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PubMedDate not supplied

Effect of aspirin on renal function and the prostaglandin-kallikrein systems early after myocardial infarction.

Using a double-blind procedure, 29 patients with a recent myocardial infarction were randomly allocated to a placebo group (n = 14) and to a group receiving aspirin, 300 mg three times a day (n = 15) over 7 days. No change in renal function was observed in either treatment group. Compared with the placebo group, the 24-h urinary excretion of prostaglandin E2 (PGE2) was significantly suppressed in the aspirin group, but the urinary kallikrein activity was unchanged. These results contrast with our previous study of similar patients, in which sulfinpyrazone decreased renal function, as well as the urinary PGE2 and kallikrein excretions. These divergent effects of aspirin and sulfinpyrazone on urinary kallikrein activity could explain the different trends in renal function observed early after myocardial infarction.

Aged↗

PubMed1981

Idiosyncrasy to pyrazolone drugs.

Studies carried out in 68 patients with idiosyncratic reactions to noramidopyrine and/or aminophenazone led to distinction of two different groups. In the first group: 1) noramidopyrine, aminophenazone, phenylbutazone and sulfinpyrazone as well as several other inhibitors of cyclooxygenase, including aspirin, precipitated bronchoconstriction; 2) skin tests with pyrazolone drugs were virtually negative; 3) all patients had chronic asthma. In the second group: 1) noramidopyrine and aminophenazone induced anaphylactic shock and/or urticaria; 2) skin tests with these drugs were highly positive; 3) phenylbutazone, sulfinpyrazone and several other cyclooxygenase inhibitors, including aspirin, could be taken with impunity; 4) chronic bronchial asthma was present in only one-fourth of the patients. We suggest that the pathogenic mechanisms responsible for the idiosyncratic reactions involve inhibition of cyclooxygenase in the first group, and allergic reactions in the second group. Distinction of these two groups is of clinical importance since in individual patients it gives insight into the safe administration of pyrazolone and aspirin-like drugs.

Adult↗

PubMed2000

Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions.

The human multidrug resistance protein MRP1 and its homolog, MRP2, are both suggested as being involved in cancer drug resistance and the transport of organic anions. We expressed MRP1 and MRP2 in Spodoptera frugiperda ovarian cells and compared their ATP-dependent transport properties and vanadate-sensitive ATPase activities in isolated membrane vesicles. Both MRP1 and MRP2 actively transported leukotriene C(4) and N-ethylmaleimide glutathione (NEM-GS), although the relative affinity of MRP2 for these substrates was found to be significantly lower than that of MRP1. Methotrexate was actively transported by both proteins, although more efficiently by MRP2. ATP-dependent NEM-GS transport by MRP1 and MRP2 was variably modulated by organic anions. Probenecid and furosemide inhibited, whereas under certain conditions sulfinpyrazone, penicillin G, and indomethacin greatly stimulated, MRP2-mediated NEM-GS uptake. Vanadate-sensitive ATPase activity in isolated membranes containing MRP1 or MRP2 was significantly stimulated by NEM-GS and reduced GS, although these compounds acted only at higher concentrations in MRP2. ATP hydrolysis by MRP2 was also effectively stimulated by methotrexate. Probenecid, sulfinpyrazone, indomethacin, furosemide, and penicillin G all significantly increased MRP2-ATPase activity, whereas these compounds acted more as ATPase inhibitors on MRP1. These results indicate that MRP1 is a more efficient transporter of glutathione conjugates and free glutathione than MRP2, whereas several anions are preferred substrates for MRP2. Our data suggest that MRP2 may be responsible for the active secretion of pharmacologically relevant organic anions, such as diuretics and antibiotics, and indicate different modulation possibilities for MRP1 or MRP2 in drug-resistant tumor cells.

Adenosine Triphosphatases↗

PubMed1991

Antithrombotic therapy for deep arterial injury by angioplasty. Efficacy of common platelet inhibition compared with thrombin inhibition in pigs.

