Biomedical subjects

M Prosdocimi

Publications and source records attributed to M Prosdocimi.

At least 19 recordsLinked to original sources

PubMed2000

Cognitive impairment in old rats: a comparison of object displacement, object recognition and water maze.

The behavioral performance of young and aged rats was studied in a repeated-trials test. Young animals reacted to both spatial displacement and novelty, whereas most aged rats lost the ability to react to novelty although maintaining spatial memory. The cluster analysis procedure performed on all the tested subjects enabled the recognition of a consistent group of the aged sample (35%) with a mild degree of spatial and non-spatial memory impairment. Spatial memory impairment of some of the aged animals was also evaluated in the Morris water maze test. On the fifth day of the task, we observed a very low percentage of impaired aged animals, which partially corresponded to the impaired group identified by the object recognition test. In contrast, the subgroup of mildly impaired rats performed similarly to the young animals. We advance that the Morris water maze might represent a stressful experimental condition for aged rats, enhancing the motivational level of animals subjected to this procedure. This condition may alter the cognitive responses. As a consequence, the "mildly impaired" rats, which may be considered an interesting group for investigating memory-enhancing drugs, will infrequently be recognized with the Morris water maze test. Cognitive impairment in aged rats should be studied utilizing a sensitive test in which motivation does not substantially influence the results of the test.

Aging↗

PubMed1998

Cryodamage of the vessel wall accelerates the development of atherosclerotic lesions in arterial vessels of Watanabe hyperlipidemic rabbits.

In the present study we developed an experimental model, resembling human atherosclerosis, by removing the endothelial layer in Watanabe heritable hyperlipidemic (WHHL) rabbits (10 months old) by application of cryodamage on the external surface of arterial vessels. In age-matched New Zealand white (NZW) rabbits, used as control, after two months following cryodamage, carotid artery and infrarenal segments of abdominal aorta did not show any particular change in the ultrastructure of vessel wall. In WHHL rabbits, two months after cryodamage, atherosclerotic lesions (fatty streaks and fibrous plaques) were observed in both arteries. Many lipid-laden endothelial cells, subendothelial foam cells and smooth muscle cells were found in cryodamaged areas. In some areas, the cap of plaques appeared to be thinned and ruptured. Increased number of collagen and elastic fibrils was also observed in atherosclerotic regions. We conclude that this simple technique on WHHL rabbits provides a model of atherosclerosis with a high degree of morphological similarity between the artificially-induced plaque and human atherosclerotic plaque.

Animals↗

PubMed1996

Inhibition of PAF synthesis by stimulated human polymorphonuclear leucocytes with cloricromene, an inhibitor of phospholipase A2 activation.

1. A phospholipase A2 (PLA2) represents the key enzyme in the remodelling pathway of platelet-activating factor (PAF) synthesis in human polymorphonuclear (PMN) leucocytes. 2. PLA2 activation is also the rate-limiting step for the release of the arachidonic acid utilized for the synthesis of leukotrienes in stimulated leucocytes; however, it is unknown whether the PLA2s involved in the two biosynthetic pathways are identical. 3. Cloricromene (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxy- carbonylmethoxy coumarin) is an antithrombotic coumarin derivative which inhibits platelet and leucocyte function and suppresses arachidonic acid liberation by interfering with PLA2 activation. 4. The aim of the present study was to assess whether chloricromene inhibits PAF synthesis by stimulated human polymorphonuclear leucocytes (PMNs). 5. Cloricromene (50-500 microM) inhibited in a concentration-dependent manner the release of PAF, as measured by h.p.l.c. bioassay, from A23187-stimulated PMNs. Significant inhibition (45%) of PAF-release was obtained with 50 microM cloricromene and the IC50 was 85 microM. Mepacrine (500 microM), a non-specific PLA2 inhibitor, strikingly reduced PAF release. 6. The incorporation of [3H]-acetate into [3H]-PAF induced by serum-treated zymosan in human PMNs was also inhibited concentration-dependently by cloricromene, with an IC50 of 105 microM. Mepacrine also suppressed [3H]-acetate incorporation into [3H]-PAF. 7. Cloricromene did not affect the activities of the enzymes involved in PAF-synthesis acetyltransferase or phosphocholine transferase. 8. Our data demonstrate that cloricromene, an inhibitor of PLA2-activation in human leucocytes, reduces the synthesis of PAF by stimulated PMNs. This finding has a twofold implication: the PLA2s (or the mechanisms that regulate their activation) involved in PAF synthesis and arachidonate release in human leucocytes are either identical or else indistinguishable by their sensitivity to cloricromene; the inhibition of PAF release by activated leucocytes may contribute to the antithrombotic and anti-ischaemic activities exerted by cloricromene.

