The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats.

The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.

Mechanisms involved in the gastro-protective effect of STW 5 (Iberogast) and its components against ulcers and rebound acidity.

The protective effect of a commercial preparation (STW 5, Iberogast), containing the extracts of bitter candy tuft, lemon balm leaf, chamomile flower, caraway fruit, peppermint leaf, liquorice root, Angelica root, milk thistle fruit and greater celandine herb, against the development of gastric ulcers was previously reported in an earlier publication (Khayyal et al., 2001). All extracts produced a dose dependent anti-ulcerogenic effect associated with a reduced acid output, an increased mucin secretion, an increase in prostaglandin E(2) release and a decrease in leukotrienes. The effect on pepsin content was not uniform and did not seem to bear a relationship with the anti-ulcerogenic activity. The best effects were observed with the combined formulation, STW 5. Furthermore, the effect of the latter in protecting against the development of rebound gastric acidity was examined experimentally in rats and compared with the effect of some commercial antacid preparations (Rennie, Talcid and Maaloxan). A model of testing rebound acidity was developed by inducing a marginal increase in gastric acidity through the administration of indomethacin, in such a way that it could be easily neutralized, allowing any eventual secondary increase in acidity to be measured within a few hours of administration. In addition, the serum gastrin level was measured after drug treatment to establish any correlation between it and any rebound acidity. The results obtained demonstrated that STW 5 did not only lower the gastric acidity as effectively as the commercial antacid, but it was more effective in inhibiting the secondary hyperacidity. Moreover, STW 5 was capable of inhibiting the serum gastrin level in rats, an effect which ran parallel to its lowering effect on gastric acid production.

A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients.

The aqueous extract of propolis has been formulated as a nutritional food product and administered, as an adjuvant to therapy, to patients with mild to moderate asthma daily for 2 months in the framework of a comparative clinical study in parallel with a placebo preparation. The diagnosis of asthma was made according to the criteria of patient classification of the National Institutes of Health and Global Initiative for Asthma Management. At inclusion, the pulmonary forced expiratory volume in the first second (FEV1) as a percentage of the forced vital capacity (FVC) was more than 80% in mild persistent cases, and between 60 and 80% in moderate persistent cases, showing an increase in the degree of reversibility of > 15% in FEV1. All patients were on oral theophylline as controller therapy, none was receiving oral or inhaled corticosteroids, none had other comorbidities necessitating medical treatment, and all were from a middle-class community and had suffered from asthma for the last 2-5 years. Twenty-four patients received the placebo, with one drop-out during the study, while 22 received the propolis extract, with no drop-outs. The age range of the patients was 19-52 years; 36 were male and 10 female. The number of nocturnal attacks was recorded on a weekly basis, while pulmonary function tests were performed on all patients at the beginning of the trial, 1 month later and at the termination of the trial. Immunological parameters, including various cytokines and eicosanoids known to play a role in asthma, were measured in all patients at the beginning of the trial and 2 months later. Analysis of the results at the end of the clinical study revealed that patients receiving propolis showed a marked reduction in the incidence and severity of nocturnal attacks and improvement of ventilatory functions. The number of nocturnal attacks dropped from an average of 2.5 attacks per week to only 1. The improvement in pulmonary functions was manifested as a nearly 19% increase in FVC, a 29.5% increase in FEV1, a 30% increase in peak expiratory flow rate (PEFR), and a 41% increase in the forced expiratory flow rate between 25 and 75% of the vital capacity (FEF25-75). The clinical improvement was associated with decreases by 52, 65, 44 and 30%, respectively, of initial values for the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, ICAM-1, interleukin (IL)-6 and IL-8, and a 3-fold increase in the 'protective' cytokine IL-10. The levels of prostaglandins E2 and F2alpha and leukotriene D4 were decreased significantly to 36, 39, and 28%, respectively, of initial values. Patients on the placebo preparation showed no significant improvement in ventilatory functions or in the levels of mediators. The findings suggest that the aqueous propolis extract tested is potentially effective as an adjuvant to therapy in asthmatic patients. The benefits may be related to the presence in the extract of caffeic acid derivatives and other active constituents.

Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination.

Extracts from the plants Iberis amara, Melissa officinalis, Matricaria recutita, Carum carvi, Mentha x piperita, Glycyrrhiza glabra, Angelica archangelica, Silybum marianum and Chelidonium majus, singly and combined in the form of a commercial preparation, STW 5 (Iberogast) and a modified formulation, STW 5-II, lacking the last 3 constituents, were tested for their potential anti-ulcerogenic activity against indometacin induced gastric ulcers of the rat as well as for their antisecretory and cytoprotective activities. All extracts produced a dose dependent anti-ulcerogenic activity associated with a reduced acid output and an increased mucin secretion, an increase in prostaglandin E2 release and a decrease in leukotrienes. The effect on pepsin content was rather variable and did not seem to bear a relationship with the anti-ulcerogenic activity. The most beneficial effects were observed with the combined formulations STW 5 and STW 5-II in a dose of 10 ml/kg b.w., comparable with cimetidine in a dose of 100 mg/kg b.w. The anti-ulcerogenic activity of the extracts was also confirmed histologically. The cytoprotective effect of the extracts could be partly due to their flavonoid content and to their free radical scavenging properties.

The possible "chondroprotective" effect of the unsaponifiable constituents of avocado and soya in vivo.

An experimental in vivo model for studying cartilage destruction has been used to study the possible chondroprotective effect of the unsaponifiable constituents of avocado, soya and their combination at a ratio of 1:2. The method consists of implanting rat articular cartilage wrapped in cotton subcutaneously in mice, treating the animals daily for 2 weeks with the preparations in question, then sacrificing the animals and measuring some biochemical parameters related to cartilage integrity. The chosen parameters involved the glycosaminoglycan and hydroxyproline content of the cartilage, as well as the hydroxyproline content of beta-D-glucosaminidase activity of the granulomatous tissue induced by the cotton covering the cartilage. The unsaponifiables of both avocado and soya significantly reduced the degenerative changes induced by the granuloma tissue on the implanted cartilage in control animals as reflected by the preservation of the glycosaminoglycan and hydroxyproline content, and also reduced the proliferation of hydroxyproline and beta-D-glucosaminidase activity of the granulomatous tissue. The effect was even more marked when animals were treated with the combination of the two unsaponifiables at a 1:2 ratio. The preservation of the cartilage from destruction may have been associated with a diminished release of inflammatory mediators due to the effects of the unsaponifiables. In this context, the results point to a possible "chondroprotective" effect of these agents in vivo. This is in keeping with previous reports of chondroprotection by these unsaponifiables in vitro. The effect of the fixed dose combination in the 1:2 ratio was dose dependent.

Effect of magnesium pyridoxal 5-phosphate glutamate on vascular reactivity in experimental hypercholesterolemia.

Hypercholesterolemia is known to affect the responsiveness of various blood vessels to endogenous and to exogenous vasoactive agents. Of particular interest is the increased responsiveness to vasoconstrictors, e.g., 5-hydroxy tryptamine and noradrenaline, and the decreased reactivity towards vasodilators, e.g., acetylcholine. This, together with the development of arteriosclerosis, could play an important role in the progression of many vascular complications, such as hypertension and coronary heart disease. Magnesium pyridoxal 5-phosphate glutamate (MPPG) has been shown to effectively reduce serum lipids in animals and in man, and to retard the progression of atherosclerotic lesions in experimental animals. It was therefore considered of interest to investigate the reactivity of both the aorta and the renal artery to different vasoactive substances in hypercholesterolemic rabbits under the influence of MPPG as well as the effect of such substances on the blood pressure of the anesthetized animals. The rabbits were fed a high cholesterol diet for 2 months, followed by MPPG for 1 month, while keeping the rabbits on the same diet. One batch of animals was used for blood pressure recording and testing drug effects, and another was used for testing the responsiveness of their aortae and renal arteries to the different mediators. In hypercholesterolemic rabbits, treatment with MPPG tended to normalize the increased responsiveness of the blood pressure to the vasoconstrictors: noradrenaline and angiotensin and the diminished sensitivity to histamine and acetylcholine. For the isolated arteries, however, MPPG did not significantly affect the responses to noradrenaline nor potassium chloride, but tended to normalize responses to clonidine and acetylcholine. It could be concluded from the present findings that the high cholesterol diet induces changes in vascular reactivity which are possibly related to endothelial and/or receptor sensitivity changes. Treatment with MPPG helps to reverse these changes and to restore normal vascular reactivity, a fact that could have important clinical implications in the management of cardiovascular diseases.

