Development of controlled release captopril granules coated with ethylcellulose and methylcellulose by fluid bed dryer

Captopril granules of controlled release with different polymers as ethylcellulose, ethyl/methylcellulose, and immediate release with polyvinylpyrrolidone (PVP) were developed by fluid bed dryer technique. The formulations were analyzed by scanning electron microscopy, X-ray powder diffraction, and dissolution profiles. To compare the formulations an in vivo setting rat blood pressure assay was performed, using angiotensin I as a vasoconstrictor agent. The scanning electron microscopy of granules showed differences in morphology, and X-ray powder diffraction technique presented some modification in crystalline structure of captopril in granules coated with PVP and ethyl/methylcellulose. The dissolution profile of granules coated with ethylcellulose showed a median time release of 4 hr whereas for granules coated with ethyl/methylcellulose, this time was 3.5 hr. The blockage of angiotensin I-induced hypertensive effect lasted 8 hr in granules coated with PVP and of more than 12 hr in the granules coated with ethylcellulose and ethyl/methylcellulose.     

Structural defects play a major role in the acute lung toxicity of multiwall carbon nanotubes: toxicological aspects

Experimental studies indicate that carbon nanotubes (CNTs) have the potential to induce adverse pulmonary effects, including alveolitis, fibrosis, and genotoxicity in epithelial cells. Here, we explored the physicochemical determinants of these toxic responses with progressively and selectively modified CNTs: ground multiwall CNTs modified by heating at 600 degrees C (loss of oxygenated carbon functionalities and reduction of oxidized metals) or at 2400 degrees C (annealing of structural defects and elimination of metals) and by grinding the material that had been heated at 2400 degrees C before (introduction of structural defects in a metal-deprived framework). The CNTs were administered intratracheally (2 mg/rat) to Wistar rats to evaluate the short-term response (3 days) in bronchoalveolar lavage fluid (LDH, proteins, cellular infiltration, IL-1beta, and TNF-alpha). The long-term (60 days) lung response was assessed biochemically by measuring the lung hydroxyproline content and histologically. In vitro experiments were also performed on rat lung epithelial cells to assess the genotoxic potential of the modified CNTs with the cytokinesis block micronucleus assay. The results show that the acute pulmonary toxicity and the genotoxicity of CNT were reduced upon heating but restored upon grinding, indicating that the intrinsic toxicity of CNT is mainly mediated by the presence of defective sites in their carbon framework.     

Antinociceptive and anti-allodynic effects of oral PL37, a complete inhibitor of enkephalin-catabolizing enzymes, in a rat model of peripheral neuropathic pain induced by vincristine

Vincristine is a common anti-cancer therapy administered for the treatment of many types of tumors. Its dose-limiting side effect is the production of peripheral neuropathy, resulting in chronic neuropathic pain in many patients. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in male rats and used in the present work to study the effects of PL37, an orally active complete dual inhibitor of enkephalin-catabolizing enzymes, on mechanical hypersensitivity and allodynia and on cold allodynia. We used the Electronic Von Frey filament (mechanical static allodynia), acetone test (cold allodynia), and a new behavioural test we first describe in this study, the “paint-brush test” which evaluates dynamic mechanical allodynia and dynamic mechanical hypersensitivity. We used a smooth paint brush leading to an innocuous stimulus, and a rough-one leading to an intense mechanical stimulus. Mechanical hypersensitivity and allodynia due to vincristine-induced neuropathy, but not cold allodynia, are strongly reduced by oral or i.p. injected PL37, the dose-dependent effects being reversed by naloxone-methiodide supporting the peripheral action of the dual inhibitor. These results show that enkephalins protected from degradation by PL37 could bind to peripheral opioid receptors expressed only on C- and Aδ-mechanonociceptors but not on cold thermonociceptors. The fact that PL37 is also active on small intensity mechanical stimulus could reveal an expression of opioid receptors on low threshold mechanoreceptors in the vincrisitine-evoked pathological conditions. Thus the increase in endogenous enkephalin levels induced by PL37 offers a new way to reduced neuropathic pain without the possible side effects of opiates.     

Rebeccamycin derivatives as dual DNA-damaging agents and potent checkpoint kinase 1 inhibitors

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogs with the sugar moiety attached to either one or both indole nitrogens. Some analogs, especially those with substitutions at the 6' position of the carbohydrate moiety, exhibit potent inhibitory activity toward checkpoint kinase 1 (Chk1), a kinase that has a major role in the G(2)/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.     