BACKGROUND: Platelet-thrombus formation is a complication of arterial wall deep injury by balloon angioplasty that may lead to acute arterial occlusion and may contribute to restenosis. METHODS AND RESULTS: Because common platelet-inhibitor drugs with a heparin bolus (100 units/kg) may be effective in inhibiting platelet-thrombus formation after arterial angioplasty, these were compared with a bolus of heparin alone (control), the specific thrombin inhibitor hirudin (1.0 mg/kg), and saline (hirudin control) in normal pigs after angioplasty of the common carotid arteries. In the presence of deep arterial wall injury (injury exposing the media), indium-111-labeled platelet deposition (x 10(6)/cm2) was 68.8 +/- 12.3 and 48.1 +/- 16.9 in the control animals. This was significantly reduced by pretreatment with low-dose aspirin (1 mg/kg/day), by high-dose aspirin (20 mg/kg/day) plus dipyridamole, and especially by thrombin inhibition with hirudin. Treatment regimens with aspirin alone (20 mg/kg/day), dipyridamole alone, or sulfinpyrazone were ineffective. Likewise, the incidence of mural thrombosis was 75% and 80% in deeply injured arteries of controls and was significantly reduced to 46% with aspirin plus dipyridamole, 25% with low-dose aspirin, and 0% with hirudin. The incidence of mural thrombosis was unchanged with high-dose aspirin (69%), dipyridamole (90%), or sulfinpyrazone (92%). This mural thrombosis could not be identified by angiography. In the presence of mild injury (deendothelialization), platelet deposition was low (less than 10 x 10(6)/cm2, a single layer) and was not changed by any therapy, including hirudin. CONCLUSIONS: These therapies do not affect platelet adhesion to deeply or mildly injured artery. These data suggest a greater role for thrombin inhibition than with thromboxane or cyclooxygenase inhibition in the pathogenesis of platelet-rich mural thrombosis after deep injury during angioplasty. Antithrombotic therapy for arterial thrombosis by thrombin inhibition appears promising.

Angioplasty, Balloon↗

PubMed1996

Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells.

The human multidrug resistance-associated protein MRP confers resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Recent evidence indicates that MRP can also transport glutathione S-conjugates across membranes. To study the transport properties of MRP in intact cells, we have expressed human MRP cDNA in the polarized pig kidney epithelial cell line LLC-PK1. MRP mainly localized to the basolateral plasma membrane of these cells, and not to the apical membrane, as determined by immunocytochemistry using confocal laser scanning and electron microscopy. In accordance with this localization, MRP caused increased transport of the glutathione S-conjugate S-(2, 4-dinitrophenyl)-glutathione and of the anticancer drug daunorubicin to the basal side of the epithelial cell layer. Sulfinpyrazone and probenecid, known inhibitors of multispecific organic anion transport, inhibited this basolateral transport, but not the apical transport of daunorubicin mediated by the apically localized human MDR1 P-glycoprotein in MDR1-transfected LLC-PK1 cells. Probenecid and sulfinpyrazone may therefore be useful lead compounds for the development of clinical reversal agents specific for MRP-mediated drug resistance.

ATP-Binding Cassette Transporters↗

PubMed1996

Clinically important drug interactions with anticoagulants. An update.

Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin.

Anticoagulants↗

PubMedDate not supplied

[Urticaria--angioedema induced by non-steroidal anti-inflammatory analgesics].

Forty-two adult patients had been evaluated with a history of Urticaria and Angioedema (U-AE) associated with ingestion of non-steroidal anti-inflammatory drugs (NSAID). None developed attacks of bronchospasm. None had chronic urticaria. The same reaction was repeated in 36 individuals on at least two different occasions following administration of these drugs. Based on patients'history we distinguished three groups: Group A: twenty-three patients who had presented U-AE with the administration of pyrazolone drugs. Thereafter, sixteen of them had taken aspirin without adverse reactions. Group B: Nine patients in whom aspirin caused U-AE, after three of them had taken pyrazolone drugs without intolerance. The remaining six had not taken analgesic drugs since the last reaction. Group C: Ten patients who had developed U-AE with aspirin as well as with pyrazolone drugs. The objective of our study was the following: 1) to observe tolerance level of these patients to other NSAID different from those which had produced the first reactions. 2) To test to see if the patients who had suffered U-AE by noramidopyrine and aminophenazone tolerated other pyrazolone drugs like sulfinpyrazone and phenylbutazone. 3) To see if reactions are produced with tartrazine in patients who had presented U-AE with pyrazolone drugs, given that this colouring (tartrazine) is a pyrazolone derivative. Skin test (prick and intracutaneous test) with noramidopyrine, phenylbutazone and noramidopyrine metasulphonate MG, were carried out on the patients in group A, group C and 30 normal controls. In all the groups oral challenge tests were performed with progressive doses of naproxen, indomethacin, paracetamol, ciclofenac, mefenamic acid, piroxicam and phenylbutazone. Oral challenge tests were accomplished with aspirin in group A and with propiphenazone in group B. Oral challenge tests with sulfinpyrazone and tartrazine were also performed on various patients in group A and group C. The interval between the administration of progressive doses of a drug was 3 and as half hours and were allowed to pass at least 24 hours before testing other different analgesics. The test was considered positive if cutaneous rash, wheals, AE or hypotension were produced. In this case, the test was halted and 7 days were allowed to pass before continuing the study with a new drug. Based on the oral challenge tests performed, three types of patients could be distinguished: 1) individuals sensitive only to the pyrazolone drugs and who can take with impunity other NSAID.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1975

Inhibitors of platelet function in the prevention of arterial thrombosis.

