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Lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and the channels play crucial roles in the lymphocyte activation and proliferation. Since nonsteroidal anti-inflammatory drugs (NSAIDs), the most commonly used analgesic and antipyretic drugs, exert immunomodulatory effects, they would affect the channel currents in lymphocytes. In the present study, employing the standard patch-clamp whole-cell recording technique, we examined the effects of diclofenac sodium, salicylate and indomethacin on the channel currents in murine thymocytes and the membrane capacitance. Diclofenac sodium and salicylate significantly suppressed the pulse-end currents of the channel. However, indomethacin suppressed both the peak and the pulse-end currents with a significant increase in the membrane capacitance. This study demonstrated for the first time that NSAIDs, such as diclofenac sodium, salicylate and indomethacin, exert inhibitory effects on thymocyte Kv1.3-channel currents. The slow inactivation pattern induced by indomethacin was thought to be associated with microscopic changes in the plasma membrane surface detected by the increase in the membrane capacitance.

Hypoxic-ischemia injury occurs after trauma causes consequential bone necrosis. Non-steroid anti-inflammatory drugs (NSAIDs) are frequently used in orthopedic clinics for pain relief. However, the underlying mechanism and outcome for usage of NSAIDs is poorly understood. To investigate the damage and loss of osteoblast function in hypoxia, two hypoxia mimetics, cobalt chloride (CoCl(2)) and desferrioxamine (DFO), were used to create an in vitro hypoxic microenvironment. The cell damage was observed by decreases of cell viability and increases in cyclooxygenase-2 and cleaved poly(ADP-ribose) polymerase (PARP). Cell apoptosis was confirmed by WST-1 cytotoxic assays and flow cytometry. The functional expression of osteoblast in alkaline phosphatase (ALP) activity was significantly decreased by CoCl(2) and inhibited when treated with DFO. To simulate the use of NSAID after hypoxic injury, four types of anti-inflammatory drugs, sulindac sulfide (SUL), indomethacin (IND), aspirin (Asp), and sodium salicylate (NaS), were applied to osteoblasts after 1 h of hypoxia mimetic treatment. SUL and IND further enhanced cell death after hypoxia. ALP activity was totally abolished in hypoxic osteoblasts under IND treatment. Facilitation of osteoblast apoptosis occurred regardless of IND dosage under hypoxic conditions. To investigate osteoblast in vivo, local hypoxia was created by fracture of tibia and then treated the injured mice with IND by oral feeding. IND-induced osteoblast apoptosis was confirmed by positive staining of TUNEL assay in fractured mice. Significant delay of fracture healing in bone tissue was also observed with the treatment of IND. These results provide information pertaining to choosing appropriate anti-inflammatory drugs for orthopedic patients., (Copyright © 2011 Wiley Periodicals, Inc.)

Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-kappaB appears to be a well-conserved response in tumor cells exposed to IR. Recently, it also has been demonstrated that nonsteroidal anti-inflammatory agents inhibit tumor necrosis factor and interleukin-1-induced NF-kappaB activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF-kappaB may be a protective cellular factor responding to the cytotoxicity of IR and other damaging stimuli. As such, we addressed the idea and mechanism that NF-kappaB is a downstream target of the nonsteroidal anti-inflammatory agent indomethacin and is involved in the process of radiosensitization. In this study, we report that indomethacin inhibited IR-induced activation of NF-kappaB and sensitized HeLa cells to IR-induced cytotoxicity at similar concentrations. Pretreatment of HeLa cells with SB 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (MAPK), abrogated the ability of indomethacin to inhibit IR-induced activation of NF-kappaB and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38(MAPK) inhibited IR induction of NF-kappaB gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-kappaB, because of expression of a dominant negative I-kappaBalpha gene, demonstrated increased sensitivity to IR-induced cytotoxicity. Taken together, these results suggest that p38 MAPK is a target involved in indomethacin-induced radiosensitization and that NF-kappaB may be one downstream target in this process.

