Treatment of chronic woodchuck hepatitis virus infection in the Eastern woodchuck (Marmota monax) with nucleoside analogues is predictive of therapy for chronic hepatitis B virus infection in humans

The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck (Marmota monax), have been established as a model of hepatitis B virus (HBV)-induced disease. Several published studies have used this experimental animal model system to demonstrate potential antiviral therapies for chronic HBV infections. However, there has been little comparative information available on compounds used in clinical anti-HBV studies in WHV-infected woodchucks, thereby making interpretations of the potential relative effectiveness of new antiviral agents in humans more difficult. In this report, using a series of placebo-controlled studies, we compared the relative effectiveness of several nucleoside analogues that have been used in clinical trials for the treatment of chronic HBV infection against WHV replication in chronically infected woodchucks. Adenine-5'-arabinoside monophosphate (Ara-AMP [vidarabine]), ribavirin, (-)beta-L-2',3'-dideoxy-3'-thiacytidine (3TC [lamivudine]), and famciclovir (oral prodrug of penciclovir) induced depressions in viremia and intrahepatic WHV-DNA replication that were consistent with their relative effectiveness in anti-HBV human clinical trials. As observed in HBV-infected patients, 3' azido-3'-deoxythymidine (AZT [zidovudine]) had no effect on WHV replication in these studies. These experimental results more firmly establish chronic WHV infection in woodchucks as an accurate and predictive model for antiviral therapies against chronic HBV infection in humans and provide a baseline for comparative antiviral effects of other experimental antiviral agents in the WHV/woodchuck model system.     

Construction of modern Australian first trimester ultrasound dating and growth charts

Accurate pregnancy dating is vital to obstetric management. However, first trimester fetal charts commonly used in Australia rely on data reported more than three decades ago. This study reports first trimester dating and growth charts for crown‐rump length between 5 and 14 weeks of gestation and biparietal diameter between 9 and 14 weeks of gestation on an Australia population using modern real‐time ultrasound equipment. All consenting eligible women attending a large Sydney clinic for first trimester ultrasound between March 2005 and December 2006 were recruited. Measurements were carried out to Australasian Society for Ultrasound in Medicine standard protocols. Statistical analyses were undertaken using polynomial regression models and thorough diagnostic checks made. Overall 396 eligible women consented to the study, with 268 between 9 and 14 weeks of gestation. The average participant age was 34 years (range 22–45 years), 371 and all yielded valid biometry measurements. Equations, means and 90% reference intervals for crown‐rump length measurements and biparietal diameter measurements were derived using polynomial regression models. Thorough residual and diagnostic checks were made. Once validated by others, we believe they will warrant consideration for use by Australasian Society for Ultrasound in Medicine.     

Effect of sleep on regional blood flow distribution in piglets

The regional distribution of blood flow to the brain and to other major organs was studied during wakefulness and sleep in growing piglets. A young group was studied at 6.8 +/- 1.3 d of age and an older group at 33.5 +/- 5.5 d. Two d before the experiments, we instrumented the animals for measurement of blood flow by the microsphere technique. We determined sleep state using EEG and behavioral criteria. Although we did not find significant differences in blood gas tensions and cardiac output with changes in behavioral states, we did note a number of important changes in brain and muscle blood flow with sleep. 1) Although total brain blood flow changed little between wakefulness and sleep at both ages, regional differences existed. Indeed, at both ages, during rapid eye movement sleep (active sleep), blood flow to the thalamus-hypothalamus and brainstem was significantly higher than during wakefulness (p less than 0.025); in older piglets, blood flow to these two regions was significantly lower in quiet sleep than in wakefulness (p less than 0.05). 2) Blood flow to most skeletal muscle groups, and particularly to the diaphragm, was lower during sleep than during wakefulness. 3) Age did not have a significant effect on the regional distribution of blood flow during sleep. We conclude that behavioral states influence the regional distribution of blood flow in early life, but not in an age-dependent fashion. We speculate that, because no difference was observed in other hemodynamic variables, the regional changes in organ blood flow with sleep most probably reflect the differences in local metabolic needs.     

Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases

Two patients aged 11 and four years, were accidentally given a 10-fold overdose of intrathecal methotrexate while being treated for malignant disease. Neither patient developed any signs of neurotoxicity and exchange of lumbar cerebro-spinal fluid was started 3 and 5 h later, respectively. In one of the patients, who received 120 mg of methotrexate intrathecally, 31% of the given dose was recovered during 2 h of cerebrospinal fluid exchange that was started 3 h after the accidental overdosage. No sequelae were observed in any of the patients. Cerebrospinal fluid exchange is safe and can be recommended in all cases of intrathecal methotrexate overdosage. Ventriculo-cisternal perfusion is not necessary in cases of a 10-fold overdose if the patient has no signs of acute neurotoxicity.     

