Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman.

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.

Toxicological and hematological effects of sicklepod (Cassia obtusifolia) seeds in Sprague-Dawley rats: a subchronic feeding study.

Cassia obtusifolia and its seeds, common contaminants of agricultural commodities, are toxic to cattle and poultry. Toxicity has been attributed to anthraquinones which are major constituents of C. obtusifolia, but studies of the subchronic and chronic toxicity of naturally occurring anthraquinones are limited. To investigate the subchronic (greater than 30 days) toxicity of C. obtusifolia seed, ten rats/sex were fed diets containing 0, 0.15, 0.50, 1.5 or 5.0% C. obtusifolia seed for 13 weeks. Intermittent mild diarrhea was found in high-dose animals and body weights of high-dose males were decreased to week 10. Myeloid hyperplasia with peripheral leukocytosis, thrombocytosis and mild anemia were found in males and females fed diets containing greater than or equal to 0.50% C. obtusifolia seed. Leukocytosis resulted from neutrophilia, whereas peripheral lymphocyte counts were unaffected. Lymphoid hyperplasia and/or histiocytosis were found in the mesenteric lymph nodes in groups fed C. obtusifolia seed. Thus, a dietary 'no observable effect level' for subchronic ingestion of C. obtusifolia seed in rats was less than 0.15%.

Pharmacological dissociation of the motor and electrical aspects of convulsive status epilepticus induced by the cholinesterase inhibitor soman.

In an effort to validate methods to be used in a screen for drugs effective as anticonvulsants for soman-induced convulsions, scopolamine (0.2 mg/kg) or diazepam (1 mg/kg) were given (i.m.) to male guinea pigs as a pretreatment 30 min before a convulsant dose of soman. Pyridostigmine, atropine and pralidoxime chloride also were given to counteract the lethality of soman. All animals challenged with soman and which did not receive either diazepam or scopolamine exhibited convulsive status epilepticus (SE), identified by continuous electrographic seizure activity (EGSA) and continuous motor convulsions. Despite the presence of continuous motor convulsions in all animals pretreated with diazepam and challenged with soman, EGSA was not observed in five of the seven animals. Continuous motor convulsions developed in four of seven animals pretreated with scopolamine and challenged with soman, but EGSA was not observed in any scopolamine-pretreated guinea pig. Neuronal necrosis was observed in the hippocampus, thalamus, amygdala, and cerebral and pyriform cortices in each animal with EGSA, but not brain damage was found in subjects without EGSA. Thus, although convulsions, EGSA and brain damage normally occur together in animals exposed to soman, the convulsions can be pharmacologically dissociated from the EGSA and brain damage, demonstrating that the clinically manifested convulsions are not dependent on EGSA recorded from the cortex or on abnormal activity which leads to neuronal necrosis in the forebrain.

Prevention of soman neurotoxicity by non-opioid antitussives.

The antitussives dextromethorphan (DM), carbetapentane (CBP), and caramiphen (CM) are known to have anti-convulsant properties. They were given individually to guinea pigs prior to poisoning with 2 x LD50 soman to test their efficacy against organophosphorus-induced convulsions, brain damage, and lethality. All subjects received an injection of pyridostigmine coincident with the antitussive, and were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman administration. CM, in a dose-dependent manner, protected against lethality and either prevented or reduced the intensity of convulsions, electrographic seizure activity (EGSA), and brain damage. CBP delayed the onset of EGSA and reduced its intensity. DM prevented EGSA at higher doses, but neither DM nor CBP protected against the lethal effects of soman. CM is known to possess relatively stronger anticholinergic properties than the other antitussives used in this experiment, which may have contributed to its relatively superior efficacy against soman.

Subchronic toxicology studies of hexachloro-1,3-butadiene (HCBD) in B6C3F1 mice by dietary incorporation.

Two-week repeated-dose and 13-week subchronic studies of HCBD were conducted in B6C3F1 mice. Groups of five mice/sex received 0, 30, 100, 300, 1,000, or 3,000 ppm HCBD in feed for 15 days. Toxic responses, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough coat, sensitivity to light, and/or incoordination), mortality (all mice in the top two dose groups died by day 7), body and organ weight depression, and gross and histopathological changes. The most prevalent microscopic lesion, seen in all HCBD-treated mice of both sexes, was renal tubular cell necrosis and/or regeneration. Regeneration was seen only in the lower dose groups. Thirteen-week studies were conducted in which groups of 10 mice/sex received 0, 1, 3, 10, 30, or 100 ppm HCBD in feed. No treatment-related clinical signs or mortality were observed. Body weight gain was reduced in the 30- and 100-ppm males (-49 and -56, respectively), and the 100-ppm females (-47). Significant reduction in kidney weights was seen in the 30- and 100-ppm males and 100-ppm females. A treatment-related increase in tubular cell regeneration in the renal cortex occurred in both male and female mice. This lesion was characterized by an increase both in number and basophilic staining intensity of the tubular epithelial cells. Regeneration was seen in the outer stripe of the outer medulla and extended into the medullary rays (pars recta); severity increased with dose. Female mice were more susceptible to the toxicity of HCBD than male mice. Although no adverse effects were observed at the 10-ppm level for male mice in the subchronic study, the regenerative lesion was present in female mice at 1 ppm, the lowest dose administered.

13-week inhalation toxicity study of menthol cigarette smoke.