The purpose of this study was to investigate the effects of aspirin-like drugs on nitric oxide (NO) synthesis in rat vascular smooth muscle cells (VSMCs). We measured the accumulation of nitrite, a stable oxidation product of NO, and the expression of inducible NO synthase (iNOS) mRNA and protein in rat cultured VSMCs. Sodium salicylate, aspirin, and indomethacin dose-dependently enhanced nitrite production by interleukin (IL)-1beta-stimulated VSMCs at therapeutic plasma concentration ranges. Increased nitrite production by aspirin-like drugs was accompanied by increased iNOS mRNA and protein accumulation in VSMCs. Addition of IL-1beta activated nuclear factor kappaB (NF-kappaB) in VSMCs, but sodium salicylate did not affect IL-1beta-induced NF-kappaB activation. The nonselective lipoxygenase (LO) inhibitor nordihydroguaiaretic acid inhibited sodium salicylate-induced nitrite production, whereas the selective 5-LO inhibitor caffeic acid did not influence production of nitrite. The 12-LO product 12-HETE dose-dependently enhanced nitrite production by IL-1beta-stimulated VSMCs, whereas the 15-LO product 15-HETE did not. Our study demonstrates that aspirin and the aspirin-like drugs, sodium salicylate and indomethacin, increase NO synthesis in IL-1beta-stimulated VSMCs by upregulation of iNOS transcription via a 12-LO pathway. These effects were independent of NF-kappaB activation. In addition to the direct inhibition of platelet function, aspirin-like drugs may contribute to the reduction of atherothrombotic risk in myocardial ischemia via enhancing NO production by VSMCs.

It is known that the concentration of nerve growth factor (NGF) is increased in inflamed tissue, a phenomenon thought to induce long-lasting sensitization of afferent neurons. Although the effects of NGF may be of pathophysiological relevance, there is little known about the effects of non-steroidal anti-inflammatory drugs on the inflammation-induced increase in NGF. In the present study, therefore, we used the non-steroidal anti-inflammatory drugs indomethacin and sodium salicylate in carrageenan-induced rat paw inflammation, in order to compare their anti-inflammatory action (determined as inhibition of edema) with their effects on the concentration of NGF in inflamed tissue. Carrageenan-induced inflammation increased the concentration of NGF in the paw 2-fold compared to non-inflamed controls. Indomethacin (0.66-2 mg/kg) and sodium salicylate (100-300 mg/kg) inhibited carrageenan-induced paw edema and indomethacin also inhibited the ex-vivo release of immunoreactive prostaglandin E2 from inflamed paw skin. However, at these doses, neither anti-inflammatory agent reduced the elevated levels of NGF. In contrast, a supramaximal dose of indomethacin (6 mg/kg) partially inhibited, and dexamethasone completely prevented the carrageenan-induced increase in NGF. These results suggest that the anti-inflammatory potency of drugs as determined in the carrageenan edema model is not necessarily predictive for their ability to inhibit the NGF response. It seems possible, therefore, that even if anti-inflammatory treatment prevents the appearance of visible signs of inflammation, there may be still long-lasting effects of NGF on the phenotype of primary afferent neurons.

Little is known about the anti-asthmatic effects of powerful anti-inflammatory agents such as aspirin-like drugs. We compared the effects of two aspirin-like drugs with different pharmacologic activities, sodium salicylate (SSA) and indomethacin, with the effect of lysine acetylsalicylate (LASA), inhaled 30 min before challenge, on the early and the late asthmatic response induced by a single dose of allergen causing a 25% decrease in FEV1 in a preliminary challenge. Inhaled SSA partially prevented both the early and late response, providing a protection with respect to placebo of 22 +/- 6% in the early phase and 23 +/- 9% in the late phase of the response. These values were lower (but not significantly) than those of LASA (41 +/- 9% and 39 +/- 11%, respectively). In a second group of patients, indomethacin failed to affect the early response, while LASA provided a protection of 31 +/- 7%. However, these two drugs were equally effective in reducing the late response (44 +/- 18% and 39 +/- 17% protection for LASA and indomethacin, respectively). In subjects with an early response, despite being ineffective in preventing allergen-induced bronchoconstriction, indomethacin blocked the allergen-induced increase in bronchial hyperresponsiveness measured 2 h after challenge. We conclude that inhaled salicylates, but not indomethacin, exert a protective activity against the early allergic response. This difference is not explained by the different pattern of cyclooxygenase inhibitory activity of these drugs.

