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PubMed2002

Possible role of the vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis.

OBJECTIVE: To analyze tissue matrix metalloproteinase (MMP) expression in three patients who developed postoperative corneal melts after treatment with topical diclofenac sodium 0.1% (Falcon; Fort Worth, TX) ophthalmic solution. DESIGN: Retrospective noncomparative interventional case series with tissue analysis. MAIN OUTCOME MEASURES: Three patients were examined in this study. We report two patients from the same center with acute corneal melts after uncomplicated photorefractive keratectomy (PRK). Prior to these cases, 1500 patients were treated at the Zale Lipshy University Laser Center for Vision with no adverse effects. All 1500 patients were treated with the same postoperative regimen of ciprofloxacin, rimexolone, and suprofen ([Profenal, (CIBA, Duluth, GA]). The next 27 cases were treated postoperatively with ciprofloxacin and rimexolone. However, diclofenac sodium 0.1% was used instead of Profenal. A third case was also discussed. This melt occurred at another center in a postoperative cataract patient who developed cystoid macular edema after cataract extraction with intraocular lens placement. He was initially treated with diclofenac sodium 0.1% (Ciba Vision, Duluth, GA) then with diclofenac sodium 0.1%. He subsequently developed a corneal perforation requiring penetrating keratoplasty. All tissue specimens were examined by light microscopy. Microbiologic cultures and stains were also performed. Immunolocalization and in situ hybridization were performed on all keratoplasty specimens to detect expression and localization of MMPs. All patients had a complete diagnostic evaluation for systemic autoimmune diseases. RESULTS: Postoperatively, all patients developed corneal perforations requiring surgical intervention while being treated with diclofenac sodium 0.1%. Microbiologic cultures and special stains were negative for microorganisms. Induced expression of specific tissue degrading enzymes of the matrix metalloproteinase family was demonstrated within corneal epithelial cells, stromal keratocytes, and at the level of Descemet's membrane. The uniform distribution pattern of expression was not consistent with the localization expected of a repair response, suggesting the involvement of some outside agent. CONCLUSIONS: Whereas MMP expression is a normal component of repair, excessive or inappropriate MMP activity is associated with corneal keratolysis. Our study provides preliminary evidence that topical application of diclofenac sodium 0.1% may be associated with aberrant MMP expression in the cornea.

Administration, Topical↗
PubMedDate not supplied

Characteristics of rat platelets and relative contributions of platelets and blood coagulation to haemostasis.

In order to understand some of the haemostatic mechanisms in rats for the interpretation of toxicological data, basic haemostatic parameters with a special emphasis on platelet functions were first measured in vitro. The results of reactions of rat platelets to many aggregating agents suggest that only ADP may be a consistently significant aggregator. The search for physiologic aggregators revealed ADP to be available from erythrocytes. Adhesion reaction also required ADP. Collagen was not considered to be essential for either reaction. Aggregation and adhesion were probably both reversible in flowing blood, while irreversible thrombi were formed in blood at rest ex vivo. Blood coagulation parameters determined revealed that the intrinsic pathway may be more important than the extrinsic one. The rate of intrinsic coagulation reaction was rapid, and plasma coagulation appeared to be of primary importance while the influence of platelet aggregation was minor. A simple model of rat haemostatic mechanism is proposed based on these results. Additionally, to define the relative contribution of platelets versus other cellular and plasma coagulation in vivo, rats were administered antiplatelet drugs (ticlopidine, suprofen and clopidogrel) and an anticoagulant (warfarin) intraperitoneally. Bleeding times (BTs) were significantly increased in all treated groups. ADP-induced platelet aggregations were significantly depressed by the administration of the three antiplatelet drugs, while kaolon-activated partial thromboplastin time and prothrombin time were greatly increased in the warfarin-treated rats. The increase in BT may be due to the inhibition of platelet activity or blood coagulation defect in rats given antiplatelet drugs or warfarin, respectively. These results suggest that platelets play a key role in haemostasis in the rat. Two possible explanations of the disparity between in vitro and in vivo results may be that functional tests used here are not adequate to cover the properties of rat platelets or that mechanisms leading to the formation of platelet thrombi in rats are ADP-dependent adhesion and ADP-induced aggregation.

Animals↗
PubMed1999

Molecular mechanisms of photosensitization XIII: a combined differential scanning calorimetry and DNA photosensitization study in non steroidal antiinflammatory drugs-DNA interaction.

