Epinephrine-induced pulmonary oedema in rats is inhibited by corticotropin-releasing factor.

In various animal models of injury to skin, mucous membranes, muscle and brain, corticotropin-releasing factor (CRF) attenuated vascular leakage in the injured tissues. Here, the effects of CRF on a rat model of pulmonary oedema were examined. Male albino rats (220-290 g) received saline or CRF s.c., 30 min before pentobarbital anaesthesia, 60 mg/kg i.p., and 1 h before 1-epinephrine bitartrate (Epi), 30 micrograms/kg i.v. Within 30 min after Epi all (n = 27) saline-pretreated rats were dead from pulmonary oedema, but animals receiving human/rat CRF at doses of 7 to 57 micrograms/kg s.c. (n = 25) were all alive. Body wt, wet and dry wt of lungs were used to calculate an oedema index. This index increased from 3.6 +/- 0.1 to 9.6 +/- 0.3 after Epi but was inhibited by 87% after CRF 28 micrograms/kg s.c. The ED50 of CRF for reducing pulmonary oedema was 3.2 (1.3-7.4) micrograms/kg s.c. Mean arterial pressure increased from 119 +/- 4 to 167 +/- 2 mmHg after Epi 10 micrograms/kg i.v., but was not different (118 +/- 3 to 169 +/- 4 mmHg) after CRF pretreatment, 6 micrograms/kg s.c., a dose which reduced lung oedema. Pharmacokinetic estimates suggest that plasma levels of CRF sufficient to attenuate lung oedema in rats approximate those seen in pregnant women at delivery, raising the possibility that endogenous CRF may protect the maternal organism during parturition.     

曲妥珠单抗引起过敏样反应

1例52岁女性患者,因乳腺癌术后辅助化疗给予曲妥珠单抗220mg加入0.9%氯化钠注射液250ml静脉滴注,滴速为50滴/min。输入约30min时,患者出现寒战、胸闷、口唇发麻、呼吸困难,心率165次/min,血压199/99mm Hg。立即停止输液,行对症治疗。50min后上述症状消失,心率及血压恢复正常。21d后再次化疗,曲妥珠单抗110mg加入0.9%氯化钠注射液250ml静脉滴注,滴速30滴/min。5min后,患者再次出现过敏样症状。停药10min后症状消失。     

Mast cell amines and the oedema induced by zymosan and carrageenans in rats

Cimetidine and metiamide suppressed the paw swelling induced in rats by low doses of histamine while these H2 antagonists had little effect on the oedema induced by 100 micrograms of histamine and inhibited by mepyramine. When administered 0.5 h before the inflammagens, H2 antagonists reduced the oedema induced by zymosan and iota carrageenan; they had a slight effect on the oedema induced by lambda and kappa carrageenans and no effect on the oedema induced by compound 48/80. When administered 18 h before the inflammagens, cimetidine greatly increased zymosan oedema and slightly increased lambda carrageenan oedema. Mepyramine, methysergide or depletion of the 5-hydroxytryptamine stores in mast cells by pretreatment with reserpine inhibited the oedema induced by compound 48/80 and zymosan but did not affect the oedema induced by lambda and kappa carrageenans. Histamine may play a dual role in inflammatory reactions. Mast cell amines take a part in the development of zymosan oedema though they play a minor role in the oedema induced by the carrageenans.     

Co-administration of pentoxifylline and thiopental causes death by acute pulmonary oedema in rats

BACKGROUND AND PURPOSE: Pentoxifylline exhibits rheological properties that improve microvascular flow and it is widely used in vascular perfusion disorders. It also exhibits marked anti-inflammatory properties by inhibiting tumour necrosis factor alpha production. Thiopental is one of the most widely used drugs for rapid induction of anaesthesia. During experimental studies on the treatment of acute pancreatitis, we observed that when pentoxifylline was administered after anaesthesia with thiopental, most of the rats exhibited dyspnea, signs of pulmonary oedema and died. The aim of the work described here was to investigate the cause of the unexpected toxic effect of the combined treatment with thiopental and pentoxifylline. EXPERIMENTAL APPROACH: Pulmonary vascular permeability and arterial blood gases were measured, and a histological analysis was performed. The possible role of haemodynamic changes in the formation of pulmonary oedema was also assessed. KEY RESULTS: Co-administration of pentoxifylline and thiopental increased pulmonary vascular permeability and markedly decreased arterial pO2, with one third of rats suffering from hypoxemia. This combined treatment caused death by acute pulmonary oedema in 27% of normal rats and aggravated the respiratory insufficiency associated with acute pancreatitis in which the mortality rate increased to 60%. This pulmonary oedema was not mediated by cardiac failure or by pulmonary hypertension. CONCLUSIONS AND IMPLICATIONS: Co-administration of pharmacological doses of pentoxifylline and thiopental caused pulmonary oedema and death in rats. Consequently, pentoxifylline should not be administered when anaesthesia is induced with thiopental to avoid any possible risk of acute pulmonary oedema and death in humans.     