The use of platelet inhibiting drugs in the prevention of arterial thromboembolic occlusive disease demonstrates that only a few trials have been adequately designed to provide conclusive results. Dipyridamole is effective in preventing the thromboembolic complications of prosthetic heart valves and sulfinpyrazone reduces occlusive events in A-V silastic cannulae, while clofibrate is clearly ineffective in secondary prevention of myocardial infarction. No antiplatelet agent has yet been convincingly shown to exert any antithrombotic effect in venous thromboembolism, although the results with hydroxychloroquine deserve further study. Currently, only two antiplatelet drugs, dipyridamole and sulfinpyrazone are clearly proven clinically effective in reducing arterial thromboembolism. The promising results using ASA are under active study.

Anticoagulants↗

PubMedDate not supplied

[Platelet aggregation model in vivo (rabbits)].

The purpose of this study was to establish a blood platelet aggregation model that would permit "in vivo" (New Zealand rabbits) evaluation of hemodynamic and microscopic parameters. The platelet aggregation was induced by the administration of collagen I.V. 75 micrograms/kg/min, which produced a decrease of systolic arterial pressure from mean = 69 to mean = 55 mm Hg and diastolic pressure from mean = 43 to mean = 27 mm Hg, with ventricular increase from mean = 25 to mean = 41 mm Hg. Aspirin, dypiridamol or sulfinpyrazone was administered 10 mg/kg, half hour before the administration of collagen and prostacycline 100 mg/kg/min starting 3 minutes before until 10 minutes after the collagen injection. With the joint administration of collagen and aspirin, collagen and dypiridamol both systolic and diastolic arterial pressure were lowered with no modification in the ventricular values. No hemodynamic changes were observed with the joint administration of sulfinpyrazone-collagen or prostacycline-collagen. Histology demonstrated multiple vascular lung thrombosis with the administration of collagen and in less intensity when jointly administered with an antiaggregant drug. This model permits to measure hemodynamically and histologically pro and antiaggregant substances.

Animals↗

PubMed1976

Effects of antithrombotic agents evaluated in a nonhuman primate vascular shunt model.

The effects of aspirin, cyproheptadine, dextran, dipyridamole, and sulfinpyrazone on thrombus deposition were determined. These antithrombotic agents were evaluated in a nonhuman primate model for thrombus generation that employed test devices exposed to blood in an arteriovenous shunt. Thrombus deposition on test devices was quantitated gravimetrically. Of the antithrombotic agents tested, cyproheptadine was found to be the most effective, and aspirin, dextran, and dipyridamole were each somewhat less effective. Sulfinpyrazone had only a slight antithrombotic effect. Ultrastructual studies of thrombus deposited in test devices showed that the various antithrombotic agents tested did not prevent completely the formation of fibrin, aggregation of platelets, or adhesion and spreading of platelets and leukocytes. This model for thrombus generation is felt to be a more efficient means for evaluating antithrombotic agents than previously described nonhuman primate models.

Animals↗

PubMed1977

Platelet-latelet-.

Two patients with thrombotic thrombocytopenic purpura were seen. Aspirin, dipyridamole, and sulfinpyrazone were administered to patient 1 after splenectomy, and administration of high-dose prednisone and methylprednisolone failed to induce remission. The platelet count rose, but the patient had a relapse when the dipyridamole dose was tapered. This condition responded to an increase of the drug, and the patient obtained a long-lasting remission. A splenectomy was not performed on patient 2, and all three platelet-inhibiting drugs, together with prednisone, were given. This resulted in a prompt remission that has been sustained for 29 weeks. Morphologic changes in the peripheral blood smear remained for several weeks after other features of the disease had resolved. Thus, in both cases, platelet-inhibiting drugs appeared to induce a remission.

Adult↗

PubMed1981

Therapeutic implications of drug interactions with acetaminophen and aspirin.