Acetyltransferases↗

PubMed1995

Endothelial nucleotide-mediated aorta relaxation in aged Watanabe heritable hyperlipidemic rabbits.

We investigated the activity of muscarinic and purinergic endothelial receptors during atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbit aorta. Experiments were performed on isolated thoracic aorta from WHHL rabbits aged 1 and 2.5 years. The relaxant response to acetylcholine (ACh) was progressively reduced with aging, being almost completely abolished in 2.5-year-old rabbits. The relaxant effect of ATP was not affected by the P2-purinoceptor antagonist suramin, thus excluding any involvement of relaxant P2y purinoceptors in both considered ages. The pyrimidine UTP, acting on nucleotide (P2U) receptors, produced concentration-dependent relaxation in 1-year-old WHHL rabbit aorta only in the presence of endothelium; relaxation was reduced in older animals. In 1-year-old WHHL rabbits, the endothelium-dependent relaxant effect of UTP was not antagonized by suramin, but was by the inhibitors of nitric oxide (NO) effect, methylene blue (MB) and L-NG-nitroarginine methyl ester (L-NAME), suggesting involvement of NO in the UTP-mediated relaxation. Morphological data from electron microscopy observations indicated the presence of typical atherosclerotic lesions and extensive dystrophic changes in endothelial cells, gradually evolving at 1 and 2.5 years of age. The present data suggest that progressive atherosclerosis differentially affects the activity of endothelial receptors: The most precociously altered is the P2y-purinoceptor, followed by an impairment of the muscarinic and finally of the P2U-purinoceptor.

Acetylcholine↗

PubMed1994

Platelet aggregation, ATP release and cytoplasmic Ca2+ movement: the effects of cloricromene.

A placebo-controlled, double-blind, randomized, cross-over study was performed in 24 healthy volunteers. 12 volunteers received Cloricromene (100mg gastroresistant capsules twice a day) for 7 days, the other volunteers received identical placebo capsules. Subsequently, after a 7-day wash-out period, at day 15, each subject received the other treatment. Blood samples were taken on days 1 and 15 (1st day of each treatment) as well as on days 7 and 21 (7th day of each treatment) before the morning drug administration and 2 and 4 hours later. Platelet aggregation and ATP secretion were studied in whole blood (WB) using ADP and collagen as stimulating agents. Ca2+ fluxes were studied in aequorin-loaded, washed platelets stimulated with ADP and collagen, while aggregation in platelet-rich plasma (PRP) was studied using PAF, ADP and adrenaline as agonists. Consistent inhibition of aggregation and release induced by both ADP and collagen was observed in WB after Cloricromene administration. Similarly, Ca2+ flux was also inhibited after drug administration. Platelet aggregation in PRP was inhibited only after 7 days of Cloricromene treatment with ADP and adrenaline as stimuli. We conclude that oral administration of Cloricromene leads to significant antiplatelet activity in healthy volunteers, in particular when platelets are studied in the presence of other blood elements.

Adenosine Diphosphate↗

PubMed1994

Urinary bladder dysfunction in the BB/W diabetic rat: effect of ganglioside treatment on functional and structural alterations.

Urinary bladder dysfunction in the diabetic BB/W rat is characterized by infrequent irregular contractions of high amplitude. Initially these occur in the absence of detectable neuroanatomical lesions of sensory afferent and parasympathetic fibers of the pelvic nerve, which constitute the micturition reflex arc. Structural lesions consisting of progressive axonal atrophy of myelinated and unmyelinated fibers become detectable only after 4 months of diabetes. In the current study we evaluated the effect of ganglioside treatment (10 mg./kg. body weight) for one month. This drug regimen was initiated at 4 months of diabetes, when functional bladder abnormalities were well established, whereas structural lesions were yet to appear. Animals examined 1 or 3 months after termination of the one-month treatment protocol showed sustained normalization of the characteristic functional abnormalities, accompanied by prevention of the neuroanatomical lesions of sensory afferent and parasympathetic efferent myelinated fibers in the pelvic nerve. These data suggest that ganglioside treatment may be beneficial in delaying the progression of diabetic autonomic neuropathy in this experimental animal model.