A combined differential scanning calorimetry (DSC) and photosensitization study has been carried out on the interaction of several NSAID on DNA, both from calf thymus and pBR 322 plasmid. The investigated compounds were both non-steroidal anti-inflammatory drugs as well as compounds related to NSAIDs for structural similar properties, to find evidence for their ability to interact with DNA as a function of steric hindrance and polarity of the chemical structures. The considered NSAIDs were diflunisal (DFN, a salicylic derivative), naproxen (NAP), ketoprofen (KPF), suprofen (SPF) and tiaprofenic acid (TIA, arylpropionic acids). The structural criterion used was related to three different aromatic groups, biphenyl, naphthalene and benzophenone (BZP). In fact drug-DNA interaction can be revealed by variations of the enthalpies and temperatures of unfolding of DNA obtained by comparison of calorimetric peaks, where a decrease of the enthalpy is associated with the drug-DNA interaction, by engaging electrostatic bonds. Testing their ability in inducing DNA cleavage when UVA irradiated can evidence the photosensitizing properties of the drug. A good correlation was found between calorimetric and photosensitization studies. From the results obtained it can be reasonably supposed that the photocleavage depends only on the drug molecules bound to DNA.

Animals↗
PubMed1998

Photosensitizing drugs containing the benzophenone chromophore.

The nonsteroidal anti-inflammatory agents ketoprofen, tiaprofenic acid, suprofen and tolmetin, together with the anti-hyperlipoproteinemic drug fenofibrate and the anti-arrhythmic amiodarone can be included in the group of benzophenone-derived photosensitizing drugs. They contain a diaryl ketone chromophore and mediate the development of phototoxic reactions. In some cases, photoallergic responses have been reported. These properties have been substantiated in clinical reports, as well as by means of in vivo and in vitro assays. Tolmetin is phototoxic in vitro, however there are no reports on photosensitization by this drug in humans. In general, photochemical and photobiological studies strongly suggest that photosensitization involves formal hydrogen abstraction (either in a single step or via electron transfer followed by proton transfer) by the benzophenone-like chromophore from the excited triplet state. In the case of amiodarone, the radicals generated by photodehalogenation from the triplet are responsible for the photosensitivity side-effects.

Animals↗
PubMed1998

Effect of the microenvironment on the efficiency of singlet oxygen (O2(1 delta g)) production by photosensitizing anti-inflammatory drugs.

The influence of the medium on the quantum yields of singlet oxygen (O2(1 delta g)) production (phi delta) by a series of photosensitizing non-steroidal anti-inflammatory drugs (NSAID) derived from 2-arylpropionic acid (APA) has been investigated. Four-component oil-in-water and water-in-oil microemulsions, based on anionic and cationic surfactants, have been employed as the simplest models to mimic more complex biological environments. phi delta values have been determined by monitoring the singlet oxygen (1O2) luminescence at 1270 nm upon continuous excitation of the drugs under air-equilibrated conditions. Results indicate that phi delta values are highly affected by the medium, being higher in microheterogeneous systems than in (homogeneous) solution. Some of the anti-inflammatory derivatives are very efficient 1O2 sensitizers: e.g., values of apparent phi delta as high as 0.86 (+/- 0.04) and 0.70 (+/- 0.03) have been found for tiaprofenic acid and suprofen, respectively. The location of the drugs in the interfacial region of the microemulsions combined with their high phi delta values suggest that type II reactions may play a significant role in the overall photodynamic process in more complex organized media, such as biological membranes.

Absorption↗
PubMed2002

Differential binding mode of diverse cyclooxygenase inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii.

The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids: ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and alpha-methoxyphenylpropionic acid. The results demonstrated that V. lecanii is capable of inverting the chirality of all the 2-arylpropionic acids investigated. All were inverted in the (R) to (S) direction with the exception of ketoprofen, where inversion was observed in the reverse direction. Using the structurally related compounds as substrates, the size of the alkyl substitutent at the alpha-carbon at the methyl group, and the presence of the methyl group at the chiral centre, were found to be critical. These results suggest that V. lecanii could be used as a basis for the production of pure enantiomers of the 2-arylpropionic acids in commercial biotransformations.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Photocontact dermatitis to ketoprofen.

A case of photocontact dermatitis from ketoprofen is described in a 19-year-old woman with a 3-day history of pruritic lesions on the right forearm. Physical examination revealed a 105 x 46 mm, dark reddish lesion consisting of edematous erythema and papules on the extensor aspect of the right forearm. In photopatch testing, positive reactions to as-is (Mohrus compress [Hisamitsu Pharmaceutical Co, Inc, Tosu, Japan]), ketorofen 1% in petrolatum (pet.), suprofen 1% pet., and tiaprofenic acid 1% pet. were seen. We must consider the anatomic sites on which nonsteroidal anti-inflammation medicaments are applied, as well as their effects.