Only drug-drug interactions that are believed clinically important and that are primarily pharmacokinetic in nature are discussed in this article. Drugs reported to interact with aspirin are oral anticoagulants, methotrexate, probenecid, and sulfinpyrazone; those that are believed to interact with acetaminophen are propantheline bromide, narcotics, and metoclopramide hydrochloride, as well as food (carbohydrates). Ethyl alcohol, ammonium chloride, antacids, oral antidiabetic agents, corticosteroids, and heparin sodium probably interact with aspirin. Fenoprofen calcium, gold sodium thiomalate, indomethacin, naproxen, penicillin, phenylbutazone, phenytoin sodium, and spironolactone may also cause such interactions. Ethyl alcohol, beta-adrenergic blockers, oral anticoagulants, chlorpromazine hydrochloride, and miscellaneous mutual toxicities may cause interactions with acetaminophen. The concomitant use of drugs that are believed to interact importantly with either aspirin or acetaminophen should be avoided when designing a treatment regimen. The remaining agents discussed here (of doubtful importance in man) demand careful monitoring in difficult clinical situations and must be submitted to further controlled studies.

Acetaminophen↗

PubMed2000

Role of multidrug-resistance protein 2 in glutathione S-transferase P1-1-mediated resistance to 4-nitroquinoline 1-oxide toxicities in HepG2 cells.

Previous studies in our laboratory have shown that the phase III efflux transporter multidrug-resistance protein (MRP)1 can act synergistically with the phase II conjugating glutathione S-transferases (GST) to confer resistance to the toxicities of some electrophilic drugs and carcinogens. To determine whether the distinct efflux transporter MRP2 could also potentiate GST-mediated protection from electrophilic toxins, we examined the effect of regulatable GSTP1-1 expression in MRP2-rich HepG2 cells on 4-nitroquinoline 1-oxide (4NQO)-induced cytotoxicity and genotoxicity (nucleic-acid adduct formation). Expression of GSTP1-1 was associated with a fourfold to tenfold protection from 4NQO-induced cytotoxicity. Inhibition of MRP2-mediated efflux activity by sulfinpyrazone or cyclosporin A completely reversed GSTP1-1-associated resistance-a result indicating that GSTP1-1-mediated cytoprotection is absolutely dependent on MRP2 efflux activity. Moreover, MRP2 efflux activity also augmented GSTP1-1-mediated protection from 4NQO-induced nucleic-acid adduct formation. We conclude that MRP2-mediated efflux of the glutathione conjugate of 4NQO and/or another toxic derivative of 4NQO is required to support GSTP1-1-associated protection from 4NQO toxicities in HepG2 cells.

4-Nitroquinoline-1-oxide↗

PubMed2002

Accumulation of intracellular ascorbate from dehydroascorbic acid by astrocytes is decreased after oxidative stress and restored by propofol.

Primary rat astrocyte cultures absorbed dehydroascorbic acid from the medium and reduced it to intracellular ascorbate. Uptake of dehydroascorbic acid (5-200 microM) was inhibited only partially by glucose (10 mM). The remaining glucose-insensitive component of dehydroascorbic acid uptake was inhibited reversibly by sulfinpyrazone (IC(50) = 80 microM). Dehydroascorbic acid uptake was not mediated by Na(+)-ascorbate cotransporters or volume-sensitive anion channels because it was neither Na(+)-dependent nor blocked by the channel antagonist, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. Oxidative stress, induced in astrocytes by the lipophilic radical generator tert-butyl hydroperoxide, decreased intracellular glutathione concentration and inhibited accumulation of intracellular ascorbate from dehydroascorbic acid. Subsequent administration of either the native antioxidant alpha-tocopherol (200 microM) or anesthetic concentrations of the antioxidant sedative propofol (1-8 microM, administered 30 min after tert-butyl hydroperoxide), did not change glutathione concentration but restored the ability of astrocytes to accumulate intracellular ascorbate from dehydroascorbic acid. These results are consistent with a novel mechanism of astrocytic ascorbate accumulation that is inhibited by lipophilic radicals and protected by lipophilic antioxidants such as propofol.

Animals↗

PubMed1991

Ascorbate uptake by ROS 17/2.8 osteoblast-like cells: substrate specificity and sensitivity to transport inhibitors.