Glucocorticoids attenuate taste aversions produced by toxins in rats

Conditioned taste aversions (CTAs) develop if toxicosis is induced after an animal eats or drinks. Usually, if a second drug is administered after consumption and prior to the toxin, it either adds to the CTA produced by the toxin or else has no noticeable effect. However, glucocorticoids (dexamethasone, cortisol, methylprednisolone, and prednisolone) attenuate CTAs produced by cyclophosphamide. Dexamethasone was tested most extensively and is also effective against CTAs produced by carmustine, cisplatin, copper sulfate, cytarabine, dactinomycin, doxorubicin, lithium chloride, and mechlorethamine. Delta-9 THC, domperidone, haloperidol, metoclopramide, and scopolamine were ineffective against CTAs produced by cyclophosphamide, although they are used medically for palliative purposes. Prochlorperazine attenuated CTAs but to a much smaller extent than the glucocorticoids. These results are interpreted as cross-validation of recent reports that glucocorticoids alleviate clinically observed distress produced by cancer chemotherapies.     

Ethanol dependence produced in rats by nutritionally complete diets

Nutritionally complete diets formulated according to American Institute of Nutrition guidelines were used to make rats dependent upon ethanol. When intubated with a diet-ethanol solution for four days rats maintained initial body weight. When forced to consume the solution as the sole source of nutrients and water for nineteen days, rats gained weight. All animals developed severe withdrawal signs as measured by the intensity of tremors ans spatic rigidity. The diet ingredients did not alter the absorption of the ethanol. The results demonstrate that physical dependence on ethanol can be induced in the rat without nutritional impairment.     

Neurotoxicity produced by intracranial administration of methylmercury in rats

Methylmercuric chloride administered as a single intracranial injection in μg quantities produced a neurological syndrome in rats within 24 hr that resembled the effects produced by repeated sc injections of 10 mg/kg over a period of 7–14 days. Neuromuscular function evaluated semiquantitatively by graded performance in simple strength and coordination tests showed severe impairment at 24 hr in intracranially methylmercury-treated animals, with recovery taking place by 72 hr. Body weight decreased and recovered during a similar time course. Incorporation of tritiated leucine into brain protein was increased significantly at 24 hr as measured in vitro in brain homogenates and in vivo by administering the labeled amino acid ip. Incorporation returned to control values by 72 hr after the methylmercury injection. Residual brain mercury concentrations at 24 hr were about 5-fold lower than those accompanying overt neurological signs in rats produced by sc administration. Histological examination of brains from intracranially and subcutaneously dosed rats revealed that the lesions produced by the 2 methods were substantially different. Intracranial injection of methylmercury was found to produce an isolated neurotoxic syndrome similar in some respects to the neurotoxicity seen in systemic intoxications but dissimilar histopathologically.     

Intracerebroventricularly administered bradykinin augments carrageenan-induced paw oedema in rats

Intracerebroventricular (i.c.v.) administered bradykinin (2.5 and 5.0 micrograms/rat) was found to augment carrageenan-induced acute paw oedema throughout the 4 h post-carrageenan observation period. The effect was statistically significant with the higher dose. The pro-inflammatory effect of i.c.v. bradykinin was antagonized following pretreatment with hemicholinium and atropine ethoiodide administered i.c.v., drugs that reduce central cholinergic activity. Similarly, central administration of drugs that inhibit the synthesis of eicosanoids, hydrocortisone, diclofenac and paracetamol, also attenuated the pro-inflammatory effect of bradykinin. The findings indicate that the inflammation-promoting effect of centrally administered bradykinin involves the central prostaglandin and cholinergic neurotransmitter systems.     

