients on dialysis: analysis of Lombardy Registry data

METHODS.: This 1993 Lombardy Registry Report refers to all of the dataregarding treated diabetics collected between 1 January 1983and 31 December 1992 by means of individual patient questionnairessent to all of Lombardy's 44 Renal Units (100% replies). RESULTS.: The acceptance rate of diabetics for dialysis increased from5.6 in 1983 to 10.4 patients per million population in 1992for a total of 731 patients (379 type I, 352 type II). The yearlypercentage of new diabetics increased from 9 to 11%, and theproportion of patients with two or more risk factors increasedfrom 14.7% in 1983–1987 to 22.0% in 1988–1992. Theuse of peritoneal dialysis declined over the 10-year periodfrom 50% in 1983–1984 to 30% in the last 2 years. Thedifference in age of the patients on peritoneal and haemodialysistended to decrease. The survival of all diabetic patients was82% at 1 year, 48% at 3 years, and 28% at 5 years. The relativedeath risk of the patients on peritoneal dialysis compared tothose on haemodialysis, after taking into account age and themain comorbid conditions (type of diabetes, severe vasculardisease, cirrhosis and the generic other risk factors), didnot differ significantly from one, as estimated by the Cox proportionalhazard regression model (344 events). The main causes of deathof these patients were cardiovascular diseases (about 50.0%),cachexia (from 17.2% in 1983/1984 to 22% in 1991/1992), andinfections (about 11%). The mean hospitalization rate was higherin diabetics than in patients with standard nephropathies (i.e.in 45–64-year-old patients: 32.8 versus 13.9 days/patient-year). CONCLUSION.: Multivariate analysis showed that age, type of diabetes, severevascular disease, cirrhosis, and the generic other risk factorswere significantly related to survival; but diabetic patientswithout any baseline risk factors also had a poor prognosisand morbidity was very high in absolute terms. Medical caretherefore needs to be improved in order to reverse prognosticrisk factors and prevent cardiovascular and non-cardiovascularevents.     

Altered peripheral and brainstem auditory function in aged rats

A technique for conducting free-field brainstem auditory evoked potential (BAEP) audiometry in unanesthetized, unrestrained rats revealed a non-recruiting 18 dB elevation of click threshold in aged rats. BAEPs were first recorded in young and aged rats to clicks of equal intensity (80 dB SPL). Compared to the young group, aged animals exhibited longer wave I and wave IV latencies with no difference seen in the I–IV central conduction time. The prominent negative wave (No) following wave IV was also delayed and the I-No and IV-No conduction times increased in the aged group. When BAEPs were recorded to clicks with intensities adjusted to 35 dB above individual threshold, no differences in wave I or wave IV latencies or in the I–IV central conduction time were found between groups. However, the No component was delayed and the I-No and IV-No conduction times remained prolonged in the aged group. The results suggest that in addition to changes in peripheral auditory structures, changes in the rostal auditory brainstem accompany age-related hearing loss in rats.     

Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts

The anti-apoptotic protein Bcl-2 has been implicated in the intrinsic resistance of melanoma to chemotherapy. The aim of this study was to investigate the effects of anti-Bcl-2 oligonucleotide oblimersen on the antitumour activity of gimatecan, a novel lipophilic camptothecin currently undergoing clinical phase II studies. Results showed a reduced sensitivity of melanoma cells to gimatecan following Bcl-2 transfection and inversely, increased cell sensitivity to gimatecan in combination with oblimersen. In in vivo studies performed in two melanoma xenografts expressing different Bcl-2 levels, the antitumour activity of oblimersen itself was modest, but the combination with gimatecan produced a significant therapeutic advantage. The combination therapy inhibited tumour growth and delayed regrowth of the two tumours tested. The enhancement of antitumour activity was observed at doses that were tolerated well. The effects of oblimersen on antitumour activity and toxicity of gimatecan were dose-dependent. The capability of oblimersen to improve the efficacy of gimatecan supports the therapeutic potential of the drug combination in the treatment of human melanoma.     

Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors

BACKGROUND: Patients with unresectable biliary tract carcinomas have a very poor prognosis. To improve the efficacy and tolerance of the ECF regimen (epirubicin at a dose of 50 mg/m2, cisplatin at a dose of 60 mg/m2, and 5-fluorouracil [5-FU] at a dose of 200 mg/m2 per day by continuous infusion), the authors designed a novel approach that combined locoregional and systemic chemotherapy with the same agents at the same dosages. METHODS: Thirty consecutive patients with advanced or metastatic biliary tumors were treated with epirubicin at a dose of 50 mg/m2 and cisplatin at a dose of 60 mg/m2 administered as a bolus in the hepatic artery on Day 1, combined with systemic continuous infusion of 5-FU at a dose of 200 mg/m2 per day, from Day 1 to Day 14, every 3 weeks. RESULTS: Tumor sites were the intrahepatic bile ducts in 25 patients and the gallbladder in 5 patients. The overall response rate was 40% (12 of 30 patients), including 1 complete response and 11 partial responses. Stable disease was observed in 12 of 30 patients (40%) and progressive disease in 6 of 30 patients (20%). The median progression-free and overall survival periods were 7.1 and 13.2 months, respectively, and the 1-year and 2-year survival rates were 54% and 20%, respectively. Performance status improved in 9 of 30 patients (30%) and a weight gain of > 7% was observed in 4 of 30 patients (13%). The treatment was well tolerated with minimal hematologic toxicity. The major clinical problem was the deep venous thrombosis related to the central venous catheter, which occurred in 5 patients (17%). CONCLUSIONS: This novel combined locoregional and systemic chemotherapeutic regimen was found to be active and safe for patients with advanced biliary tract carcinoma.     