Nitric oxide synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation in rheumatic and autoimmune diseases. We report that exposure of lipopolysaccharide-stimulated murine macrophages to therapeutic concentrations of aspirin (IC50 = 3 mM) and hydrocortisone (IC50 = 5 microM) inhibited the expression of iNOS and production of nitrite. In contrast, sodium salicylate (1-3 mM), indomethacin (5-20 microM), and acetaminophen (60-120 microM) had no significant effect on the production of nitrite at pharmacological concentrations. At suprapharmacological concentrations, sodium salicylate (IC50 = 20 mM) significantly inhibited nitrite production. Immunoblot analysis of iNOS expression in the presence of aspirin showed inhibition of iNOS expression (IC50 = 3 mM). Sodium salicylate variably inhibited iNOS expression (0-35%), whereas indomethacin had no effect. Furthermore, there was no significant effect of these nonsteroidal anti-inflammatory drugs on iNOS mRNA expression at pharmacological concentrations. The effect of aspirin was not due to inhibition of cyclooxygenase 2 because both aspirin and indomethacin inhibited prostaglandin E2 synthesis by > 75%. Aspirin and N-acetylimidazole (an effective acetylating agent), but not sodium salicylate or indomethacin, also directly interfered with the catalytic activity of iNOS in cell-free extracts. These studies indicate that the inhibition of iNOS expression and function represents another mechanism of action for aspirin, if not for all aspirin-like drugs. The effects are exerted at the level of translational/posttranslational modification and directly on the catalytic activity of iNOS.

The present study examined the effect of sodium salicylate and indomethacin on the recruitment of osteoclast-like cells in vitro. When mouse bone marrow cells were cultured for 8 days with 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3, 10(-8) M), prostaglandin E2 (PGE2, 10(-6) M) and recombinant human interleukin-1 alpha (rHIL-1 alpha, 2 ng/ml), numerous tartrate-resistant acid phosphatase (TRAP-positive) multinucleated cells (MNCs) formed. Adding sodium salicylate or indomethacin inhibited the formation of TRAP-positive MNCs in a dose-dependent manner. This inhibitory effect was more pronounced when the drugs were given at a later stage in the culture period. Indomethacin appeared to be more potent than sodium salicylate. PGE2 production was inhibited by sodium salicylate or indomethacin. Exogenous PGE2 failed to overcome the inhibitory effect of both drugs. These results suggest that sodium salicylate and indomethacin have inhibitory effects on the recruitment of osteoclast-like MNCs, preferentially on the later stage, and that PGE2 is not the only compound targeted by these drugs in reducing osteoclast-like cell formation in mouse bone marrow culture.

We investigated the effects of sodium salicylate on the elimination kinetics of indomethacin in bile duct-cannulated beagles. Indomethacin and metabolites were quantified by HPLC in plasma, bile, and urine. Indomethacin was administered as iv bolus injection and iv infusion to yield a steady-state plasma concentration of approximately 1 microgram/ml. Following sodium salicylate, given either iv (25 mg/kg) or via duodenal fistula (50 mg/kg), the indomethacin plasma level dropped instantaneously by 60-70%. Concomitantly, total systemic clearance from the plasma and biliary clearance were increased significantly. In addition, a reduced plasma protein binding of indomethacin and a significant increase in the volume of distribution were observed. The amount of indomethacin, excreted as free and conjugated drug in bile, was significantly increased temporarily by sodium salicylate. The total amount eliminated in bile (approximately 70% of the dose), however, was not changed by sodium salicylate co-administration. The bile flow was significantly enhanced for at least 4 hr. Both phase 1 metabolism and renal excretion of indomethacin remained practically unaffected by sodium salicylate treatment.