Adult↗
PubMed1996

Prostaglandin E2 modulates neurally induced nonadrenergic, noncholinergic gastric relaxations in the rabbit in vivo.

BACKGROUND & AIMS: Prostaglandin (PG) E2 has been shown to modulate adrenergic and cholinergic neurotransmission in the gut. This study investigated PGE2 influence on vagally induced, nonadrenergic, noncholinergic (NANC) gastric relaxations. METHODS: Mechanical activity of the stomach was recorded in anesthetized rabbits. RESULTS: In atropine-treated animals, electrical vagal stimulation or arterial bolus injection of the ganglion stimulant dimethyl phenylpiperazinium iodide (DMPP) evoked inhibitory responses that varied from a brisk relaxation, interrupted by a poststimulus excitatory motility (biphasic response), to a long-lasting relaxation (monophasic response). PGE2 reduced and, at the highest doses, abolished the neurally induced relaxant responses elicited either by vagal stimulation or DMPP administration but did not affect the gastric relaxation caused by adenosine triphosphate (ATP), sodium nitroprusside (SNP), or vasoactive intestinal polypeptide (VIP). ATP or 2-methylthioadenosine triphosphate (2-MeSATP) reduced and then suppressed vagally induced inhibitory motility; the relaxant responses elicited by SNP, VIP, and ATP itself were not influenced. After administration of the prostaglandin synthesis inhibitor suprofen, ATP and 2-MeSATP failed to block vagally induced inhibitory responses. Arterial infusion of adenosine at the highest rates did not influence the amplitude of the vagally induced relaxant responses. Following theophylline administration, ATP still blocked the relaxation elicited by vagal stimulation. CONCLUSIONS: PGE2 may modulate NANC inhibitory neurotransmission in the stomach. The effects of ATP on the neurally induced NANC gastric relaxation may be caused by PGE2.

Adenosine↗
PubMed1995

Inflammatory and fibrotic mediator release by alveolar macrophages from coal miners.

Eicosanoids and cytokines produced by alveolar macrophages (AM) are key mediators of pulmonary inflammation and fibrosis. In order to determine if eicosanoid production and cytokine production are altered in AM obtained from coal miners, we compared production of prostaglandin E2 (PGE2), thromboxane A2 (TXA2), leukotriene B4 (LTB4), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) by cultured AM from normal human subjects and coal miners. The recovery of AM from miners' lungs by bronchoalveolar lavage was significantly greater than that from control subjects. Mean eicosanoid and cytokine production by AM from active miners was also increased compared to AM from control subjects, but this increase was not statistically significant. AM from control subjects produced significantly more TXA2 and TNF alpha when exposed to lipopolysaccharide than did AM from miners. The cyclooxygenase inhibitor suprofen reduced PGF2 and TXA2 production and TNF alpha release but had no effect on LTB4 production of IL-1 beta release by miners' AM. The lipoxygenase inhibitor nordihydroguaiaretic acid attenuated TNF alpha release, as well as that of LTB4, but had no effect on IL-1 beta release. Inhibition of thromboxane synthase by UK 38,485 also reduced TNF alpha release by active miners' AM but had no effect on PGE2, LTB4 production, or IL-1 beta release. The results of these studies suggest that occupational inhalation of coal dust may increase total lung eicosanoid and cytokine levels and reduce the reactivity of AM to bacterial endotoxin. Furthermore, coal dust-induced changes in both eicosanoid and cytokine release may be subject to pharmacological modulation.

Adult↗
PubMed1990

Arachidonic acid metabolites, ADP and thrombin modulate occlusive thrombus formation over extensive arterial injury in the rat.

