Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis c: a randomized, controlled study

The two available pegylated interferon formulations, peginterferon alpha-2a and peginterferon alpha-2b, have different pharmacokinetic profiles; as a result they may have differing abilities to suppress the hepatitis C virus. A recently reported study by Formann and colleagues assessing early viral kinetics among 20 patients receiving peginterferon alpha-2b either once or twice weekly suggests that once-weekly administration of peginterferon alpha-2b is not sufficient for continuous exposure to interferon over 160 h. Twice-weekly administration is recommended to avoid increases in viral load as interferon levels decline prior to the end of the one-week dosing period. The objective of this study was to compare viral dynamics and pharmacokinetics between peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive chronic hepatitis C patients. Patients were randomized to receive peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12) once weekly. Serum peginterferon concentrations were measured at baseline, 24, 48, 120 and 168h. Hepatitis C virus (HCV) RNA was measured at baseline, 24, 48, 120 and 168 h during week 1 and then at 4 and 12 weeks. Peginterferon alpha-2b achieved maximal serum levels at 24 h, and then decreased rapidly. Of the 12 patients who received peginterferon alpha-2b, no drug was detectable in seven (58%) patients at 120 h and in 11 (92%) at 168 h. In contrast, peginterferon alpha-2a concentrations increased continuously over time, reaching maximal serum levels from 48 to 168 h. Drug was detectable in all 10 patients at 168 h. At weeks 1 and 4 no significant difference was observed in mean HCV RNA between the groups. However, at week 12, mean HCV RNA was significantly lower in the peginterferon alpha-2a group versus the peginterferon alpha-2b group (2.8126 vs 3.8726; P<0.01). The differences in mean HCV RNA values at 12 weeks may be related to the different absorption and distribution profiles of the two drugs. In conclusion, once-weekly administration of peginterferon alpha-2b (1.0 microg/kg/wk) may be insufficient for continuous interferon exposure; twice-weekly administration may help avoid increases in viral replication as interferon levels decline. Larger-scale studies assessing both viral kinetics and sustained virological responses are needed to confirm these observations.     

MRI evaluation of the antitumor activity of paramagnetic liposomes loaded with prednisolone phosphate

The design of long circulating liposomes co-loaded with the glucocorticoid prednisolone phosphate (PLP) and the amphiphilic paramagnetic contrast agent Gd-DOTAMA(C(18))(2) allowed the MRI-guided in vivo visualization of the delivery and biodistribution of PLP, as well as the monitoring of drug efficacy. The performance of this theranostic probe was investigated in a mouse model bearing a melanoma B16 syngeneic tumor. The release kinetics of the drug were evaluated in vitro where it displayed a peculiar behavior characterized by a fast process (completed in few hours) involving only a small portion (<5%) of the drug. Interestingly, the incorporation of the amphiphilic imaging reporter in the liposomal bilayer slightly increased the amount of the fast-release portion (<10%), thus suggesting that it could be attributed to a drug fraction embedded in the liposomal bilayer. In fact, the release of a hydrophilic imaging probe encapsulated in the inner core of the same long circulating liposomes formulated for carrying the drug, displayed different, single-step, kinetics. The in vivo monitoring of the antitumor activity of the nanomedicine revealed that the incorporation of the MRI probe into the liposome bilayer did not significantly affect the drug efficacy. The in vivo experiments also indicated a relevant and fast liposome uptake from macrophage-rich organs like spleen and liver, which reduced the tumor accumulation of the liposomes. The accumulation of the amphipatic MRI label caused the occurrence of a long-term residual T(1) contrast still detectable 1week after injection.     

Pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naïve patients with chronic hepatitis C: a randomized, controlled study

BACKGROUND: Peginterferon alpha-2a and alpha-2b, the two commercially available pegylated interferons, have different pharmacokinetic properties that produce differing abilities to suppress replication of the hepatitis C virus. AIM: To compare the pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive patients with chronic hepatitis C. METHODS: Patients were randomized to receive peginterferon alpha-2a, 180 microg (n = 10) or peginterferon alpha-2b 1.0 microg/kg (n = 12) once weekly. The enzymatic activity of 2'5'-oligoadenylate synthetase and levels of neopterin and beta(2)-microglobulin were measured at baseline and at 24, 48, 120 and 168 h. RESULTS: Oligoadenylate synthetase activity and serum neopterin and beta(2)-microglobulin concentrations did not differ significantly between the two patient groups at any time point, nor was there a significant correlation between the serum area under the concentration-time curve of either peginterferon and the area under the concentration-time curve for 2',5'-oligoadenylate synthetase, neopterin and beta(2)-microglobulin. The area under the concentration-time curves calculated for these three markers did not correlate with body mass index stratified at <25 and >or=25 kg/m(2) for either peginterferon. CONCLUSIONS: Despite pharmacokinetic differences between peginterferon alpha-2a and peginterferon alpha-2b, the pharmacodynamic profiles of the two formulations appear to be comparable.     

Selective inhibition of plasma kallikrein protects brain from reperfusion injury

We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 microg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.     

The current role of abdominal ultrasound in the clinical management of patients with AIDS

Patients with AIDS present a wide variety of clinical manifestations through involvement of various organs. Ultrasonography (US) is easy to perform, safe, inexpensive, not invasive and repeatable. Those features are crucial for AIDS patients, who in industrialised countries are now mostly seen on an outpatient basis thanks to the introduction of Highly Active Antiretroviral Therapy. US can investigate most of the organs affected in AIDS and can guide biopsies, allowing the cyto-histological and microbiological investigations needed for a definitive diagnosis. This paper reviews the wide variety of applications of abdominal US and stresses its importance in the management of a complex and changing condition, particularly in settings where other more expensive imaging techniques are not--and will not be for a long time--available. The increasing use of portable/hand-carried scanners further adds to the value of the technique in such settings. With new treatments, prevalence and morbidity/mortality rates change, but new conditions and new side effects appear. US applications to these new conditions are discussed as well.     

Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model

Cardiovascular Drugs and Therapy - Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated...     

The effect of menopause on blood lipid and lipoprotein levels. The Icarus Study Group.

There is increasing evidence from epidemiological studies that exogenous estrogen (hormone replacement therapy) protects against the elevated risk of cardiovascular disease in women after the menopause. However, it is still uncertain whether the postmenopausal decrease in endogenous estrogen in itself contributes significantly to this increase in risk. Most of the studies that have provided evidence linking cardiovascular disease with menopause have involved North American women, who may differ significantly from Europeans in terms of lifestyle and diet. ICARUS (Italian Climacteric Research Group Study) is an observational study that involves Italian Menopause Clinics, with the objective of collecting observational data on menopause and its management. The results of a cross-sectional analysis of 9309 women, free from any hormonal treatment and enrolled up to March 1997, are reported here. Data show that the menopause has a marked effect on the circulating levels of lipids and lipoproteins. From pre- to post-menopause there are significant increases in total cholesterol (6.9% before and 4.4% after adjustment for covariates including chronological age, educational level, center, BMI, smoking habits, hypertension and diabetes, previous contraceptive use, and time since menopause), LDL (7.5% before, 4.0% after), and triglycerides (9.0% before, 3.2% (ns) after). However, there is no significant change in HDL. Among postmenopausal women, no effect on lipid profile of time since menopause was observed.     

La 8.ª edición de la clasificación AJCC-TNM: nuevas aportaciones a la estadificación del cáncer de la unión esofagogástrica

The new 8th edition of the TNM classification system for esophageal and cardia or esophagogastric junction cancer provides important innovations in the TNM stages. Two classifications are presented, updated by stages, clinical (cTNM) and pathological (pTNM) methods, together with another pathological classification applicable to cases receiving neoadjuvant treatment (ypTNM). There is a notable increase in complexity compared to previous versions, but it is still early to determine whether the current modifications will result in a clear improvement in the prognostic discrimination of survival among the patient groups (which is their main objective), although the initial expectations are favorable.