Thromboxane formation during spontaneous blood clotting as well as plasma levels of TXB2 and 6-keto-PGF1 alpha, the stable metabolites of TXA2 and prostacyclin, were measured by radioimmunoassay two hours after oral administration of indomethacin (25 mg), sodium salicylate (250 mg) and their combination to human volunteers. Indomethacin effectively suppressed the tremendous formation of TXB2 during blood clotting whereas sodium salicylate had only a slight inhibitory effect on TXB2 synthesis. The combination of indomethacin and sodium salicylate inhibited the formation of thromboxane even slightly more effectively than indomethacin alone. Plasma TXB2 level was decreased after the combination treatment but not after administration of either of the drugs alone. Plasma 6-keto-PGF1 alpha level was not changed by any of the treatments. The present study suggests that simultaneous oral administration of sodium salicylate together with indomethacin at a combination ratio of 10 to 1 does not significantly interfere with the inhibitory effects of indomethacin on thromboxane synthesis in human blood ex vivo.

In the present work it has been tested if associations of indomethacin or aspirin with diflunisal or sodium salicylate block PGI2 release from gastric mucosa less than the administration of the compounds alone. PGI2 production was determined on aliquots of incubated mucosal strips, tested for ADP-induced aggregation of human platelet rich plasma. The obtained data indicate that PGI2 generation found in rats treated with indomethacin or aspirin associated with diflunisal or sodium salicylate was higher than that found in rats treated with indomethacin or aspirin alone. This effect may be likely explained by competition between salicylates and other non steroidal anti-inflammatory drugs for binding sites on PG-synthetase and plasma proteins.

When 160 microgram/ml sodium salicylate was added to the culture medium, glycosaminoglycan synthesis in slices of normal articular cartilage from habitually loaded areas of canine femoral condyles was diminished by 24% (P less than 0.01). Although glycosaminoglycan synthesis in cartilage from habitually unloaded regions of the same joints was similar to that in cartilage from loaded sites, the mean uronic acid content of the former was about 25% less, and salicylate suppressed glycosaminoglycan synthesis in unloaded cartilage to a much greater extent (42% of control) than it did in loaded cartilage (P less than 0.01). Furthermore, 1.5 micrograms/ml indomethacin, which had no effect on cartilage from loaded regions, suppressed glycosaminoglycan synthesis in cartilage from unloaded regions by 31%. However, if cartilage from loaded regions was treated with testicular hyaluronidase, indomethacin inhibited glycosaminoglycan synthesis, and inhibition of glycosaminoglycan metabolism by salicylate in hyaluronidase-treated cartilage was greater than in untreated cartilage. The data suggest that the effects of nonsteroidal antiinflammatory drugs on glycosaminoglycan metabolism in articular cartilage are dependent on proteoglycan content of the extracellular matrix.

The interaction of salicylates and other non-steroidal anti-inflammatory drugs was studied in rats. Concurrent oral administration of sodium salicylate (SS) or salicylic acid (SA) and indomethacin (IND) significantly reduced the gastro-ulcerogenicity and the plasma concentrations of IND. Acetylsalicylic acid (ASA) failed to do so. IND had no significant influence on plasma concentrations of SA. Simultaneous administration of SS and IND intraperitoneally or subcutaneously showed the same pattern of interaction as for oral administration. Concurrent oral administration of SS and IND exerted similar anti-inflammatory activity as the single drugs. SS significantly antagonized the ulcerogenicity of ibuprofen and tended to antagonize the ulcerogenic activity of ASA, phenylbutazone, tolfenamic acid and naproxen. The results suggest that in rats SS and SA (but not ASA) interact with IND concerning both gastro-ulcerogenicity and plasma concentrations of IND (but not of SA) and that the interaction is systemic in nature. We propose that the ulcerogenic interaction might be explained partly by the reduced IND plasma concentrations and partly by a weaker inhibition by SS of the prostaglandin system in the rat stomach.