Menthol is a common pharmaceutical, food and tobacco flavouring ingredient used for its minty characteristics and cooling effects. A 13-wk comparative nose-only smoke inhalation toxicity study was conducted using an American-style, cellulose acetate-filtered, non-menthol reference cigarette and a similarly blended test cigarette containing 5000 ppm synthetic l-menthol tobacco. Male and female Fischer 344 rats were exposed for 1 hr/day, 5 days/wk for 13 wk at target mainstream smoke particulate concentrations of 200, 600 or 1200 mg/m3, while control rats were exposed to filtered air. Internal dose biomarkers (blood carboxyhaemoglobin, serum nicotine and serum continine) indicated equivalent exposures were obtained for the two cigarettes. Effects typically noted in rats exposed to high levels of mainstream tobacco smoke were similar for both cigarette types and included reduced body weights (males slightly more affected than females), increased heart-to-body weight ratios and lung weights, and histopathological changes in the respiratory tract. Rats exposed to reference cigarette smoke displayed a dose-related increase in nasal discharge that was not observed in menthol smoke-exposed rats. All smoke-related effects diminished significantly during a 6-wk non-exposure recovery period. The results of this 13-wk smoke inhalation study indicated that the addition of 5000 ppm menthol to tobacco had no substantial effect on the character or extent of the biological responses normally associated with inhalation of mainstream cigarette smoke in rats.

Transjugular intrahepatic portosystemic shunts formed with polyethylene terephthalate-covered stents: experimental evaluation in pigs.

PURPOSE: To evaluate the safety, efficacy, and tissue response associated with Wallstents covered with polyethylene terephthalate (PETP) compared with those associated with uncovered Wallstents for creation of transjugular intrahepatic portosystemic shunts (TIPS) in a porcine model. MATERIALS AND METHODS: Thirteen TIPS were created in 13 minipigs: eight with PETP-covered Wallstents, five with standard Wallstents. Shunt venography was performed at 5-8 weeks, and necropsy was performed at 7-8 weeks. Histopathologic, immunohistochemical, and scanning electron microscopic examinations were performed. RESULTS: Mean shunt stenoses of the control and graft groups were 45% and 53%, respectively. Graft stenoses involved the entire graft-bearing segment, whereas bare stent stenoses were localized within the liver tract. Myofibroblast and extracellular collagen matrix proliferation encompassed both control and graft-covered stents. There was one graft TIPS occlusion. One control TIPS stenosis was due to transstent proliferation of normal porcine hepatic tissue. A small focus of bile staining was seen on the abluminal surface of one TIPS, which was a patent PETP-lined shunt. CONCLUSION: PETP graft TIPS provided equal, but not superior, patency to that of bare stent TIPS. The pattern of PETP TIPS graft healing differed from that of bare stents but was similar to that reported with other polyester graft vascular implants and consisted of diffuse transmural penetration and paving of the graft surface by extracellular collagen matrix and myofibroblasts.

Comparison of covered versus uncovered wire mesh stents in the canine biliary tract.

Self-expanding wire mesh stents have been developed for endoscopic placement across malignant biliary strictures, but tumor ingrowth may limit the usefulness of open mesh stents. We reasoned that coating the wire mesh might prevent tumor ingrowth. Tissue response to covered and uncovered stents was compared in dogs. Stents were surgically placed in the bile ducts of 22 mongrel dogs through the sphincter of Oddi. Either a silicone-covered stent or an uncovered stent was inserted. Liver function test values remained normal throughout a 1- or 3-month study. Necropsy revealed that all ducts were unobstructed. Bile duct histologic examination revealed mild-to-moderate cellular infiltration in all animals. Mucosal hyperplasia was more marked in the animals with uncovered stents and the bare wires became deeply embedded in bile duct epithelium, whereas the wires of covered stents did not. We conclude that covered stents are well tolerated by the canine bile duct. These results suggest that such stents may be removable, making self-expanding metal stents an appropriate treatment for both benign and malignant biliary strictures.

Tissue response to covered Wallstents.

PURPOSE: To evaluate and compare the healing response related to two types of graft-covered Wallstents (WSs) and an uncovered WS in the canine iliac artery. MATERIALS AND METHODS: Eight bare mesh WSs, 10 polyethylene terephthalate interbraided WSs (PET-WSs), and six polytetrafluoroethylene covered WSs (ePTFE-WSs) were placed in the iliac arteries of 12 dogs. Arteriograms were obtained before and after implantation and at explantation. Devices were explanted at 1 month (n = 8), 3 months (n = 6), and 6 months (n = 10) and sent for histologic study. RESULTS: One ePTFE-covered stent-graft was found to be thrombosed at 3 months; the remaining 23 of 24 implants remained patent to the time of explantation. The WS and ePTFE-WS both generated a uniform myointimal cell response without inflammation. The PET-WS induced a fibrous luminal response with substantial foreign body-type inflammatory reaction around the PET fibers. Although neointima associated with the PET-WS appeared thicker than that associated with either the ePTFE-WS or the bare WS, none of the patent implants developed greater than 50% angiographic narrowing. CONCLUSION: The PET-WS induced chronic inflammation, a response not seen with either the WS or ePTFE-WS. This may explain the occurrence of pain and/or fever in human studies of arterial PET endoluminal stent-grafts. Patency for all three implants was excellent in this model.

Pathological characterization of male Wistar rats from the gerontology research center.

Male Wistar rats aged 6-26 months were obtained from the colony of The Gerontology Research Center of the National Institute on Aging, and pathological profiles were assessed. One hundred animals were sacrificed at 6, 12, 18, 21, 24, and 26 months and used for cross-sectional determinations; also, 150 animals were followed longitudinally and sacrificed when clinical signs of moribundity appeared. Renal disease contributed the most common pathology observed in both studies (found in over 70% of the animals examined), with neoplasms a secondary problem (pituitary tumors were by far the most prevalent, with adenomas present in approximately 20% of the animals). This analysis represents the first complete pathological characterization of this commonly used rat model for aging research, and offers an opportunity for comparison with other rat strains.