Liver transplantation in children weighting less than 6 kg: the Bergamo experience

Liver transplantation (OLT) remains a major medical and surgical challenge in small patients. From October 1997 through July 2004, 17 babies less than 6 kg underwent 18 OLTs. Median age and weight were 3 months (range = 1 to 9) and 4.7 kg (range = 2.2 to 5.8). Two whole, one reduced, and 15 split-liver grafts (left lateral segments) were obtained from donors of median age and weight of 11.6 years (range = 0.5 to 62) and 50 kg (range = 7 to 63). Donor-to-recipient median weight ratio (D/R) was 9.1 kg (range = 1.3 to 17.6) and median graft-to-recipient weight ratio (GRWR) was 5% (range = 3.1 to 10). The incidence of biliary complications was 23%. The only vascular complication was a portal vein thrombosis (6%). Fourteen patients (79%) are alive with good graft function at a median follow-up of 39 months (range = 0.5 to 74). Three patients (all status 1) died on postoperative day 285 (brain death), 17 (multiorgan failure), and 229 (cardiovascular failure during retransplantation). Actuarial patient survivals at 6 months and 6 years are 94% and 78% while graft survivals are 89% and 74%, respectively. Currently all the patients listed as UNOS status 2 and 3 (73%) at the time of transplant are alive. During the same period one premature neonate (1.8 kg) who presented with fulminant hepatic failure died on the waiting list after 12 days. Our data confirm that the extensive use of a split-liver technique from small adult or pediatric cadaveric donors can offer the benefits of liver transplantation to small pediatric candidates with excellent results.     

Randomized, double-blind, phase III, controlled trial comparing levobupivacaine 0.25%, ropivacaine 0.25% and bupivacaine 0.25% by the caudal route in children

Background. The rationale for replacing racemic bupivacainewith the s-enantiomers levobupivacaine and ropivacaine is toprovide a wider margin of safety with the same analgesic efficacyand less postoperative motor block. In a randomized, double-blind,phase III, controlled trial we compared the caudal administrationof levobupivacaine 0.25% and ropivacaine 0.25% with bupivacaine0.25% in children. Methods. Ninety-nine ASA I–II children less than 10 yrold scheduled for elective sub-umbilical surgery were randomizedto receive caudal block with bupivacaine 0.25%, ropivacaine0.25% or levobupivacaine 0.25%. The primary outcome of the studywas the clinical efficacy of the caudal block during the operation.Secondary outcome measures were analgesic onset time, pain reliefafter the operation and residual motor blockade. Results. The proportion of children with effective analgesiaduring the operation was similar among groups. There were nosignificant differences in the analgesic onset time of the caudalblock. Bupivacaine produced a significant incidence of residualmotor block compared with levobupivacaine or ropivacaine atwake-up (P<0.01). There were no significant differences inthe number of patients receiving rescue analgesia after surgery.However, analgesic block lasted significantly longer in patientsreceiving bupivacaine (P=0.03). Conclusion. During sub-umbilical surgery, caudal levobupivacaine,ropivacaine and bupivacaine provided comparable analgesic efficacy.Bupivacaine produced a higher incidence of residual motor blockadeand a longer analgesic block than ropivacaine and levobupivacaine.      

Synthesis and antimalarial activities of some furoxan sulfones and related furazans

Furoxan derivatives bearing a sulfone moiety at position 3 or 4 were synthesized and tested for their antimalarial action on the chloroquine-sensitive D10 and the chloroquine-resistant W2 strains of Plasmodium falciparum. The furazan analogues were considered for comparison. The most active compounds were the products in which the -SO2R groups are at the 3-position of the furoxan system. These latter substances displayed an antimalarial activity in the microM range, possibly related in part to their ability to release NO.     

Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure

BACKGROUND AND AIM: Mitral regurgitation (MR) has been demonstrated to be a powerful predictor of adverse outcome in middle-aged patients with chronic heart failure (CHF). In this study, we sought to define the prognostic impact of functional mitral regurgitation in a population of elderly patients with systolic CHF. METHODS: One hundred seventy-five outpatients aged >70 years with validated CHF and left ventricular ejection fraction <40% underwent clinical and echocardiographic evaluations at baseline. Mitral regurgitation was diagnosed by Color Doppler and quantified in 5 categorical values using a 0-4+ grading system. Outcome measures included 1-year mortality and hospitalization for worsening CHF. RESULTS: The distribution of patients according to the 5 different degrees of MR detected at baseline was: absent=11%, 1+=31%, 2+=38%, 3+=16%, 4+=4%. The relationship between MR and mortality was direct and approximately linear (r=0.39, p=0.00001). The prevalence of death in the 5 subgroups was 0%, 7%, 15%, 45%, 57%, respectively. Multivariate logistic regression analysis showed that MR was the strongest predictor of death (OR 4.47, 95% CI 1.50-13.0), independently of the presence of diabetes mellitus, older age and larger left ventricular end-diastolic volume. No association was found between MR and hospitalization for worsening CHF (r=0.08, p=0.41). CONCLUSIONS: This study establishes the direct and independent relationship between MR severity and one-year mortality among elders with systolic CHF. Conversely, MR does not provide useful information regarding the risk of subsequent hospitalization for worsening CHF.