The effects of 20 mM aspirin (ASA), 20 mM sodium salicylate (SA), or 10(-4) M indomethacin placed in the nutrient solution (N) to stimulate systemic administration were investigated at pHN 7.3 in Ussing-chambered amphibian gastric mucosae. In histamine-stimulated tissues, the initial rise and subsequent rapid fall in potential difference, rise in resistance, and inhibition of hydrogen ion (H+) secretion induced by SAN did not occur with ASAN unless hydrolysis of ASAN produced a SAN of greater than 3 mM. In metiamide-treated tissues, 20 mM SAN caused an immediate fall in potential difference and an increase in resistance; 2 mM SAN and 20 mM ASA produced similar qualitative electrical changes, but only those induced by ASA were reversible. IndomethacinN caused no significant changes in potential difference, resistance, or H+ secretion in histamine- or metiamide-treated tissues. Despite producing highly significant reductions in generation of prostaglandin E2, and prostaglanndin F2 alpha and 6-keto prostaglandin F1 alpha, ASAN and indomethacin caused no surface ulceration. Sodium salicylate placed in the nutrient solution caused only a small reduction in prostaglandin F2 alpha, without change in the other prostaglandins, and produced extensive edema in the lamina propria, histologically. We conclude the following: (a) The inhibition of H+ secretion and electrical changes caused by SAN in histamine-treated gastric fundus are not observed with ASAN unless there is hydrolysis to [SAN] greater than 3 mM. (b) Our data strongly implicate the SAN in ASAN-containing solutions as being responsible for the electrical effects and inhibition of H+ secretion. (c) There is no correlation in vitro between inhibition of prostaglandin synthesis and the electrical or morphologic changes produced by nutrient exposure to ASA, SA, or indomethacin.

The effects of acetylsalicylic acid (ASA, aspirin), indomethacin and sodium salicylate on the metabolism of exogenous 14C-arachidonic acid (AA) were studied in intact human platelets in vitro. ASA (100 microM) and indomethacin (1 and 10 microM) suppressed the metabolism of AA via the cyclo-oxygenase but had no effect on the lipoxygenase pathway. Sodium salicylate at 1 mM was ineffective whereas 2 mM salicylate significantly decreased the formation of TXB2 and HHT and increased that of other cyclo-oxygenase products without clearly affecting total cyclo-oxygenase activity. The formation of 12-HETE, the main metabolite of AA in human platelets, was decreased by 2 mM sodium salicylate as well as by the combination of 1 mM salicylate plus ASA or indomethacin. Pretreatment of platelets with sodium salicylate (1 or 2 mM) effectively prevented the inhibition of the cyclo-oxygenase by ASA (100 microM) but had no effect on the inhibition produced by indomethacin (1 or 10 microM). When sodium salicylate was added to the platelet-containing buffer after ASA or indomethacin it did not reverse the effects of these drugs on the cyclo-oxygenase. The present study suggests that sodium salicylate effectively prevents the inhibitory effect of ASA but not that of indomethacin on human platelet cyclo-oxygenase at the concentrations used. In addition, a high concentration of sodium salicylate (2 mM) may selectively inhibit the formation of TXB2 without clearly affecting total cyclo-oxygenase activity.

It has been found that gastrointestinal side-effects of indomethacin could be abolished when administered in combination indomethacin:sodium salicylate (ratio 1:10). In this paper comparative pharmacological data of this combination and its basal compounds are presented. Acute toxicity of the combined preparation was 72 times less in rats than that of indomethacin alone. All therapeutic indexes were markedly increased in the combination of indomethacin-sodium salicylate compared with the separate drug treatments.

Approximately 60% of methotrexate in serum is protein bound and this binding occurs primarily to serum albumin. The fraction of methotrexate bound remains relatively constant despite changes in free methotrexate concentrations over the range observed clinically. Indomethacin did not influence methotrexate-albumin binding, but salicylate in therapeutic concentrations produced a 20% to 60% decrease in binding. The clinical significance of these findings for patients requiring concomitant methotrexate and salicylate is discussed.

Non-steroidal antiinflammatory agents are well known to cause gastrointestinal damage in many species including the rat and human. Pelsonin a combination of indomethacin and sodium salicylate (1:10 ratio) has a cytoprotective effect against acidic-alcohol induced gastric necrosis, and it does not induce intestinal ulceration. Pelsonin is capable of blocking the formation of intestinal ulcers induced by oral indomethacin 10 mg/kg (curative cytoprotection). The cytoprotective potency of Pelsonin is due to sodium salicylate.