Indomethacin reverts sleep disorders produced by ozone exposure in rats

Ozone (O(3)) exposure causes pulmonary biochemical changes both in humans and experimental animals, inducing the release of inflammatory mediators such as cytokines and eicosanoids. Some of these reaction products have been characterized as endogenous sleep-promoting substances and have been implicated in the development of sleepiness in patients with inflammatory disease. Furthermore, sleep alterations are known to occur in O(3)-exposed humans and experimental animals. In order to test the probable involvement of such inflammatory mediators in O(3)-induced sleep disorders, we blocked prostaglandin synthesis administrating the cyclooxygenase inhibitor indomethacin (IM) and compared conventional electrographic sleep parameters in rats under four different experimental conditions: treatment with IM alone, O(3)-exposure, pre-treatment with IM plus O(3) exposure, and control conditions. We found that O(3) exposure increased slow wave sleep (SWS) and decreased rapid eye movement sleep (REMs) significantly, while IM pre-treatment reduced these O(3)-induced sleep disorders. IM treatment alone did not affect sleep. These findings strongly support a role for inflammatory mediators in O(3) exposure-induced neurological alterations.     

Modification by steroids of pulmonary oedema and prostaglandin E2 pharmacokinetics induced by endotoxin in rats.

1. A single i.p. injection of bacterial endotoxin in rats (3.5 mg kg-1) caused lung injury assessed as changes in lung dry:wet weight ratio and leukopaenia over the subsequent 28 h. 2. This treatment also slowed the efflux of 14C from [14C]-prostaglandin E2 (PGE2), i.e., increased t1/2 and increased the survival of PGE2 in isolated perfused lungs over the same period. 3. These effects of endotoxin were reversed by methylprednisolone (30 mg kg-1), given 30 min after the endotoxin. 4. Another synthetic corticosteroid, budesonide (1.2 mg kg-1) given 1 h before endotoxin partially prevented the lung injury and leukopaenia but did not affect the increased t1/2 for PGE2 nor its survival. 5. The reversal by methylprednisolone of both the physical signs of lung injury and the changes in PGE2 pharmacokinetics caused by endotoxin suggests that changes in PGE2 pharmacokinetics could serve as an index of acute lung injury following sepsis.     

硝呋太尔阴道片致过敏性休克

一例31岁女性患者,剖宫产后45d,因患滴虫性阴道炎使用硝呋太尔阴道片（商品名：麦咪诺）,用药10min后出现全身皮肤潮红、肿胀、瘙痒、恶心和呕吐,30min后血压下降至70/38mmHg。经过抗过敏治疗和2次阴道冲洗后,过敏反应治愈。结合相似病例的文献检索,我们进一步讨论了此次罕见的过敏反应。     

Effect of central prostaglandins on carrageenan-induced pedal oedema in rats

The possible modulatory effect of central prostaglandins (PGs) on carrageenan-induced pedal inflammation, was investigated in rats. Intracerebroventricularly (i.c.v.) administered arachidonic acid, the PG precursor, produced a statistically insignificant increase in the inflammatory response, though PG synthesis inhibitors, administered by the same route, markedly attenuated the oedema. Centrally administered PGE₂ had a significant proinflammatory effect, whereas PGF_2α exerted an antiinflammatory action. The results indicate that central PGs may modulate peripheral inflammation and that, at least partly, the anti-inflammatory activity of PG synthesis-inhibiting non-steroidal anti-inflammatory agents may involve central PGs, as has been proposed for their analgesic effect.     

Effect of pre-existing inflammation on carrageenan-induced paw oedema in rats

Twenty-four hours after injection of carrageenan into one hind paw, injection of the same amount into the contralateral paw produced a significantly attenuated inflammatory response. However, when the second injection was given 7 days later, the inflammation induced in the contralateral paw was comparable with the initial response to carrageenan. A time-course study of carrageenan-induced inflammation in rats showed that significant oedema persisted 24 h after carrageenan administration and complete recovery was achieved in 7 days. The attenuated inflammatory response in the contralateral paw after 24 h was antagonized by bilateral adrenalectomy and chemical sympathectomy induced by 6-hydroxydopamine. Carrageenan-induced paw oedema was also significantly less in rats with subacute inflammation induced by the croton oil granuloma pouch technique. This attenuated response was antagonized by pretreatment of the rats with metyrapone, an inhibitor of adrenocorticoid synthesis, and by 6-hydroxydopamine. It is likely that the pre-existing acute or subacute inflammation attenuates the inflammatory response of carrageenan, by acting as a stressor, inducing activation of the sympatho-adrenal system.     