Characterization of a new rat model of head and neck squamous cell carcinoma

AIM: To develop and characterize by imaging and pathological examination a new immunocompetent rat model of head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Prospective animal research. MATERIALS AND METHODS: Frozen specimens of HNSCC induced chemically by 4-nitroquinoline 1 oxide (4-NQO) in Sprague Dawley rats were used for the first graft. Serial allografts were then performed with fresh specimens of tumor in twenty-five Sprague Dawley rats. A specimen of tumor (100 mm3) was picked up by head and neck dissection during an autopsy. The graft was performed in a subcutaneous manner, in the ventral part of the neck, using an incision of 4 mm, through the masseter muscle. Tumors were clinically measured once a week and volumes were calculated. 2-[18F]Fluoro-2-deoxy-D-glucose positron emission tomography coupled with computed tomography (FDG-PET/CT) was performed on days 14 and 30 after the graft. Rats were euthanized and pathological features were assessed using hematoxylin-eosin (HE) staining and immunohistochemistry markers to characterize the tumor. RESULTS: An 80% take rate was achieved using fresh tumor specimens. Tumors grew rapidly; the mean tumoral volume was 1.013 cm3 on day 14 and 7.994 cm3 on day 30. FDG-PET/CT imaging targeted regions of metabolically active tumor. It showed a uniform uptake of 18F-FDG on day 14 and a large area of central necrosis on day 30. Pathological examinations showed a typical squamous cell carcinoma, with similar immunohistochemical analyses to the human squamous cell carcinoma. CONCLUSION: We propose a new allograft HNSCC rat model which is easily reproducible and rapidly obtained in comparison to that induced chemically with 4-NQO. This model was developed in immunocompetent rats, with similar conditions to human carcinogenesis and could be used for testing new therapeutics.     

A national survey of acute hepatitis E in France

Background  Few data are available on the incidence, risk factors and contamination pathways involved in acute indigenous hepatitis E in developed countries.
Aims  To draw up an overall picture of hepatitis E cases, to confirm whether or not the majority of the cases were indigenous and to attempt to identify the risk factors and contamination pathways involved in hepatitis E.
Methods  This study was performed in the framework of a national network (ANGH) including 96 participating centres. The 19 centres with at least one case of acute HEV reported a total number of 53 cases.
Results  A decreasing South-to-North geographic gradient was observed. A nonspecific clinical profile was observed in many cases. Acute hepatitis E was of indigenous origin in 90% of the patients. The most relevant and/or frequent possible risk factors among the 47 indigenous metropolitan cases were water consumption from a personal water supply, uncooked shellfish consumption and the recent acquisition of a pet pig.
Conclusions  This national survey confirmed that acute indigenous hepatitis E is an emerging disease in developed countries such as France, and suggests that various risk factors are responsible for acute indigenous hepatitis E contamination in non-endemic countries.     

Connections of the dorsolateral prefrontal cortex with the thalamus: a probabilistic tractography study

Purpose

The dorsolateral prefrontal cortex (DLPFC) is a cortical area involved in higher cognitive functions, and at the center of the pathophysiology of mental disorders such as depression and schizophrenia. Considering these major roles and the development of deep brain stimulation, the object of this study was to assess the patterns of connectivity of the DLPFC with its main subcortical relay, the thalamus, with the help of probabilistic tractography.

Methods

We used T1-weighted imaging and diffusion data from 18 subjects from the Human Connectome Project. The DLPFC and the thalamic nuclear groups were defined using the combination of atlases, sulcogyral anatomy and cytoarchitectonic data. Probabilistic tractography was performed from the DLPFC to the thalamus. The patterns of connectivity were assessed using two indexes: (1) a connectivity index (CI) which evaluate the strength of connection (2) an asymmetry index (AI) which explores the inter-hemispheric variability.

Results

The analysis of CI showed significant connections between the DLPFC and the dorsomedial nuclei (p < 0.05), the anterior nuclear groups (p < 0.05) and the right centromedian nucleus (p < 0.05). No link was found between handedness and AI (p > 0.05). Most of subjects (15/18) had a right predominance of the thalamo cortical connections of the DLPFC.

Conclusions

Probabilistic tractography appears as a valuable non-invasive tool for the exploration of the thalamocortical connections between the dorsolateral prefrontal cortex and thalamic nuclei. It allowed to show different inter-hemispheric patterns of connectivity, and highlighted the centromedian nucleus as a key subcortical relay of executive functions.

     

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes.

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellular accumulation of various anticancer drugs including anthracyclines and vinca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitro and in animal models. Here, we report an open phase I dose escalation trial in patients with refractory or relapsed malignant lymphoid diseases. Cinchonine dihydrochloride was administered by continuous i.v. infusion for 48 h and escalated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infusion started 24 h before i.v. doxorubicin (25 mg/m2), vinblastine (6 mg/m2), cyclophosphamide (600 mg/m2) and methylprednisolone (1 mg/kg/d) (CHVP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four patients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine administered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolarization was the main dose-limiting toxicity. No ventricular arrhythmia including 'torsade de pointes' was observed. An MDR reversing activity was identified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinchonine might be started 12 h before MDR-related chemotherapy infusion and requires continuous cardiac monitoring but no reduction of cytotoxic drug doses.