Animals↗

PubMed1994

Functional depression of isolated perfused rat heart mediated by activated leukocytes: protective effect of cloricromene.

Langendorff rat heart preparations were perfused with suspensions of human leukocytes containing approximately 65% polymorphonuclear cells (PMN). The cells were either unstimulated or activated with 1.6 x 10(-8) phorbol 12-myristate 13-acetate (PMA). Left ventricular developed pressure (LVDP), coronary flow (CF), and heart rate (HR) were recorded during PMN infusion (10 min) and for the recovery period (30 min). PMN were also pretreated with cloricromene (CLO 10-50 microM), a drug that inhibits platelet aggregation and PMN adhesion to endothelial cells (EC). Infusion of unstimulated cells did not affect cardiac function. Infusion of activated cells caused CF reduction (-44 +/- 4% at end of infusion; -24 +/- 4% at end of recovery, expressed as percentage of variation vs. basal value), LVDP decrease (-44 +/- 5% at end of infusion, -26 +/- 6% at end of recovery) endothelial damage, and leukocyte accumulation in heart as compared with hearts infused with unstimulated PMN and sham hearts. PMN accumulation was quantified as myeloperoxidase (MPO) activity (260 +/- 35, 39 +/- 6, 19 +/- 1 U/g, respectively). Superoxide dismutase (SOD 600 U/ml), catalase (2,200 U/ml), thiourea (10 mM) added to PMN suspension blunted CF decrease but not LVDP reduction and MPO increase. CLO (25-50 microM) pretreatment inhibited PMN accumulation, LVDP, and CF reduction by approximately 50%. These data suggest a role of leukocyte activation in the genesis of heart damage and raise the possibility of a pharmacologic intervention with drugs such as CLO that can interfere with this process.

Animals↗

PubMed1993

Cloricromene inhibits leukotriene formation by human polymorphonuclear leucocytes by suppressing arachidonate release from membrane phospholipids.

Cloricromene, an antithrombotic agent known to inhibit the release of arachidonic acid (AA) in stimulated human platelets, was tested for its effects on arachidonate release and metabolism in human polymorphonuclear leucocytes (PMNs). Cloricromene dose-dependently suppressed the release of leukotriene B4 (LTB4), as assessed by radioimmunoassay, from both isolated PMNs and human whole blood stimulated with the calcium ionophore A23187 or with serum-treated zymosan (STZ). The inhibitory effect was higher when the concentration of the stimulating agent was weaker. Cloricromene also inhibited dose-dependently the liberation of LTB4, LTC4, LTD4 and 5-hydroxy-6,8,11,14-eicosatraenoic acid as assessed by HPLC in the supernantant of A23187-stimulated PMNs. Finally, the drug was able to suppress the release of [3H]AA from purified human PMNs prelabeled with the radioactive fatty acid and stimulated with either A23187 or with STZ. The A23187-induced decrease in the radioactivity of phosphatidylinositol, the phospholipid class mainly involved in AA release in stimulated PMNs, was also inhibited by cloricromene. Cloricromene suppresses leukotriene formation in human PMNs by reducing AA release from membrane phospholipids, possibly through interference with phospholipase A2 activation; this activity may contribute to the leucocyte-inhibitory effects reported previously for cloricromene.

Arachidonic Acid↗

PubMed1993

Changes in vessel ultrastructure during ischemia and reperfusion of rabbit hindlimb: implications for therapeutic intervention.