Oral antinociception and oedema inhibition produced by NPC 18884, a non-peptidic bradykinin B2 receptor antagonist

This study investigates the antinociceptive and the oedema inhibition properties of the novel non-peptide bradykinin (BK) B2 receptor antagonist, NPC 18884. Given by i.p. or p.o. routes NPC 18884 produced graded and long-lasting (at least 2.5h and 5.0h, respectively, for i.p. and p.o. administration) inhibition of acetic acid-induced abdominal constrictions in mice, with mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibited kaolin-induced abdominal constrictions (44+/-9% and 48+/-3% of inhibition, for i.p. and p.o. routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as formalin-induced oedema formation. At similar doses NPC 18884 produced significant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but not HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 value of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalgesia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg9-bradykinin (DABK) or by prostaglandin E2 (PGE2). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine8-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induced by PGE2. Thus, the novel non-peptide BK B2 receptor antagonist NPC 18884 produces rapid onset, potent and relatively long-lasting oral antinociceptive and oedema inhibition properties. The anti-BK actions of NPC 18884 are quite selective towards the BK B2 receptor-mediated responses.     

Dopaminergic mediation of the interoceptive cue produced by d-amphetamine in rats

After rats were trained to differentiate between the effects of d-amphetamine and saline in a state-dependent task, pretreatment with the tyrosine hydroxylase inhibitor, -methyl-p-tyrosine, significantly decreased amphetamine discrimination. Pretreatment with the dopamine--hydroxylase inhibitor, disulfiram, or with the tryptophan hydroxylase inhibitor, p-chloro-phenylalanine, was observed to have no effect on the rats' ability to discriminate d-amphetamine. Administration of haloperidol, a selective dopamine receptor blocker, completely abolished the amphetamine discrimination, whereas - and -adrenergic receptor blockade had no effect. Apomorphine, a dopamine receptor stimulant, produced amphetamine-like responses and this was, likewise, abolished by pretreatment with haloperidol. These data suggest that dopaminergic systems mediate the interoceptive cue produced by d-amphetamine in rats, and these results are discussed in relation to possible dopamine mediation of amphetamine psychosis and paranoid schizophrenia.Supported as an Americal Medical Association Education and Research Foundation Senior Research Fellow.     

Behavioral evaluation of the neurotoxicity produced by dichloroacetic acid in rats

Dichloroacetic acid (DCA) is commonly found in drinking water as a by-product of chlorination disinfection. It is a known neurotoxicant in rats, dogs, and humans. We have characterized DCA neurotoxicity in rats using a neurobehavioral screening battery under varying exposure durations (acute, subchronic, and chronic) and routes of administration (oral gavage and drinking water). Studies were conducted in both weanling and adult rats, and comparisons were made between Long–Evans and Fischer-344 rats. DCA produced neuromuscular toxicity comprised of limb weakness and deficits in gait and righting reflex; altered gait and decreased hindlimb grip strength were the earliest indicators of toxicity. Other effects included mild tremors, ocular abnormalities, and a unique chest-clasping response (seen in Fischer-344 rats only). Neurotoxicity was permanent (i.e., through 2 years) following a 6-month exposure to high dose levels, whereas the effects of intermediate dose levels with exposures of 3 months or less were slowly reversible. The severity, specificity, and recovery of neurological changes were route, duration, and strain dependent. Fischer-344 rats were more sensitive than Long–Evans rats, and weanling rats may be somewhat more sensitive than adults. Oral gavage produced significantly less toxicity compared to the same intake level received in drinking water. Neurotoxicity was progressive with continued exposure, and was observed at exposure levels as low as 16 mg/kg/day (lowest dose level tested) when administered via drinking water in subchronic studies. The data from these studies characterize the neurotoxicity produced by DCA, and show it to be more pronounced, persistent, and occurring at lower exposures than has been previously reported. Further research should take into account these marked route, age, and strain differences. Published by Elsevier Science Inc.