Gemcitabine-induced severe pulmonary toxicity

Gemcitabine is a relatively new deoxycytidine analog (2',2'-difluorodeoxycytidine) with structural similarities to cytosine arabinoside (Ara-C). Activity of gemcitabine is demonstrated in the treatment of many solid tumors, like pancreas, ovarian and nonsmall cell lung cancer (NSCLC). Although gemcitabine is considered as a drug with a good safety profile, cases of gemcitabine-induced severe pulmonary toxicity (GISPT) were reported as for Ara-C. We performed a systematic review of reported cases on the GISPT. Twenty-nine clinical trials especially interesting NSCLC patients (21) and 21 reported cases recording 40 patients were analyzed. The incidence of the GISPT varies from 0 to 5%. The clinical presentation is a subacute clinical syndrome and is frequently nonspecific. The predominant radiographic pattern on chest X-ray are reticulo-nodular interstitial infiltrates. It was postulated that the physio-pathological mechanism of the GISPT was an inflammatory reaction of the alveolar capillary wall cytokine-mediated, which created an abnormal permeability of its membrane. After the differential diagnosis were ruled out, the discontinuation of the drug and the early initiation of steroids and diuretics are the most frequently performed treatments. Under these conditions, the outcome was favorable in a delay of few days generally for a majority of patients but 20% of patients died. Some risk factors, as a previous pulmonary disease or a previous thoracic irradiation, for the occurrence of the GISPT were proposed. GISPT is rare but sometimes fatal. Its a necessity to increase awareness about it to enhanced an early and suitable management of patients developing such a toxicity after gemcitabine administration.     

Mechanisms of Moisture Sorption in Barrier Polymers Used in Food Packaging: Amorphous Polyamide vs. High‐Barrier Ethylene‐Vinyl Alcohol Copolymer Studied by Vibrational Spectroscopy

The nature of the association between sorbed water and two high‐barrier hydrophilic polymers used in oxygen‐sensitive food packaging, and exhibiting opposite oxygen barrier behavior in the presence of moisture, has been studied by FT‐Raman and FT‐Infrared spectroscopy. The polymers considered in this work were an ethylene‐vinyl alcohol copolymer with superior oxygen barrier properties (32 mol‐% of ethylene EVOH) and an amorphous polyamide (aPA). The results revealed that for the latter glassy amorphous polymer, water molecules associate with the C?O and N? H groups of the ca. 10% “free” amide moieties, being the excess sorbed water self‐associated in clusters; thus, moisture sorption does not appear to disrupt the originally present hydrogen‐bonded amide groups. This “unusual” behavior leads to an overall increase in the extension of the hydrogen‐bonding, which may help explain the lower oxygen permeability displayed by the aPA with increasing relative humidity on the basis of the known free‐volume competing mechanism. Differently, water sorption appears to progressively disrupt the strong polymer self‐association present in the very efficient high‐barrier semicrystalline EVOH material by hydrogen‐bonding to hydroxyl groups, hence leading to the well‐known highly plasticized rubbery structure with much lower intermolecular cohesion and oxygen barrier.

FT‐IR spectra of severely dried, dry (dotted), and water‐equilibrated (thicker line) aPA in the range 2 600–3 800 cm^?1.     

Effects of entorhinal cortex lesions on sensory integration and spatial learning

BACKGROUND: The entorhinal cortex provides sensory information to the hippocampus for memory and learning. Damage to the entorhinal cortex is common in patients who experience traumatic brain injury, stroke, and Alzheimer's disease. Entorhinal damage is assumed to interfere with sensory integration; however, substantive knowledge of behavioral patterns is lacking. OBJECTIVES: To describe specific behavioral deficits associated with entorhinal cortex injury related to special senses identification, sensory integration, and spatial learning. METHOD: Adult male rats received bilateral entorhinal cortex damage (n = 19) or sham surgery (n = 11) with a subset randomized to participate in special senses identification, exploration, and sensory integration testing. Spatial learning was examined using a water maze. RESULTS: Lesion and control animals were similar in special senses identification testing. Sensory integration was markedly impaired in lesion animals over 3 days for all integration tasks; however, travel deficit persisted for 4 days. By day 5 sensory integration ability was equal. Lesion animals were significantly impaired across all days of spatial learning for swim time (p = .0001) and directional heading error (p = .03). Control animals exposed to sensory testing demonstrated significantly more efficient learning (p = .005) on swim days 2 and 3 versus control animals not exposed to sensory testing. CONCLUSIONS: Early and prolonged behavioral changes are evident following entorhinal cortex damage including sensory integration deficits and persistent spatial learning impairment.     