Platelet-dependent occlusive thrombosis at sites of deep vessel wall injury elicited by electrical stimulation of rat carotid arteries was significantly reduced by thromboxane A2 (TXA2) synthetase inhibition and/or TXA2/prostaglandin endoperoxide receptor antagonism (ridogrel 1.25 mg/kg i.v.; dazoxiben 5 mg/kg i.v.; sulotroban 20 mg/kg i.v.), by inhibition of ADP-dependent platelet responses (ticlopidine 3 x 200 mg/kg orally) and by anticoagulation (heparin 250 U/kg i.v.; warfarin 1.25 mg/kg i.p.). This points to an involvement of arachidonic acid metabolites, ADP and thrombin as modulators of the thrombotic process. The antithrombotic effect of ridogrel (IC50 = 0.22 mg/kg i.v.) was abolished by cyclooxygenase inhibition (suprofen 5 mg/kg i.v.) but enhanced by cAMP phosphodiesterase inhibition (HL 725 6 micrograms/kg/min i.v.), demonstrating the importance of platelet inhibitory prostanoids such as PGD2, and prostacyclin formed after TXA2 synthetase inhibition. High doses of ridogrel (1.25 mg/kg i.v.) producing additional TXA2/prostaglandin endoperoxide receptor antagonism were more effective than lower doses (0.16 mg/kg i.v.) providing TXA2 synthetase inhibition alone. The antithrombotic effect of ridogrel, when combined with ticlopidine or heparin, exceeded that of the single compounds, pointing to interactions between arachidonic acid metabolites, ADP and thrombin in the formation of occlusive thrombosis at sites of arterial injury.

Adenosine Diphosphate↗
PubMed1975

Dissociation of clot retraction from platelet granule fusion and degranulation: an ultrastructural study of Reptilase-human platelet-rich plasma clots.

Human platelet-rich plasma clots, formed with Reptilase, do not retract. Electron microscopy of such a clot reveals platelets of normal shape and ultrastructural features surrounded by fibrin. When ADP is added before Reptilase, the clot strongly retracts. A sequential ultrastructural study of this process shows that, before visible fibrin formation, the platelets form small clusters and show shape change, granule centralization and pseudopod formation. Upon immobilization of the platelets by fibrin, the pseudopods develop into large cytoplasmatic protrusions, which allow cell contact. During the retraction process, the platelet granules remain intact; some granule fusion only becomes apparent in fully retracted clots. When Thrombofax is added to platelet-rich plasma before Reptilase, the clots formed also retract. With this aggregation inducer, granule fusion occurs earlier and in more platelets. Platelet pseudopod enlargement and fibrin concentration around the platelet mass are similar to that in ADP-treated samples. Inhibitors of granule fusion and secretion (suprofen, indomethacin) do not modify ADP-Reptilase nor Thrombofax-Reptilase clot retraction but reduce the incidence of granule fusion in Thrombofax-Reptilase clots. Retraction of Thrombofax-Reptilase clots is unaffected by concentrations of apyrase which completely block ADP-Reptilase clot retraction. Prostaglandin E1, papaverine and amitryptiline inhibit both ADP-and Thrombofax-Reptilase clot retraction, platelet pseudopod formation and cell-to-cell adhesion. These findings suggest that interaction of fibrin with the mass of fused granules (granulomere) or platelet secretion are not responsible for clot retraction. Rather, contraction around adhesion sites formed by cytoplasmic protrusions from adjacent platelets would seem to be involved.

Adenosine Diphosphate↗
PubMed1984

Studies on the influence of non-steroidal anti-inflammatory drugs upon trypanosomiasis in goats and sheep.

The non-steroidal anti-inflammatory drug (NSAID) flurbiprofen caused a rise in parasitaemia in goats infected with Trypanosoma vivax, Trypanosoma congolense and Trypanosoma brucei. All trypanosome-infected goats treated with flurbiprofen showed many dividing trypanosomes. This also included the short-stumpy forms of T. brucei. In T. vivax-infected goats flurbiprofen treatment resulted in 100% mortality in the acute and chronic stages of the infection. The increase in parasitaemia of T. brucei infected goats, treated with flurbiprofen, was not associated with an increase in mortality. The increase in parasitaemia of T. congolense-infected goats, treated with flurbiprofen, tended to be associated with a somewhat higher mortality but this was statistically not significant. The significant rise in parasitaemia could be reproduced in T. brucei-infected sheep without, however, killing the animals. Two other NSAIDs were also studied. Suprofen caused a rise in parasitaemia and 100% mortality when given to goats in the acute stage of T. vivax infection. Results with flunixin meglumine, when tested in T. brucei infected goats, were not conclusive.

Acute Disease↗
PubMed1980

Contribution of prostaglandins to the adenosine triphosphate-induced contraction of rabbit urinary bladder.