Influence of certain calcium-channel blockers on some aspects of lorazepam-dependence in mice.

The effect of acute and chronic treatments of the calcium-channel blockers, isradipine, diltiazem and flunarizine in protecting against lorazepam dependence has been demonstrated in mice. Dependence was induced by twice-daily administration of lorazepam (1 mg kg-1) for 10 days, doubling the dose during the next 10 days. Withdrawal symptoms and changes in the noradrenaline, dopamine and 5-hydroxytryptamine content of different regions of the brain were observed after either 24-h withdrawal or flumazenil administration. Isradipine inhibited lorazepam withdrawal symptoms, the effect being accompanied in the 24-h withdrawal group by significant decreases in the noradrenaline and dopamine content of the thalamus and hypothalamus and in the noradrenaline content of the mid-brain. In the flumazenil-treated group isradipine produced significant decreases in mid-brain noradrenaline and dopamine levels and in the dopamine content of the thalamus and hypothalamus. Diltiazem did not, on the other hand, afford significant protection against lorazepam withdrawal symptoms and did not induce any significant change in the neurotransmitters studied. Flunarizine significantly inhibited lorazepam withdrawal symptoms, an effect accompanied by significant reduction in noradrenaline and dopamine levels in the thalamus and hypothalamus. Dopamine was also significantly reduced in the cerebral cortex. Similar effects were produced in the flumazenil-treated group, and the noradrenaline content was reduced in the medulla, pons and cerebellum. It was concluded that isradipine and flunarizine might be of value in ameliorating lorazepam withdrawal symptoms.

The protective effect of aqueous propolis extract on isolated rat hepatocytes against carbon tetrachloride toxicity.

The protective effect of honeybee aqueous propolis extract (APE) against the hepatotoxicity of carbon tetrachloride was investigated using isolated liver-cell suspensions as the experimental model. Various concentrations of the extract were preincubated with the hepatocyte suspensions for 30 min before being subjected to the hepatotoxin for a further 30 min. The hepatocyte toxicity was assessed using three parameters, namely, the release of lactate dehydrogenase, the formation of lipid peroxides and the depletion of intracellular reduced glutathione. It was found that a dose-related protection against the induced cell injury was conferred by APE as evidenced by its inhibitory influence on the changes induced by CCl4 on the measured parameters. The hepatocyte protective effect of APE is probably a result of its antioxidant and free-radical-scavenging properties which in turn help to maintain the intracellular level of reduced glutathione.

The influence of carbon tetrachloride-induced liver damage on the inflammatory reaction elicited by carrageenan and its treatment with diclofenac.

The effect of impaired hepatic function on the development of the inflammatory process as well as on treatment with diclofenac was investigated. Carbon tetrachloride was used to induce liver injury and the elevation of serum transaminases was taken as evidence for impaired hepatic function. The carrageenan-induced rat hind paw oedema and the granuloma pouch were chosen as models of inflammation. The results of the study revealed that: (1) The intensity of inflammation in both models was markedly attenuated in CCl4-treated animals. (2) Serum total proteins were decreased in liver-injured animals particularly in acute experiments. (3) In liver-injured groups diclofenac showed more pronounced anti-inflammatory activity in chronic experiments, but not in acute ones. (4) Neither CCl4 nor diclofenac affected the levels of histamine and serotonin in the granuloma pouch exudate. The level of prostaglandins was decreased in CCl4 and in diclofenac-treated animals. At the same time, the leukotriene content was elevated. The mechanism by which CCl4 induced liver injury attenuates inflammatory response to carrageenan is not entirely understood. Its effect on protein metabolism and extravasation as well as on PG synthesis could play a possible role. Decreased drug metabolism may be, at least in part, responsible for the enhanced response of diclofenac in the cases of liver-injured animals. Dose adjustment of the drug in case of hepatic impairment might be necessary.

