Update on hepatitis C: epidemiology, treatment and resistance to antiviral therapies.

Chronic hepatitis C (HCV) is a major cause of morbidity and mortality due to chronic liver disease worldwide. Exposure to the virus leads to chronic infection in the majority of cases and may be associated with progression to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment of HCV has been challenging until recently, requiring combination treatment with interferon injections and ribavirin, both associated with significant toxicities and sustained virologic response (SVR) rates of 50% for most patients. Recent advances in therapy have allowed for all-oral treatments with SVR rates >90% with as little as 8 weeks of therapy. This review describes the developments in HCV therapy over the last two decades, the current treatment regimens and the rates of antiviral resistance with the new therapies on the horizon.

Abdominal diameter index: a more powerful anthropometric measure for prevalent coronary heart disease risk in adult males.

AIM: The authors wished to compare the strength of association of several anthropometric measures of body size and fat distribution among themselves and in comparison with other known risk factors for prevalent coronary heart disease (CHD). METHODS: Prevalent CHD was assessed in 466 middle-aged, male, multiracial Triborough Bridge and Tunnel Authority officers in New York City by verified history, electrocardiogram or exercise stress test. Anthropometric measures included body mass index, waist, hip and thigh circumferences, waist-hip ratio, waist-thigh ratio, sagittal abdominal diameter and abdominal diameter index (sagittal abdominal diameter/thigh circumference). Results were compared with other CHD risk factors measured simultaneously (history of diabetes, smoking, blood pressure, lipid profile, apolipoproteins A and B, lipoprotein (a), homocysteine, fibrinogen, urinary microalbumin, serum vitamin E and ferritin) and a calculated 10-year CHD risk using a Framingham algorithm (10-year Framingham CHD risk). RESULTS: CHD was found in 29 individuals. Of the six anthropometric measures, abdominal diameter index gave the largest and most significant standardized odds ratio (OR) for CHD [1.80, 95% confidence interval (CI) 1.20, 2.71], equivalent to 10-year Framingham CHD risk. Men in the highest compared with the lowest tertile of abdominal diameter index had a univariate OR of 5.47 (95% CI 1.55, 19.28) which was the only anthropometric measure that remained significant after adjusting for 10-year Framingham CHD risk. CONCLUSIONS: For middle-aged American men, abdominal diameter index may be the most powerful anthropometric measure of risk for prevalent CHD.

[Emergency psychiatric departments are not refusing admissions]. / Akuttpsykiatrien i Oslo er ikke avvisende ved mottak.

The staff at the psychiatric emergency out-patient clinic in Oslo evaluated the services of the acute psychiatric wards when admitting patients to the hospital. Of 93 admittances during three months in 1998, the referring doctor was satisfied with the hospital's response in 84% of the cases. The mean time from contact was taken with the hospital till the admittance was accepted was 19 minutes. The admittance of patients in acute psychiatric hospitals in Oslo is straightforward, and reasonably well organized.

A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors.

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.

A Phase I study of LGD1069 in adults with advanced cancer.

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.

Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.

PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Cigarette smoking is not associated with hyperinsulinemia: evidence against a causal relationship between smoking and insulin resistance.

Previous reports of a relationship between cigarette smoking and hyperinsulinemia and insulin resistance provide an important possible mechanism by which smoking could be associated with the metabolic cardiovascular syndrome and hence with ischemic heart disease. However, few previous studies have been able to adjust for all the possible confounding factors related both to smoking and to insulin resistance. Therefore, we examined this association in a population-based cohort study of 1,122 individuals aged 40 to 65 years who underwent a 75-g oral glucose tolerance test with specific measurement of insulin, 32,33-split proinsulin, and intact proinsulin concentrations. Physical activity was quantified using the Paffenbarger questionnaire, and smoking status and alcohol consumption were determined using the Health and Lifestyle Survey questionnaire; 17.4% of the population were current smokers and 32.4% were ex-smokers. Current smoking was associated with reduced overall obesity as indicated by the body mass index (BMI) but an increase in central adiposity as measured by the waist to hip ratio (WHR). There were also significant associations between cigarette smoking and the pattern of alcohol intake and physical inactivity. In unadjusted analyses, current smoking was associated with lower fasting and 120-minute insulin and also 120-minute glucose compared with levels in nonsmokers. Adjustment for confounding by age and BMI reduced these differences, but they were increased by adjustment for central obesity. We conclude from this study that a causal relationship between cigarette smoking and insulin resistance is unlikely.

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer.

Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.

Accuracy of the acrylic resin pattern for the implant-retained prosthesis.