Home parenteral nutrition in chronic intestinal failure

In children with severe failure of intestinal function, intravenous nutrition is at present the only treatment able to maintain adequate nutrition for prolonged periods of time. Over the last five years we have discharged 10 patients home on parenteral nutrition for a total of 25 patient years and here the outcome of these children is presented. Of the 10 patients, one has discontinued home parenteral nutrition (HPN), seven patients remain well, one patient has recently moved to the USA, and one patient has died after major abdominal surgery. All children had either normal or an accelerated rate of growth on HPN and developmentally all have progressed well. All the children over 5 years attend normal schools. The major complication of treatment was line sepsis with an overall rate of one episode in 476 days and a total of nine central lines (five patients) have required replacement giving an average line life of 680 days. For those children unfortunate enough to suffer from severe intestinal failure, HPN is preferable to prolonged hospital treatment and offers the chance of a good quality of life with prolonged survival.     

Immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children

Objective: To determine the immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children in north Queensland.
Methodology: A cross-sectional survey of immunity in a sample of children; 101 fully vaccinated Aboriginal and Torres Strait Island children, with a median age of 24.5 months, from 10 communities in North Queensland participated in this study. The main outcome measures were the prevalence of adequate antibody levels against hepatitis B, poliomyelitis and measles.
Results: Only 54% (95% Cl 44–63%) of the children had adequate immunity (10 m iu/mL) to hepatitis B, and one child had been infected despite vaccination. Although all the children (95% Cl 96–100%) had adequate immunity (i.e. neutralizing antibodies at a dilution of 1:8) to poliovirus 2, only 93% (95% Cl 86–96%) and 60% (95% Cl 50–69%) had adequate immunity to polioviruses 1 and 3, respectively. Nearly all (96%; 95% Cl 90–98%) of the children had adequate immunity (i.e. detectable IgG antibody) to measles.
Conclusions: Although a relatively low proportion of the children had adequate antibody levels against hepatitis B the clinical significance of this observation is uncertain. Further studies are needed to determine whether fully vaccinated Torres Strait Island children have been adequately protected and whether they require a booster dose of hepatitis B vaccine. A substantial proportion of fully vaccinated Aboriginal and Torres Strait Island children are inadequately protected against poliomyelitis, and therefore any such child with acute flaccid paralysis should be investigated fully for poliomyelitis. Vaccinated Aboriginal and Torres Strait Island children are well protected against measles, as are other Australian children.     

Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors

BACKGROUND: We conducted a phase I and pharmacokinetic study to determinethe maximum tolerable dose (MTD), toxicities, pharmacokineticprofile, and antitumor activity of Irinotecan (CPT-11) in patientswith refractory solid malignancies. PATIENTS AND METHODS: Forty-six patients were entered in this phase I study. CPT-11was administered intravenously over 30 minutes for 3 consecutivedays every 3 weeks. Dose levels ranged from 33 mg/m²/day to115 mg/m²/day on days 1 through 3. The pharmacokinetics of totalCPT-11 and its active metabolite SN-38 were assayed by HPLC. RESULTS: The combination of leukopenia and diarrhea was dose-limitingtoxicity at 115 mg/m²/day dose level, since 50% of the patients(5/10) experienced either grade 3–4 leukopenia, or diarrhea,or both. Leukopenia appeared to be a cumulative toxicity, witha global increase in its incidence and severity upon repeatedadministration of CPT-11. Other toxicities included nausea,vomiting, fatigue and alopecia. CPT-11 and active metaboliteSN-38 inetics were determined in 21 patients (29 courses). BothCPT-11 and SN-38 pharmacokinetics presented a high interpatientvariability. CPT-11 mean maximum plasma concentrations reached2034 ng/ml at the MTD (115 mg/m²). The terminal-phase half-lifewas 8.3 h and the mean residence time 10.2 h. The mean volumeof distribution at steady state was 141 l/m²/h. CPT-11 reboundconcentrations were observed in many courses at about 0.5 to1 hour following the end of the i.v. infusion, which is suggestiveof enterohepatic recycling. Total body clearance did not varywith increased dosage (mean=14.3 l/h/m²), indicating linearpharmacokinetics within the dose range administered in thistrial. The total area under the plasma concentration versustime curve (AUC) increased proportionally to the CPT-11 dose.Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD.A significant correlation was observed between CPT-11 area underthe curve (AUC) and its corresponding metabolite SN-38 AUC (r=0.52,p < 0.05). S-38 rebound concentrations were observed in manycourses at about 0.5 to 1 hour following the end of the i.v.infusion, which is suggestive of enterohepatic recycling. Mean24-h urinary excretion of CPT-11 accounted for 10% of the administereddose by the third day, whereas SN-38 urinary excretion accountedfor 0.18% of the CPT-11 dose. In this phase I trial, the hemato-logicaltoxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrheagrade correlated significantly with CPT-11 AUC. Two partial(breast adenocarcinoma and carcinoma of unknown primary) and2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responseswere observed. CONCLUSION: The MTD for CPT-11 administered in a 3 consecutive-days-every-3weeks schedule in this patient population is 115 mg/m²/day.The recommended dose for phase II studies is 100 mg/m²/day. CPT-11, camptothecin analogue, topoisomerase I inhibitor, phase I, pharmacokinetics