Tolerability of mofebutazone in asthmatic patients.

Twenty-seven human volunteer asthmatic patients were each given one tablet of mofebutazone (300 mg) twice daily for 15 days. Pulmonary ventilatory function test (forced expiratory volume test) as well as bronchoalveolar lavage (BAL) were performed one day before initiation of treatment and one day after completion of the course; in the BAL, prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha) and leukotrienes (LTs) were also estimated. It was found that there was no increase in the incidence or severity of the asthmatic attacks during the course of mofebutazone treatment. The drug tended to improve the tested pulmonary ventilatory functions or at least to leave them unchanged. All the mofebutazone-treated individuals showed a dramatic reduction in the concentrations of PGE2, PGF2alpha and LTs in their BAL, but there was no consistent correlation between the extent of reduction and the degree of benefit or worsening sustained by any individual patient. It is evident from the present study that mofebutazone has shown good tolerability which was associated with an improvement in the pulmonary ventilatory functions, a fact that would seem to advocate the use of this non-steroidal antiinflammatory drug (NSAID) in asthmatic patients whenever a need for such therapy becomes necessary.

The use of aqueous propolis extract against radiation-induced damage.

Whole body exposure to gamma radiation has been experimentally shown to exaggerate inflammatory responses and to enhance the release of mediators. A thirteen per cent aqueous extract of propolis (bee glue) was previously shown to have potent antiinflammatory activity. The present study was carried out to show whether the extract could influence the exaggerated inflammatory response in irradiated animals. Rats were exposed to acute (2 and 6 Gy) & fractionated (1 Gy/week) doses of gamma ionizing radiation. Treatment with the aqueous extract orally (5 ml/kg) before and after radiation exposure markedly reduced the exaggerated paw oedema response to carrageenan. In the acute phase of adjuvant-induced arthritis, exposure to ionizing radiation caused an increase in serum acid phosphatase level. Malondialdehyde concentration in plasma and superoxide dismutase activity in blood significantly increased. Treatment with aqueous propolis extract prior to irradiation reduced malondialdehyde concentration in plasma and normalized the serum acid phosphatase level. The extract stimulated the release of superoxide dismutase enzyme. Aqueous propolis extract could possibly be of therapeutic value in protecting against inflammatory responses induced by gamma radiation.

Schistosoma haematobium cercarial host-finding and host-recognition differs from that of S. mansoni.

Schistosoma haematobium cercarial host-finding responses differ from those of Schistosoma mansoni. The attachment response to warm substrata is more sensitive and intense and is inhibited by unphysiologically warm substrata. Attachment is also stimulated by L-arginine as the exclusive chemical cue of the human skin surface (threshold 3 microM); however, the response is drastically lower than that of S. mansoni cercariae. No chemical host stimulus could be identified for an enduring contact with the host after attachment. After attachment, the cercariae creep in a temperature gradient toward heat source; their response is, however, more sensitive than that of S. mansoni (threshold 0.03 vs. 0.15 C/mm). Creeping S. haematobium cercariae orientate in chemical gradients in the same way as S. mansoni cercariae toward L-arginine as the exclusive chemical signal of the human skin surface. The selective benefit of this behavior is not yet understood. The penetration of both species is stimulated by free fatty acids from the human skin surface, not by heat. Thus, S. haematobium responds more to thermal host signals, whereas S. mansoni prefers chemical host signals.

Hyperthermic potentiation of cisplatin cytotoxicity on solid Ehrlich carcinoma.