Peripheral ischemia was induced in the rabbit by occlusion of the left iliac artery for 6 hr, followed by 24 hr of reperfusion. Biochemical and morphological investigations were performed to evaluate the extent of vascular and tissue injury. Blood samples for plasma enzyme determinations (creatine kinase (CK) and lactate dehydrogenase (LDH) activities) were obtained at times t = 0, t = 6, t = 30 hr. Plasma CK and LDH activities in ischemic animals were approximately twice as high as those in sham-operated animals at the end of reperfusion, although no difference was observed at the end of the period of ischemia. Morphological and morphometric analysis of extensor digitorum longus muscle from ischemic animals showed a reduction in the number of patent capillary vessels per muscle fiber (1.54 +/- 0.1 and 1.04 +/- 0.09, P < 0.05, in sham and ischemic groups, respectively; mean +/- SEM). In addition, the number of microvilli on endothelial surfaces were considerably increased in the ischemic group (0.14 +/- 0.02 and 0.41 +/- 0.01 microns -2, P < 0.001, in sham and ischemic groups, respectively). A great number of adhered leucocytes were found on the vessel surface with some leucocytes having migrated through the vessel wall. Microcirculatory damage was accompanied by the formation of microthrombi which sometimes occluded the entire vessel lumen. The infusion of 1 mg/kg/hr of cloricromene for 6 hr prevented ischemic injury in microvessels and also prevented swelling of muscle mitochondria. In the treated group the number of patent capillaries per muscle fiber was very similar to that found in sham-operated animals (1.49 +/- 0.08; P < 0.01 vs. ischemic control). In conclusion, several different cell types are involved in the pathophysiological changes which occur in microvessels during ischemia/reperfusion injury. Pharmacological interventions, which inhibit the interactions of blood cells with endothelium, may be of value in the treatment of peripheral ischemia/reperfusion injury.

Animals↗

PubMed1993

Evidence for the presence of early vascular lesions in newborn Watanabe heritable hyperlipidemic (WHHL) rabbits.

We have investigated the morphology of the aortic wall of newborn New Zealand White (NZW) (n = 10) and newborn Watanabe heritable hyperlipidemic (WHHL) (n = 10) rabbits. In both strains, lipid levels (cholesterol and triglycerides) were elevated above the concentrations expected. This was particularly evident in WHHL. The morphology of the aortas of NZW rabbits suggested an intensive biosynthetic and bioenergetic activity of endothelium. This was most evident in areas where blood flow underwent division. No major abnormalities were noted in the endothelium or subendothelium. In newborn WHHL rabbits, leucocyte adhesion (usually monocytes) to endothelium and migration into the subendothelium was apparent, particularly on the aortic arch and around areas of dividing blood flow in the thoracic aorta. Tuberous raised structures were present in low numbers and distributed randomly on the aortic wall. Endothelial cells had elevated nuclear zones projecting into the vessel lumen. At regions of blood flow division, endothelium was polygonal in shape and silver staining of cell borders was more intense. Fatty streaks were present at blood flow divisions and micro-plaque was seen. Transmission electron microscopy of fatty streak-like areas showed the presence of up to two layers of smooth muscle cells and in some areas, lipid-laden macrophages were seen. The presence of atherosclerotic lesions in newborn WHHL rabbits suggests that the process may commence in utero.

Age Factors↗

PubMed1993

The effect of cloricromene, a coumarine derivative, on leukocyte accumulation, myocardial necrosis and TNF-alpha production in myocardial ischaemia-reperfusion injury.

The effects of cloricromene, a coumarine derivative, were studied in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 68 +/- 4%; necrotic area/total area = 48 +/- 3%) high serum creatinphosphokinase activity (Sham MI/R = 29 +/- 8 U/ml; MI/R = 205 +/- 11 U/ml) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation), in the area-at-risk (6.3 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (6.5 +/- 0.5 U x 10(-3)/g tissue). Furthermore, serum TNF-alpha was undetectable during the occlusion period, but upon the release of the coronary artery significantly increased. At the end of reperfusion, macrophage TNF-alpha was also enhanced. The administration of cloricromene (2 mg/kg, 5 minutes after the onset of reperfusion) significantly reduced myocardial injury (necrotic area/area-at-risk 30 +/- 1.3%; necrotic area/total area = 25 +/- 1.5) blunted the increase in serum creatinphosphokinase activity (92 +/- 5 U/ml) and lowered myeloperoxidase activity in area-at-risk (2.5 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (2.2 +/- 0.3 U x 10(-3)/g tissue) and decreased the serum and macrophage levels of TNF-alpha. These data indicate that cloricromene exerts beneficial effects on myocardial ischaemia/reperfusion injury. Finally, since we measured increased serum levels of TNF-alpha that were blunted by the cloricromene treatment, our data are consistent with an involvement of TNF-alpha in the reperfusion injury induced by myocardial ischaemia.

