Venous angiomas: plain and contrast-enhanced MRI and MR angiography

We studied 17 patients with venous angiomas, 4 of whom had associated cavernous angiomas. All underwent MRI with spin-echo T1- and T2-weighted images and T1-weighted images after Gd-DTPA; MR angiography (MRA) was also performed with 3D and 2D time-of-flight technique; 5 patients underwent conventional angiography. Contrast-enhanced MRI demonstrated all the lesions, showing the peripheral medullary veins, the collector and the type of drainage. Both 3D and 2D MRA provided diagnostic information identical to that obtained after infusion of Gd-DTPA. Contrast-enhanced were T1-weighted images and MRA superior in all the cases to images without gadolinium. The possible association with cavernous angiomas (24% in our study) indicates T2-weighted imaging.     

The influence of charge clustering on the anti-HIV-1 activity and in vivo distribution of negatively charged albumins

The substitution of human serum albumin with negatively charged molecules, such as succinic acid (Suc-HSA) or aconitic acid (Aco-HSA), resulted in proteins with potent anti-HIV activities, by binding to viral gp120 (V3 loop). The aim of the present study was to investigate whether the distribution of negative charges on the albumin backbone influences the anti-HIV activity. Therefore, we prepared albumins with clusters of negatively charged groups by coupling of heparin. The effects of this substitution on anti-HIV activity, in vivo distribution and the protein structure as compared to random succinylation were assessed. In vitro studies indicated that HSA-modified with heparin 6 or 13 kD displayed anti-HIV activity (IC50=660 and 37 nM, respectively) and exhibited affinity for gp120-V3 loop, although the activity was lower than that of Suc-HSA. Combined derivatization of HSA with heparin 13 kD and aconitic acid groups resulted in significantly increased inhibitory actions (IC50=2.8 nM). Structural analysis showed that modification of HSA with heparin did not lead to extensive unfolding of the protein, meaning that these modified proteins were still globular in structure. In contrast, succinylation of HSA resulted in a highly randomly coiled conformation. Dynamic light scattering experiments revealed that, at neutral pH, the heparin fragments attached to the protein were wrapped around the molecule rather than sticking out into the solution. In conclusion, coupling of sufficient clustered negative charges, by coupling of Hep-fragments, on HSA resulted in a clear anti-HIV activity of the protein. Yet, random distribution of anionic groups in the albumin seemed more optimal for in vitro anti-HIV activity. The higher plasma and lymphatic concentrations of Hep-HSA compared to Suc-HSA seemed more favorable for an anti-HIV activity in vivo.     

Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and protein-derived peptides

In a search for natural proteins with anti-HIV activity, we screened a large set of purified proteins from bovine milk and peptide fragments thereof. Because several charged proteins and peptides are known to inhibit the process of virus entry, we selected proteins with an unusual charge composition or hydrophobicity profile. In contrast with some chemically modified (strongly negative) milk proteins, unmodified alpha(s2)-, beta- and kappa-casein, as well as several negatively and positively charged fragments thereof, did not show significant inhibition of virus replication. In fact, HIV-1 replication was elevated in the presence of beta-casein or amphiphilic fragments thereof. Bovine lactoferrin (bLF), a milk protein of 80 kDa, showed considerable inhibitory activity against HIV-1 with an IC50 of 0.4 microM. Modest inhibition was obtained with lactoferricin, a highly positively charged loop domain of bLF, indicating that other domains within the native bLF protein may also be required for inhibition. bLF blocked HIV-1 variants that use either the CXCR4 or the CCR5 coreceptor. In order to obtain further insight into the mechanism of action of this antiviral protein, we selected a bLF-resistant HIV-1 variant. The bLF-resistance phenotype is mediated by the viral envelope protein, which contains two interesting mutations that have previously been associated with an altered virus-host interaction and a modified receptor-coreceptor interaction. These results demonstrate that bLF targets the HIV-1 entry process.     

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

AIMS

Among the main disadvantages of currently available Δ⁹-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

METHODS

This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

RESULTS

Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t_1/2 was 72–80 min, t_max was 39–56 min and C_max 2.92–4.69 ng ml⁻¹. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min^–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.

CONCLUSIONS

Oral Namisol® showed promising PK and PD characteristics. Variability and t_max of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.     

Anticipation and consumption of food each increase the concentration of neuroactive steroids in rat brain and plasma

Stressful stimuli and anxiogenic drugs increase the plasma and brain concentrations of neuroactive steroids. Moreover, in rats trained to consume their daily meal during a fixed period, the anticipation of food is associated with changes in the function of various neurotransmitter systems. We have now evaluated the effects of anticipation and consumption of food in such trained rats on the plasma and brain concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH DOC), two potent endogenous positive modulators of type A receptors for gamma-aminobutyric acid (GABA). The abundance of these neuroactive steroids was increased in both the cerebral cortex and plasma of the rats during both food anticipation and consumption. In contrast, the concentration of their precursor, progesterone, was increased in the brain only during food consumption, whereas it was increased in plasma only during food anticipation. Intraperitoneal administration of the selective agonist abecarnil (0.1 mg/kg) 40 min before food presentation prevented the increase in the brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC during food anticipation but not that associated with consumption. The change in emotional state associated with food anticipation may thus result in an increase in the plasma and brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC in a manner sensitive to the activation of GABA(A) receptor-mediated neurotransmission. A different mechanism, insensitive to activation of such transmission, may underlie the changes in the concentrations of these neuroactive steroids during food consumption.     

Effect of amantadine on weight gain during olanzapine treatment.

Patients treated with olanzapine may gain weight, especially in the first months of therapy. Amantadine (100-300 mg/day) was started in 12 patients having a mean weight gain of 7.3 kg during olanzapine treatment. The patients' weight stabilised and over 3-6 months they lost an average of 3.5 kg. No clinical deterioration occurred and no adverse effects were reported. These observations merit confirmation in randomised, controlled trials.     

Effect of the law on compulsory helmets in the incidence of head injuries among motorcyclists

The Authors report the data, relative to the province of Cagliari and its surroundings, on the rate of motorcycle road accidents, the reported head injuries, the morbidity and mortality referred to five analogous months, i.e., before and after the coming into force of the law on compulsory protective helmets. Examination of such data shows an absolute and percent reduction of the number of head injuries, serious injuries reported, and overall mortality.     

Intravesical recurrence after bladder sparing treatment of small cell carcinoma of the bladder: Characteristics,treatment, and outcome

Introduction

Small cell carcinoma of the bladder (SCCB) is a rare and lethal disease. Previously, we and others have reported a bladder sparing strategy with platinum-etoposide-based chemotherapy followed by radiotherapy of the bladder. Little is known on frequency and treatment of intravesical recurrence following this approach. The objective of this study is to describe the incidence of intravesical recurrences and their management.