BACKGROUND: Hyperthermia produces marked effects on many biochemical parameters of tumor cells and has been reported to potentiate the effect of many drugs. We therefore evaluated the possible synergistic effect between hyperthermia and cisplatin against solid Ehrlich carcinoma. The study was based on the measurement of some biologic characteristics in tumor tissues, namely: DNA, RNA, and protein content and their rate of synthesis as parameters for nuclear damage; total lipids and cholesterol as parameters for membrane damage; acid-phosphatase and acid-ribonuclease as parameters for lysosomal damage; and tumor volume as a direct parameter for tumor growth. METHODS: Treatment of solid Ehrlich carcinoma by hyperthermia at 43 degrees C for 30 min for 3 successive days produced a 41.5% decrease in tumor volume, as well as a significant decrease in nucleic acids, protein contents and their rate of synthesis, in total lipids and cholesterol, and in acid-phosphatase and acid-ribonuclease. Chemotherapeutic management of the tumor by 5 mg/kg x 3 of cisplatin alone showed a continuous increase in tumor volume but at a lower rate than that of the untreated control. However, when cisplatin was given 1 h prior to hyperthermia, the tumor volume was significantly decreased by 82.6%. RESULTS: The effects observed on all the investigated parameter were intensified when cisplatin was combined with hyperthermia. The results obtained suggest that hyperthermia may enhance the penetration of cisplatin to its target site inside the tumor cells due to a membrane-damaging effect. The enhanced lethality of cisplatin on tumor cells may also be due to the inhibition of DNA repair processes by hyperthermia.

Inhibition of leukotriene release by mofebutazone: a possible clinical advantage.

The isolated perfused lung preparation from actively sensitized guinea-pigs was used; after it was challenged with antigen, mediators such as histamine, prostaglandins and leukotrienes were released into the lung effluent. It was found that treatment of the perfused lungs before and during challenge with mofebutazone (10 micrograms/ml) inhibited the immunological release of prostaglandins as well as leukotrienes. Phenylbutazone, on the other hand, at the same dose level inhibited the release of prostaglandins, whereas the release of leukotrienes was much less affected by the drug. Histamine release was not altered by either drug. When clinically mofebutazone tablets (300 mg) were given as an analgesic twice daily for 15 days to a number of asthmatic volunteers including 3 aspirin-sensitive individuals, there was no increase in the incidence or intensity of the asthmatic attacks, even in the aspirin-sensitive patients. Pulmonary ventilatory functions which showed a certain obstructive pattern were not worsened by the treatment and even tended to be somewhat improved.

Mechanisms involved in the antiinflammatory effect of propolis extract.

Propolis is a natural product produced by the honey bee. The extract contains amino acids, flavanoids, terpenes and cinnamic acid derivatives. In various in vitro models propolis extract was shown to inhibit platelet aggregation and to inhibit eicosanoid synthesis, suggesting that it might have potent antiinflammatory properties. A 13% aqueous extract was tested orally in three dose levels (1, 5 and 10 ml/kg) on the carrageenan rat paw oedema model and on adjuvant-induced arthritis in rats. In both models, the extract showed potent dose-related antiinflammatory activity, which compared well with that of diclofenac (as a reference standard). The extract was then tested on an isolated sensitized guinea pig lung preparation to study its effect on the release of prostaglandins, leukotrienes and histamine. It is concluded that propolis extract has potent antiinflammatory properties in vivo. Its activity can be well correlated with its effects on the release of various mediators of inflammation.

Evaluation of hepatic fibrosis after oxamniquine therapy of murine schistosomiasis.

Chemical and histological indices of liver fibrosis were measured after eight, 18 and 28 weeks in mice infected with Schistosoma mansoni and treated at eight weeks with oxamniquine, in mice infected with S. mansoni and not treated and in mice not infected with S. mansoni. Total worm burdens and liver egg counts were determined in the infected mice to determine severity of infection. Treatment with oxamniquine resulted in near total eradication of S. mansoni worms after 10 weeks and in their complete killing and marked reduction of eggs in the liver at 10 and 20 weeks. Liver fibrosis 10 weeks after oxamniquine treatment was not significantly different than in the untreated, infected group but there was no progression between 10 and 20 weeks after oxamniquine treatment. Fibrosis did however increase between 10 and 20 weeks in the untreated infected group. In the murine model, oxamniquine is an effective treatment for S. mansoni and prevents progression of liver fibrosis.

Study of the anti-inflammatory activity of Populus tremula, Solidago virgaurea and Fraxinus excelsior.