Analysis of Variance↗

PubMed1993

Platelet aggregation induced by the endoperoxide analogue U46619 is inhibited by polymorphonuclear leukocyte ADPase activity.

Platelet activation by the stable endoperoxide analogue U46619 is mediated largely by ADP released from platelet-dense granules. Polymorphonuclear leukocytes (PMNs) endowed with ecto-ADPase activity may operate as antiaggregatory cells in platelet aggregation induced by U46619. Unstimulated PMNs were effective in reducing aggregation when platelets were stimulated by threshold concentrations of U46619, whereas at higher concentrations of the stimulus, PMN activation is required. Evidence that the inhibition was mediated by PMN ecto-ADPase activity was obtained by high-performance liquid chromatography analysis, indicating that PMNs were able to efficiently metabolize platelet-active ADP into AMP. Moreover, PMN-derived supernatants were able to inhibit platelet aggregation, suggesting that under this circumstance the inhibition was exerted by an uncharacterized, releasable ADPase activity. This study supports the hypothesis that, besides nitric oxide and hydrogen peroxide, ADPase activity may represent another PMN-mediated pathway capable of regulating platelet activity in areas of reduced blood flow, such as those found in conditions of myocardial ischemia.

Adenosine Diphosphate↗

PubMed1993

Cloricromene inhibits G-protein-mediated activation of phospholipase A2 in human platelets.

The coumarin derivative, cloricromene, an antithrombotic drug previously indicated as AD6, is known to inhibit the release of radioactive arachidonic acid from human platelets prelabelled with arachidonic acid and stimulated with thrombin. This effect might be due to the drug itself or to its catabolite, cloricromene acid. When added to platelet lysates neither compound inhibited phospholipase A2 activity assayed either with endogenous or with exogenous substrates. However, some inhibition was instead shown when intact platelets were first exposed to cloricromene and then enzyme activity was assayed in the lysate. Preincubation of platelets with the drug caused a dose-dependent inhibition of arachidonic acid mobilization in fluoroaluminate-stimulated platelets. beta-Thromboglobulin (beta-TG) release, a phenomenon previously shown to share common steps with phospholipase A2 activation, was also dose-dependently inhibited by cloricromene. Cloricromene also reduced the radioactivity associated with phosphatidic acid in fluoroaluminate-stimulated platelets but not in platelets stimulated with thrombin. These results are consistent with the hypothesis that cloricromene, or its catabolite, inhibits the production of arachidonic acid in stimulated platelets by interfering with a G-protein mediated activation of phospholipase A2 that is independent from the receptor-activated phosphoinositide phospholipase C.

Aluminum↗

PubMed1993

Hematologic and biochemical profiles of selectively bred WHHL rabbits.

In Watanabe heritable hyperlipidemic (WHHL) rabbits, hypercholesterolemia and hypertriglyceridemia develop from birth, because of a deficiency of low-density lipoprotein receptors, and are followed by a consequent early development of aortic atherosclerosis. This closely resembles human familial hypercholesterolemia. Starting in 1984, we have developed a closed colony by breeding two male and two female homozygous WHHL rabbits, obtained from Japan (Dr. Watanabe, Kobe University). In our facility, the application of a selective breeding program, strictly based on mating parents that both have high serum lipid concentrations, has produced markedly elevated cholesterol (701 +/- 172 mg/dl, mean +/- SD) and triglyceride (780 +/- 325 mg/dl) concentrations in weaning rabbits. Clinical chemical analysis revealed no kidney or liver function abnormalities even in animals with extremely high lipid concentrations, and hematologic profiles were very similar in WHHL and age-matched New Zealand White rabbits, with the exception of platelet count, which was significantly higher in WHHL rabbits. Platelet aggregation induced by collagen and platelet-activating factor was significantly reduced in WHHL rabbits, whereas thrombin and prothrombin times appeared normal when compared with those in New Zealand White rabbits.