Effect of the herbicide glyphosate on enzymatic activity in pregnant rats and their fetuses

To prevent health risk from environmental chemicals, particularly for progeny, we have studied the effects of the herbicide glyphosate on several enzymes of pregnant rats. Glyphosate is an organophosphorated nonselective agrochemical widely used in many countries including Argentina and acts after the sprout in a systemic way. We have studied three cytosolic enzymes: isocitrate dehydrogenase-NADP dependent, glucose-6-phosphate dehydrogenase, and malic dehydrogenase in liver, heart, and brain of pregnant Wistar rats. The treatment was administered during the 21 days of pregnancy, with 1 week as an acclimation period. The results suggest that maternal exposure to agrochemicals during pregnancy induces a variety of functional abnormalities in the specific activity of the enzymes in the studied organs of the pregnant rats and their fetuses.     

Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria

PATIENTS AND METHODS: The brain disposition of the enantiomers of the antimalarial mefloquine was studied in two post-mortem human cerebral biopsies after oral administration of the racemic mixture. BACKGROUND: Mefloquine (MQ) is an effective antimalarial drug used both for prophylaxis and treatment of chloroquine resistant Plasmodium falciparum. MQ is generally well tolerated in treatment. Minor side-effects have been described. Potentially serious neuropsychiatric reactions occur. The mechanism underlying the neurotoxicity is unknown, although a dose relationship is evidently involved. RESULTS: Mefloquine enantiomer concentrations were determined using a chiral liquid chromatographic method. Mefloquine concentrations were higher in brain compared to plasma. Studied in one patient, white matter concentrations were higher compared to grey matter concentrations. CONCLUSION: Based on the ratios brain concentration/plasma concentration, the brain penetration of the (+) enantiomer is much higher than that of the (-) enantiomer.     

Experience with hemoperfusion for organophosphate poisoning.

OBJECTIVE: To evaluate the usefulness of extracorporeal clearance techniques in the treatment of organophosphate poisoning, particularly hemoperfusion. DESIGN: Retrospective study. SETTING: An ICU of a general hospital. PATIENTS: Ten patients with organophosphate poisoning initially received classic treatment with gastric lavage and washing of the whole skin surface, as well as the administration of cathartics, activated charcoal, atropine, and obidoxime or pralidoxime. All patients underwent one to three hemoperfusions. MEASUREMENTS AND MAIN RESULTS: Plasma insecticide concentrations and cholinesterase activity were determined daily. Two to three biopsies of fat tissue were carried out at 1- to 2-wk intervals. The amount of the insecticide removed during hemoperfusions was also determined. Five patients presented with a prolonged nicotinic syndrome. Two of these patients showed sequelae of delayed neurotoxicity. Another two of the five patients died and the remaining patient recovered without sequelae. In none of the patients could > 0.1% of the total absorbed poison be removed by hemoperfusion. No changes in symptoms were observed after these procedures. Fat tissue concentrations of the insecticide were 20 to 50 times higher than the concentrations in plasma. Atropine decreased the intestinal transit time, and 10 days after poisoning, a powerful cathartic treatment indicated the persistence of gut content, which probably caused prolonged absorption of the toxin. CONCLUSIONS: Extracorporeal cleansing mechanisms did not remove any clinically important amount of insecticide from our patients due to the high lipid solubility of these agents and no changes in symptoms were observed after these methods. The use of atropine decreases bowel peristalsis. Early use of powerful cathartics could avoid protracted absorption of the poison stored in the gut, although the potential benefits of this therapy require confirmation by the performance of prospective, controlled investigations.