Aqueous/alcoholic extracts of Populus tremula, Solidago virgaurea and Fraxinus excelsior (components of Phytodolor N) were tested individually and in 3 different combinations for anti-inflammatory activity using carrageenan induced edema and/or adjuvant induced arthritis of the rat paw. The tested combinations as well as the individual extracts significantly reduced the paw edema to varying degrees and also dose dependently inhibited the arthritic paw volume. The anti-inflammatory activity of the combinations was respectively comparable to the tested doses of diclofenac.

Schistosoma mansoni: angiotensin converting enzyme activity in mice under the influence of praziquantel and/or captopril.

Murine schistosomiasis is usually associated with hepatic granulomatous lesions together with high serum and granuloma angiotensin converting enzyme (ACE) activity. Praziquantel (PRZ) which is known to reduce granuloma size was studied to show whether this effect is related to changes in ACE activity. Furthermore, captopril was studied to show whether by inhibiting ACE activity, the drug could also affect granuloma size. PRZ, captopril, and their combination led to significant reduction in liver granuloma. However, in normal mice, captopril was shown to increase rather than decrease serum ACE. The decrease in ACE activity by PRZ was correlated with its curative effect in infected mice. However, in experimentally induced pulmonary granulomata, the drug reduced granuloma size without affecting ACE activity of either serum or granuloma. It may be concluded that reduction in ACE activity may be beneficial as far as diminution of granuloma size is concerned and irrespective of whether there is an active infection or not. The possible use of Captopril as an antihypertensive in bilharzial infections associated with hypertension would probably not adversely affect the granulomatous lesions.

Effect of schistosomiasis infection on the clearance of phenazone in mice.

The disposition phenazone (antipyrine) was used to study the effect of Schistosoma mansoni infection on the activity of drug metabolizing enzymes in mice. Plasma elimination rate constant (Ke), elimination half-life (t1/2e), clearance (CL) and apparent volume of distribution (Vd) were estimated 8 and 12 weeks after infection of mice with 80 S. mansoni cercariae. Liver and kidney function tests were performed simultaneously. Infection increased the levels of glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactic dehydrogenase (LDH), alkaline phosphatase (AP) and total proteins 8 and 12 weeks post infection. At the same time a decrease was recorded in the total cholesterol level. Moreover infection with S. mansoni produced a decrease in phenazone clearance with an increase in the area under the curve (AUC) of the drug 8 and 12 weeks post infection. Elimination half-lives were 57.92 +/- 14.10 and 72.72 +/- 4.14 min 8 and 12 weeks after infection, respectively, compared to 19.29 +/- 3.30 and 26.14 +/- 5.31 min in corresponding controls. No statistically significant change was recorded in the volume of distribution of phenazone in the groups studied. In addition no significant correlation was found between parameters of phenazone disposition and the enzyme levels studied 8 and 12 weeks after infection.

Radiation exposure and the effect of piroxicam and diclofenac on mediator release from isolated guinea-pig lung.

The effects of radiation exposure and drug treatment on the immediate type of hypersensitivity reaction were studied. Guinea-pigs were sensitized by s.c. injections of antigen. The animals were killed 3 weeks later and the lungs were perfused through the pulmonary artery. The perfusate was allowed to superfuse a guinea-pig ileum to estimate its total content of mediators. Results revealed that the mere injection of antigen to the perfused lung resulted in the release of spasmogens which caused contraction of the guinea-pig ileum. Analysis of the effluent showed an increase in the amount of PGs (measured biologically) and histamine (measured fluorimetrically) released during challenge. The response of the ileum to the antigen challenge was inhibited by the infusion of diclofenac (20 micrograms.ml-1) or piroxicam (25 micrograms.ml-1). The drugs also inhibited the release of PGs and histamine from the perfused lungs. Exposure of animals to gamma-radiation, before sensitization, caused a reduction in the amount of mediators released during challenge. On the other hand, in nonsensitized animals, a single radiation dose level of 2 Gy caused fluctuation in the amount of PGs and histamine released during challenge throughout the 3 weeks period of the experiment. Diclofenac and piroxicam effectively reduced the amount of mediators released from sensitized perfused lung isolated from both nonirradiated and irradiated animals. This may, at least partly, explain their protective effect against the exaggerated inflammatory response following gamma-irradiation exposure.