The interference of sodium salicylate with the effects of acetylsalicylic acid (ASA, aspirin) and indomethacin on arachidonic acid-induced platelet aggregation and thromboxane formation was studied in human platelet rich plasma. ASA and indomethacin suppressed both aggregation and the concomitant formation of thromboxane B2 whereas sodium salicylate alone had no significant effect on these parameters of platelet function. It did, however, partially prevent the inhibitory effects of ASA and indomethacin on platelet aggregation when it was added to platelet rich plasma before ASA or indomethacin. The inhibition of thromboxane formation by indomethacin was also prevented by sodium salicylate. When sodium salicylate was added to platelet rich plasma after ASA or indomethacin it did not modify the effects of these drugs. The present study indicates that sodium salicylate interferes with the effects of ASA and indomethacin on human platelet cyclo-oxygenase in vitro.

The modulation of fetal insulin secretion by prostaglandins was studied with the aid of the prostaglandin synthesis inhibitors indomethacin and sodium salicylate in 10 chronically catheterized fetal lambs. Glucose-induced fetal insulin secretion was inhibited within 60 minutes by preinjection of either indomethacin or sodium salicylate in the fetal lambs. In the sodium salicylate experiments a significant (p less than 0.01) dose-related response (degree of insulin suppression) was noted between doses of 100 to 350 mg/kg of fetal weight. In a selected group of sodium salicylate injections prostaglandin levels were found to fall to 58% of control by 2 hours after injection. Five neonatal lambs exposed to a similar regimen were noted to have an exaggerated insulin response to glucose infusion when compared to fetal lambs. However, indomethacin or sodium salicylate pretreatment resulted in no suppression of glucose-induced insulin release. This finding may be of importance in explaining the observation of an increased incidence of fetal growth retardation after long-term exposure to salicylates in humans and in animal models.

The effects of sodium salicylate (SS) and indomethacin (INDO) on rectal temperature (RT) and on prostaglandin (PG) concentration in the anterior hypothalamus of nonfebrile rats exposed to ambient temperatures (AT) of 4 +/- 1 degrees C, 23 +/- 2 degrees C and 34 +/- 2 degrees C were investigated. In rats treated with SS and exposed to AT of 4 degrees C and 23 degrees C, RT decreased by 1-1.5 degrees C (p less than 0.01). On the other hand at AT of 34 degrees C, SS-treated rats had an elevation of RT of 2 degrees C (p less than 0.01). However, in rats treated by INDO, RT did not change, in spite of significant decreases (p less than 0.01) in PGE2 under all three environmental conditions. In SS treated rats a significant decrease (p less than 0.01) of PGE2 was observed only at At 23 degrees C, whereas hypothalamic PGE levels were not inhibited at 4 degrees C or 34 degrees C. This data do not support the hypothesis that PG is the mediator of normal thermoregulation in the rat. The changes in deep body temperature observed in nonfebrile rats treated with salicylate may be related to a mechanism that is not associated with PG cyclooxygenase inhibition.

Sodium salicylate (SA) has been reported to inhibit the formation of gastric ulcerations induced by aspirin, indomethacin, and absolute ethanol. In this study, SA dose-dependently inhibited gastric ulcers induced by three hours of cold-restraint stress (CRS); SA-induced cytoprotection was prevented by both acetylsalicylic acid (aspirin) and indomethacin pretreatment. Neurotensin (NT), which has previously been demonstrated to prevent the development of CRS-induced gastric ulcerations after intracisternal administration, was found to be ineffective in animals pre-treated with aspirin, and with indomethacin, as previously described. These data suggest that in the CRS model both NT- and SA-induced gastric cytoprotection require a functionally intact gastrointestinal prostaglandin synthetic pathway.

Administration of prostaglandin synthetase inhibitors to pregnant does and dams in late gestation was followed by in utero contraction of the fetal ductus arteriosus when studied by the whole-body freezing method. In the rat this contraction was well established within 6 h and persisted up to 36 h following 15 mg/kg indomethacin p.o. No effect was observed in the 18 d rat fetus but fetuses at 20 d and 22 d of gestation responded significantly to indomethacin. Doses of indomethacin approaching clinical usage (2.5 mg/kg also caused a positive response in utero. The rat was found to be sensitive also to sodium salicylate and in the rabbit both indomethacin and sodium salicylate were effective. Exposure in utero to prostaglandin synthetase inhibitors with resulting contraction of the ductus may seriously disturb cardiac function in the fetus.