Ascorbate (reduced vitamin C) is required for bone formation. We have shown previously that both the osteoblast-like cell line ROS 17/2.8 and primary cultures of rat calvarial cells possess a saturable, Na(+)-dependent uptake system for L-ascorbate (J Membr Biol 111:83-91, 1989). The purpose of the present study was to investigate the specificity of this transport system for organic anions and its sensitivity to transport inhibitors. Initial rates of ascorbate uptake were measured by incubating ROS 17/2.8 cells with [L-14C]ascorbate at 37 degrees C. Uptake of [L-14C]ascorbate (5 microM) was inhibited 98 +/- 1% by coincubation with unlabeled L-ascorbate (3 mM) and 48 +/- 4% by salicylate (3 mM), but it was not affected by 3 mM formate, lactate, pyruvate, gluconate, oxalate, malonate, or succinate. Uptake of the radiolabeled vitamin also was not affected by acute (1 minute) exposure of the cells to the Na+ transport inhibitors amiloride and ouabain or the glucose transport inhibitor cytochalasin B. In contrast, anion transport inhibitors rapidly (less than 1 minute) and reversibly blocked [L-14C]ascorbate uptake. In order of potency, these drugs were 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) approximately equal to sulfinpyrazone greater than furosemide approximately equal to 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). These findings indicate that the ascorbate transporter is relatively specific for the ascorbate anion, since other organic anions (with the exception of salicylate) did not compete with ascorbate for uptake. Rapid and reversible inhibition by the impermeant antagonists DIDS and SITS suggests that they interact directly with the ascorbate transporter, consistent with location of the transport system in the plasma membrane.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1988

The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits.

In anesthetized rabbits, continuous infusion of methotrexate (MTX; 30 micrograms kg-1 min-1) established steady-state plasma concentrations for MTX and the metabolite 7-hydroxymethotrexate (7-OH-MTX) within 40 min. Fifty percent of the infused dose was eliminated unchanged by the kidneys and the renal MTX clearance was slightly higher than the inulin clearance. Another 15%-30% was metabolized and excreted as 7-OH-MTX in the urine. Infusions of 7-OH-MTX, furosemide or benzarone had no influence on the clearance of MTX or 7-OH-MTX. Infusions of probenecid or piperacillin decreased the renal clearance of MTX and 7-OH-MTX mainly by reducing the tubular secretion of both compounds. In contrast, infusions of the antibiotics ceftriaxone and sulfamethoxazole increased the renal elimination of MTX and 7-OH-MTX. An increase was also observed during the infusion of the uricosuric drugs sulfinpyrazone and benzbromarone. These results are consistent with competition for tubular reabsorption between MTX, ceftriaxone and sulfamethoxazole. The pharmacokinetic drug interactions observed occurred with therapeutic drug concentrations and thus may be clinically relevant.

Animals↗

PubMed1977

[Prophylaxis and therapy of shunt thrombosis in terminal renal insufficiency (author's transl)].

In terminal renal insufficiency thrombosis occurs almost exclusively in the arteriovenous shunt. The management of this acute, life threatening thrombosis is hardly contested. On the other hand, few results are available concerning effective thrombosis prophylaxis. In addition to the effectiveness, the pharmacokinetics of a substance and also possible bleeding complications must be taken into account. The parenteral administration of heparin and its short half life restrict it to use in thehospital. Oral anticoagulants, because they are difficult to dose, should be avoided when possible. Dextrans (Rheomacrodex) and acetylsalicylic acid (Colfarit) appear to be best suited for thrombosis prophylaxis in renal insufficiency. Dextran has the disadvantage of volume overload, and acetylsalicylic acid that of stomach intolerance. Sulfinpyrazone (Anturano) also appears to be effective, although its pharmacokinetic behaviour in renal insufficiency is still not known. Dipyridamole (Persantin), whose effectiveness for this purpose has not yet been demonstrate, should be administered even more cautiously.

Anticoagulants↗

PubMed1984

Differential effects of pharmacologic agents on the reverse passive Arthus reaction in guinea pigs.

Five different pharmacologic agents were examined for their effects upon edema, hemorrhage, and vascular infiltration by neutrophils in the reverse passive Arthus reaction (RPAR) in guinea pigs. Two agents, colchicine (3.0 mg/kg p.o.) and ibuprofen (100 mg/kg p.o.) significantly inhibited all three parameters of RPAR. Cobra venom factor (100 units/kg i.p.) inhibited edema and hemorrhage but it did not inhibit neutrophil infiltration. Aminophylline and sulfinpyrazone (100 mg/kg p.o.) inhibited only hemorrhage; they did not inhibit edema or neutrophil infiltration. The results from these studies with five chemically or biologically unrelated pharmacologic agents suggest that the RPAR in guinea pigs can be separated into its basic components (edema, hemorrhage, and neutrophilic infiltration) by selective inhibitors. Inhibition of edema and hemorrhage, or hemorrhage alone of the two-hour RPAR in guinea pigs is not dependent upon inhibition of neutrophilic infiltration.

Aminophylline↗