Animal Husbandry↗

PubMed1993

Atherosclerosis-related remodeling of aortic relaxation to purines in the Watanabe heritable hyperlipidemic rabbit.

The mechanism of the unimpaired relaxant effect of ATP in the Watanabe heritable hyperlipidemic rabbit aorta was investigated to elucidate the involvement of P2y purinoceptor at the endothelial level during atherosclerosis. Experiments were carried out on isolated thoracic aorta from such rabbits that were 12 months of age. The potent P2y purinoceptor agonist, 2-methylthio-ATP, did not induce any endothelium- or smooth muscle-dependent relaxation, thus excluding any involvement by the P2y purinoceptor. ADP, but not AMP, produced relaxation of the aorta by acting at both endothelial and smooth muscle levels. Adenosine relaxed the vessel by acting only in smooth muscle. The maintained endothelial relaxant effect of ATP and ADP is therefore not due to activation of P1 or P2y purinoceptors but may involve activation of a remodeled purinergic receptor site that emerges with the progression of atherosclerosis. This site is antagonized by methylene blue. The disorganization of the endothelial monolayer observed in the morphological analysis may be related to functional remodeling of the endothelial purinergic activity in atherosclerosis.

Adenine Nucleotides↗

PubMed1992

Cloricromene synergizes with antiplatelet drugs and nitric oxide-like factor derived from rat peritoneal polymorphonuclear cells.

We report that cloricromene (5-30 microM) inhibited thrombin-induced platelet aggregation and synergized with other antiplatelet compounds. The antiaggregatory effect of subthreshold concentrations of the prostaglandin (PG)I2 analogue, iloprost (0.2 nM), or of sodium nitroprusside (1 micron), acting through a nitric oxide (NO)-like mechanism, was significantly potentiated by co-incubation with cloricromene (5 microM). In addition, cloricromene enhanced the antiplatelet activity of the NO-like factor released by peritoneal rat polymorphonuclear cells. Thus, the present results show that cloricromene possesses direct antiplatelet properties and synergizes with other endogenous as well as exogenous antiplatelet compounds.

Animals↗

PubMed1992

Neutralization of the antiheparin activity of platelet factor 4 by a monoclonal antibody.

We have produced a panel of monoclonal antibodies (mAbs) against rabbit platelet factor 4 (PF4). Two of these mAbs have been characterized in this study. In particular the antibody called 10B2, which also recognizes the human molecule, is able to block PF4's ability to neutralize heparin in a modified Heparin-Factor Xa chromogenic assay. The inhibition appears to be more than 95% at 1:1 mAb/PF4 molar ratio both for purified rabbit and human PF4. Similar results were obtained using supernatants from stimulated human platelets (90% of inhibition at 1:1 mAb/PF4 molar ratio) or using Fab fragments from 10B2. Studies to determine the antigenic determinant against which 10B2 is directed, show that this is an assembled epitope which involves disulfide bonds of the PF4.

Amino Acid Sequence↗

PubMed1992

Cloricromene, a coumarine derivative, protects against lethal endotoxin shock in rats.

Endotoxin shock was induced in male rats by an intravenous (i.v.) injection of Salmonella enteriditis lipopolysaccharide (LPS; 20 mg/kg i.v.). Survival rate, macrophage and serum tumor necrosis factor (TNF-alpha), mean arterial blood pressure (MAP) and white blood cell count were then evaluated. Furthermore the in vitro effect of cloricromene on peritoneal macrophage phagocytosis and TNF-alpha release by primed peritoneal macrophages was investigated. LPS administration caused animal death (0% survival 24 h after endotoxin challenge), hypotension, marked leukopenia and increased the levels of TNF-alpha in both serum and macrophage supernatants. Cloricromene administration (0.5, 1 and 2 mg/kg i.v. 15 min after endotoxin) protected against LPS-induced lethality (100% survival rate 24 h after endotoxin challenge), reverted LPS-induced hypotension and leukopenia, and decreased TNF-alpha in both serum and macrophage supernatants. Finally, cloricromene, added in vitro to peritoneal macrophages collected from endotoxin-treated rats increased macrophage phagocytosis and reduced TNF-alpha formation by activated mononuclear phagocytes. Our data suggest that cloricromene increases survival rate in endotoxin shock through an inhibition of TNF-alpha production.

Animals↗