Treatment with indomethacin and diclofenac sodium was found to increase granulocyte counts in the blood of sublethally gamma-irradiated mice. Treatment with sodium salicylate was ineffective in this respect, administration of sodium salicylate together with indomethacin even decreased the indomethacin-induced effects. The results suggest that the hemopoiesis-stimulating effects of non-steroidal anti-inflammatory drugs cannot be correlated with the anti-inflammatory activity but rather with the side effects of these compounds, including the action on gastro-intestinal prostanoid production. This conclusion doubts on the possibility of the usefulness of non-steroidal anti-inflammatory drugs in conditions of the radiation syndrome.

Indomethacin and salicylates are considered to be specific inhibitors of prostaglandin (PG) synthesis. If their mechanism of actin is common then similar effects would be expected in organs capable of PG production. In the present investigation the effects on renal and intrarenal haemodynamics by indomethacin and Na-salicylate were studied and compared in anaesthetized (nembutal) dogs using SAPIRSTEIN's technique. Indomethacin (4 mg per kg) raised blood pressure while cardiac output remained unaffected. Sodium salicylate (200 mg per kg) also increased blood pressure, however, this was associated with increased cardiac output. Renal blood flow was depressed by indomethacin, whereas it was not influenced by Na-salicylate (RBFcontr. = 411 +/- 97; RBFindo. = 292 +/- 53, p less than 0.01; RBFNa-salic. = 468 +/- 110 ml per min per 100 g). Renal resistance was augmented after indomethacin and unaltered by Na-salicylate (Rcontr. = 1.96 +/- 0.43; Rindo. = 3.03 +/- 0.97, p less than 0.001; RNa-salic. = 1.91 +/- 0.49). Indomethacin provoked an intrarenal blood flow redistribution, while no such effect was seen by Na-salicylate. Salt and water excretion was markedly suppressed by indomethacin, whereas Na-salicylate exhibited diuretic and natriuretic actions. It is concluded that the two agents exert their actions on renal haemodynamics and salt and water excretion by different mechanisms. The differential responses might be accounted for by the finding that Na-salicylate fails to inhibit renal PG-production.

A double-blind, prospective, randomized clinical study was carried out. Gastric microbleeding was provoked in informed patients without gastrointestinal disorders by the administration of indomethacin (4 X 25 mg, orally), sodium salicylate (4 X 250 mg, orally) or indomethacin (25 mg) plus sodium salicylate (250 mg) (Pelsonin, 4 X 1 capsules). The rate of gastric bleeding was estimated on the basis of haemoglobin losses into the gastric juice according to a rapid and sensitive chemical method (Fisher and Hunt, 1976). The observations were done before and after the day of treatment. The basic gastric bleeding was practically the same in the three groups (indomethacin, 0.91 +/- 0.12 ml/day: sodium salicylate, 0.72 +/- 0.20 ml/day: Pelsonin, 0.99 +/- +/- 0.18 ml/day: p less than 0.05). Contrary to this, the increases of gastric bleeding were found to be considerably different after a one-day application of these drugs (indomethacin, 7.3 +/- 1.2 ml/day: sodium salicylate, 1.92 +/- 0.45 ml/day, Pelsonin, 2.1 +/- 0.8 ml/day). It has been concluded that sodium salicylate can reduce the indomethacin-induced gastric microbleeding in patients.

In order to assess the role of inflammation and its components in spontaneous cure of Strongyloides ratti infestation, rats were treated with non-steroid anti-inflammatory agents (indometacin; sodium salicylate) or with antagonists of certain mediators (dexchlorpheniramin; cyproheptadin, promethazin). Results were compared with those obtained in similar treatments of rats infested by other Nematoda which also give rise to spontaneous cure: especially Trichinella spiralis, and Nippostrongylus brasiliensis. Coordinating the various findings made it possible to devise a pattern accounting for the chain of reactions that lead to rejection of the parasite.