1 Adenosine 5'-triphosphate (ATP) produced an initial rapid, phasic contraction and a later, slowly developing tonic contraction in the isolated detrusor of the rabbit but mainly a rapid, phasic response in the guinea-pig bladder. 2 Electrical field stimulation elicited only a rapid, phasic contraction in both rabbit and guinea-pig bladders. 3 Prostaglandin synthesis inhibition by means of indomethacin and suprofen abolished the tonic response to ATP in the rabbit detrusor, leaving the phasic part of the contraction almost unaffected. The ATP-induced contraction in guinea-pig bladder was not influenced by indomethacin. 4 The contractile response of rabbit urinary bladder to prostaglandins F2 alpha and E2 and to carbachol were not significantly influenced by indomethacin. The contractions induced by the prostaglandins were similar to the tonic response to ATP. 5 Tetrodotoxin, atropine, phentolamine, and theophylline did not alter the ATP-induced contraction. However, the calcium antagonists, nifedipine and nimodipine, abolished the phasic ATP response and greatly reduced the tonic part of the contraction. 6 Tachyphylaxis occurred on repeated addition of ATP; the response to field stimulation was progressively reduced only after indomethacin pretreatment. 7 ATP and prostaglandins may contribute to the non-adrenergic, non-cholinergic component of the excitation of rabbit and guinea-pig bladder.

Adenosine Triphosphate↗
PubMed1993

Virus-induced airway hyperresponsiveness in the guinea-pig: possible involvement of histamine and inflammatory cells.

1. Guinea-pig tracheal contractions by histamine and by the cholinoceptor agonist, arecoline, are significantly enhanced (30% and 20%, respectively), 96 h after intra-tracheal inoculation with Parainfluenza-3 (PI-3) virus. 2. The airway hyperresponsiveness in animals inoculated with virus coincides with a significant increase in the number of broncho-alveolar cells (82%), and in the albumin concentration (121%) in lung lavage fluid, relative to values obtained in guinea-pigs challenged with control solution. 3. The chemiluminescence production by isolated broncho-alveolar cells, obtained from virus-infected guinea-pigs 96 h after inoculation stimulated with PI-3 virus in vitro, is significantly reduced by 42% relative to broncho-alveolar cells obtained from animals inoculated with control solution. This diminution was not specific for stimulation by PI-3 virus since the chemiluminescence production was also significantly reduced by 30% in response to zymosan. 4. Pretreatment of the guinea-pigs with the anti-allergic drugs, oxatomide (2.5 mg kg-1) or nedocromil (2.5 mg kg-1), or the specific H1-histamine receptor antagonist, levocabastine (0.25 mg kg-1), administered intra-peritoneally twice a day for five successive days, inhibits the virus-induced airway hyperresponsiveness, suppresses the influx of broncho-alveolar cells and increase in albumin content, and corrects the reduced chemiluminescence production by broncho-alveolar cells in response to zymosan. 5. In contrast, the cyclo-oxygenase inhibitor, suprofen (5.0 mg kg-1), the 5-HT2 receptor antagonist, ketanserin (0.63 mg kg-1), or the Ca2+ overload blocker, flunarizine (2.5 mg kg-1) do not modify the above mentioned processes. 6. The platelet-activating factor receptor antagonist, WEB 2170 (10 mg kg-1), reduces virus-induced airway hyperresponsiveness and influx of broncho-alveolar cells into the lungs but does not attenuate the increase of albumin in the bronchial lavage fluid. 7. Guinea-pigs nebulized with histamine, twice a day (30 min) during 4 successive days, do not demonstrate an increased airway responsiveness, but instead show tachyphylaxis in response to histamine in vitro. In addition, no influx of inflammatory cells is found in these animals. 8. These results suggest that histamine does not directly increase the responsiveness of the guinea-pig trachea; however, histamine may be involved in a cascade of events leading to airway hyperresponsiveness after a viral infection, a process that could be related to an influx and/or an activation of broncho-alveolar cells after PI-3 virus stimulation.

Aerosols↗
PubMed1981

Inhibition of adrenergic neuroeffector transmission in rabbit pulmonary artery and aorta by adenosine and adenine nucleotides.