An in vitro study was conducted to determine the accuracy of fit of the acrylic resin pattern for the implant-supported prosthesis to the implant abutments. A master model containing five Nobelpharma titanium implants was fabricated using Ivocap acrylic resin. Using this model, five standardized acrylic resin patterns were fabricated from the three test dental acrylic resins. The fabricated patterns remained on the master model for 24 hours before removal and subsequent measurement. To compute the accuracy of each pattern, three special measuring points were firmly attached to each gold cylinder prior to pattern fabrication and the x, y, and z coordinates of these measuring points were determined. Measurements were made prior to pattern fabrication, with the cylinders on their respective abutments and after pattern fabrication, when the pattern had been removed from the master model. The results of this study showed that there was a significant difference in accuracy between the test acrylic resins and that none of these materials was completely accurate.

Short-term effects of rhizosphere microorganisms on fe uptake from microbial siderophores by maize and oat.

Effects of rhizosphere microorganisms on Fe uptake by oat (Avena sativa) and maize (Zea mays) were studied in short-term (10 h) nutrient solution experiments. Fe was supplied either as microbial siderophores (pseudobactin [PSB] or ferrioxamine B [FOB]) or as phytosiderophores obtained as root exudates from barley (epi-3-hydroxy-mugineic acid [HMA]) under varied population densities of rhizosphere microorganisms (axenic, uninoculated, or inoculated with different microorganism cultures). When maize was grown under axenic conditions and supplied with FeHMA, Fe uptake rates were 100 to 300 times higher compared to those in plants supplied with Fe siderophores. Fe from both sources was taken up without the involvement of an extracellular reduction process. The supply of FeHMA enhanced both uptake rate and translocation rate to the shoot (more than 60% of the total uptake). However, increased density of microorganisms resulted in a decrease in Fe uptake rate (up to 65%), presumably due to microbial degradation of the FeHMA. In contrast, when FeFOB or FePSB was used as the Fe source, increased population density of microorganisms enhanced Fe uptake. The enhancement of Fe uptake resulted from the uptake of FeFOB and FePSB by microorganisms adhering to the rhizoplane or living in the free space of cortical cells. The microbial apoplastic Fe pool was not available for root to shoot transport or, thus, for utilization by the plants. These results, in addition to the low uptake rate under axenic conditions, are in contrast to earlier hypotheses suggesting the existence of a specific uptake system for Fe siderophores in higher plants. The bacterial siderophores PSB and FOB were inefficient as Fe sources for plants even when supplied by stem injection. It was concluded that microorganisms are involved in degradation processes of microbial siderophores, as well as in competition for Fe with higher plants.

Iron uptake by plants from microbial siderophores : a study with 7-nitrobenz-2 oxa-1,3-diazole-desferrioxamine as fluorescent ferrioxamine B analog.

The synthetically produced fluorescent siderophore NBD-desferrioxamine B (NBD-DFO), an analog of the natural siderophore ferrioxamine B, was used to study iron uptake by plants. Short-term (10-hour) (55)Fe uptake rates by cotton (Gossypium spp.) and maize (Zea mays L.) plants from the modified siderophore were similar to those of the natural one. In longer-term uptake experiments (3 weeks), both siderophore treatments resulted in similar leaf chlorophyll concentration and dry matter yield. These results suggest that the synthetic derivative acts similarly to the natural siderophore. The NBD-DFO is fluorescent only when unferrated and can thus be used as a probe to follow iron removal from the siderophore. Monitoring of the fluorescence increase in a nutrient solution containing Fe(3+)-NBD-DFO showed that iron uptake by plants occurs at the cell membrane. The rate of iron uptake was significantly lower in both plant species in the presence of antibiotic agent, thus providing evidence for iron uptake by rhizosphere microbes that otherwise could have been attributed to plant uptake. Confocal fluorescence microscopy revealed that iron was taken up from the complex by cotton plants, and to a much lesser extent by maize plants. The active cotton root sites were located at the main and lateral root tips. Significant variations in the location and the intensity of the uptake were noticed under nonaxenic conditions, which suggested that rhizosphere microorganisms play an important role in NBD-DFO-mediated iron uptake.

Identification of nuclease-positive staphylococci isolated from animals.

The nuclease-neutralisation test was evaluated as a means of identifying nuclease-positive staphylococci isolated from different animals. The test identified 510 of 520 strains (98%) of staphylococci characterised by biochemical testing.

Patterns of antibodies to staphylococcal DNases in dog sera.

Sera from clinically healthy dogs and from dogs with a history of skin disease were examined for the presence of antibodies to the DNases of Staphylococcus aureus, Staphylococcus hyicus subsp. hyicus, and Staphylococcus intermedius. The antibodies found most frequently and in the largest amounts were those to the DNase of S. intermedius.