The effect of adenosine and adenine nucleotides on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta was studied. Adenosine (10(-5)-3 x 10(-4)M) decreased the contractile response of pulmonary artery and aorta evoked by electrical-field stimulation. The decrease was reversible. No tachyphylaxis developed. Inhibition of either adenosine deaminase by deoxycoformycin (3.6 x 10(-6)M) or of adenosine transport by dilazep (3 x 10(-6)M) did not alter the inhibitory effect of adenosine on the neurogenic contractions in the pulmonary artery. However, deoxycoformycin plus dilazep markedly enhanced the inhibitory effect of adenosine. The calcium antagonists nifedipine (1.5 x 10(-8)M) and nimodipine (1.3 x 10(-8)M) had no effect on the adenosine-induced inhibition. This was also the case with theophylline (5 x 10(-5)M), atropine (10(-7)M), and the prostaglandin synthetase inhibitors indomethacin (5 x 10(-5)M and suprofen (3 x 10(-5)M). The contractile response of the pulmonary artery elicited by exogenous (-)-noradrenaline (NA; 10(-9)-3 x 10(-4)M) was essentially not altered by adenosine (10(-5)-3 x 10(-4)M). Adenosine (10(-4)M) did not alter the spontaneous 3H-outflow from rabbit aorta preloaded with 3H-(-)-noradrenaline (3H-NA). Adenosine (10(-5)-3 x 10(-4)M), ADP (10(-4)M), ATP (10(-5)M), and inosine (10(-4)M) diminished the overflow of tritium from pulmonary artery and aorta preloaded with 3H-NA. The spontaneous outflow of tritium from aorta preloaded with 3H-NA consisted of 3H-NA (17%), 3H-dihydroxyphenylglycol (3H-DOPEG; 30%), 3H-dihydroxymandelic acid (3H-DOMA, 4%), 3H-O-methylated and deaminated metabolites (3H-OMDA; 42%), and 3H-normethanephrine (3H-NMN; 2%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-DOPEG and 2H-NMN, decreased 3H-NA, and did not alter 3H-DOMA and 3H-OMDA. The stimulation-evoked overflow of tritium for aorta preloaded with 3H-NA consisted of 3H-NA (31%), 3H-DOPEG (18%), 3H-DOMA (2%), 3H-ONDA (46%), and 3H-NMN (3%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-NA and 3H-DOPEG, decreased 3H-OMDA and did not alter 3H-DOMA and 3H-NMN. Adeosine (10(-6)-10(-4)M) did not alter the accumulation of 3H-NA (10(-8)M) by aorta. It is concluded that adenosine inhibits vascular sympathetic neuroeffector transmission by diminishing the release of transmitter from the nerve terminals.

Adenine Nucleotides↗
PubMed1981

Dual effect of the muscarinic agonist McN-A-343 on vascular neuroeffector transmission.

The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10(-6) - 3 x 10(-5) M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10(-4) -3 x 10(-4)M) inhibited them. McN-A-343 (10(-4)M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 x 10(-5)M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10(-5) - 10(-4)M), hexamethonium (10(-5) M), atropine (3 x 10(-7) M), suprofen (10(-5) M), and 4-aminopyridine did not alter the effect of McN-A-343 (1-(-4)M). Cocaine (3 x 10(-5)M) and (+)-amphetamine (10(-5) M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 x 10(-5) M). Atropine (3 x 10(-7) M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10(-4) M) caused a partial and transitory reversal. On the aorta McN-A-343 (10(-4)M) did not alter the contractile concentration-response curve of (-)-noradrenaline (10(-9) - 3 x 10(-4)M), while that of serotonin (10(-8) - 3 x 10(-5)M) was moved to the right in a competitive manner. McN-A-343 (10(-4)M) did not alter the contractions evoked by noradrenaline (10(-7) M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10(-4)M) slightly antagonized the contractions caused by tyramine (10(-6) - 10(-3) M) and carbachol (10(-6) - 10(-3) M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMedDate not supplied

Topical nonsteroidal anti-inflammatory therapy in ophthalmology.

Topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management and prevention of ocular inflammation and cystoid macular edema related to cataract surgery and the maintenance of mydriasis during cataract surgery. Other common uses are the reduction of discomfort after refractive surgery or in allergic conjunctivitis. NSAIDs primarily act as cyclooxygenase inhibitors and thus reduce the formation of endogenous PGs. Today, several NSAIDs are commercially available: diclofenac, flurbiprofen, indomethacin, ketorolac and suprofen. At present the ophthalmologist has to make a decision between the use of topical corticosteroids, with their potential adverse effects, or of topical NSAIDs, with their possibly increased benefit, unknown effect on ocular pressure, wound healing and corneal tissue, higher costs and limited track record. However, the improvement of surgical techniques might support an increasing use of NSAIDs in the future. Preoperative anti-inflammatory treatment should be considered in eyes at a higher risk of developing severe postoperative inflammatory reactions. This decision has to be made carefully and has to be guided by the clinical circumstances, the spectrum of diagnosis and the individual benefit-risk ratio of each patient.

Administration, Topical↗