Comparative studies of antiplatelet activity of nonsteroidal antiinflammatory drugs and new pyrazine CH- and NH-acids.

Nine known nonsteroidal antiinflammatory drugs (NSAID) and three new pyrazine derivatives possessing an active methylene moiety (pyrazine CH/NH-acids) were tested with regards to their in vitro and in vivo antiplatelet activity. Concentrations of the agents were determined which caused 25% and 50% inhibition of aggregation of human blood platelets induced by fixed concentrations of ADP, collagen and epinephrine. The in vivo test consisted in determination of percent protection of mice from pulmonary microembolism caused by injection of a mixture of collagen and epinephrine. The in vitro antiaggregatory activity of the agents studied was rather low, excepting the inhibition of the collagen-induced aggregation by ketoprofen. Several NSAID and two new pyrazine CH/NH-acids appeared highly potent antithrombotic agents in vivo. Activity of NSAID expressed as percent protection against lung thromboembolism in the mouse was demonstrated to depend quantitatively on acid properties of the agents. The new chemical class of pharmacologically active agents, pyrazine CH/NH-acids, offers an original pharmacophore which is distinctive from the carboxylic or enolic functionalities typical for the established NSAID, and as such, may be devoid of some disadvantages of known antiplatelet drugs.

Synthesis of new microsensor coatings and their response to vapors-III Arylphosphonic acids, salts and esters.

Phosphonic acids, phosphonate esters and cyclohexylammonium phosphonates, spray-coated onto surface acoustic wave (SAW) devices, were exposed to vapors of chloroethyl ethyl sulfide (CEES), dimethyl methylphosphonate (DMMP), and water. Changes in the resonance frequency of the device or the resistance of the coating were collected by computer-controlled data acquisition. Two of the esters showed major reversible and selective response to CEES, and one of the acids showed similar behavior with DMMP.

Studies on pyrazine derivatives. Part X. Synthesis and tuberculostatic activity of some 6-cyclamino-, 6-imidazolyl--and triazolylpyrazine-2-carboxylic acids derivatives.

The 6(2'-methylpiperidine-, 2',6'-dimethylmorpholino-, imidazolyl- and triazolyl)-2-cyanopyrazines were prepared from 2-cyano-6-chloropyrazine. The -CN group was then transformed into COOH, CONH2, CSNH2, CONHNH2, CONHOH and C(NOH)NH2 functions. All compounds obtained were of weak tuberculostatic activity. Comp. 13 was active against isoniazide, capreomycin and ethionamide resistent strains at the concentration range of 31.2--62.5 microgram/cm3.

Antithrombotic activity of a new pyrazine derivative determined by the mouse antithrombotic assay.

A model of pulmonary microembolization in the mouse induced by infusion of epinephrine and collagen was used to determine antithrombotic activity of indomethacin and acetylsalicylic acid and of two newly synthesized pyrazine derivatives. One of the new agents provided marked protection of mice from thrombotic challenge with epinephrine and collagen. Its effectiveness was higher than acetylsalicylic acid (especially at small doses) but smaller than that of indomethacin. The same compound was similar to acetylsalicyclic acid with respect to the inhibition of in vitro human blood platelet aggregation. The new class of pyrazine derivatives (the so-called pyrazine CH- and NH-acids) appears interesting from the view-point of the studies of platelet aggregation and may yield potential antithrombotic drugs.

Analgesic activity of new pyrazine CH and NH acids and their hydrophobic and electron donating properties.

Analgesic efficacy was determined by the hot plate method for a group of 17 new pyrazine and 3 non-pyrazine CH and NH acids. The biological data were quantitatively related to the hydrophobicity of the compounds, expressed by fragmental constant, and to the orbital energy of the highest occupied molecular orbital, calculated quantumchemically. It has been found that the higher the electron donating properties, the more active is the agent, provided that its hydrophobicity allows it to reach its site of action. The results obtained support the charge transfer model for the biological interaction of analgesic agents.

A comparison of bronchodilator responses to albuterol delivered by ultrasonic versus jet nebulization in moderate to severe asthma.

BACKGROUND: Nebulization of beta-agonists is preferred as a mode of treatment in moderate to severe asthma. Few studies, however, have compared its use in this population using an ultrasonic versus a jet nebulizer. OBJECTIVE: The purpose of the study was to compare bronchodilator responses to albuterol between an ultrasonic and a jet nebulizer in moderate to severe asthma. METHODS: Fifteen stable, moderately to severely asthmatic patients were randomized to receive the ultrasonic or jet nebulizer for 2 weeks. They were then crossed over for an additional 2 weeks. Albuterol was the agent used. The bronchodilator response was measured at baseline, and up to four hours after treatment with each nebulizer. Daily peak flows were then done for 2 weeks. RESULTS: The maximal percentage of increase in FEV1 at 30 minutes using the ultrasonic nebulizer was 39.9 +/- 8% (P < 0.001) versus 25.1 +/- 7.6% (P = .005) using the jet nebulizer. There were no other differences between the ultrasonic and the jet nebulizer in FEV1 or FVC during the 4-hour spirometry. During the home trial, the difference in evening PEFR between the jet nebulizer (69.05 +/- 14.9 L/min) and the ultrasonic nebulizer (90.11 +/- 18.7 L/min) was significant (P = .04). CONCLUSIONS: In summary, the ultrasonic and the jet nebulizer produced comparable bronchodilator responses to albuterol in stable moderately to severely asthmatic patients.

Pyrazine CH- and NH-acids. Antithrombotic activity and chromatographic behaviour.

1. A series of newly synthesized pyrazine CH- and NH-acids was subjected to analytical and pharmacological studies. 2. The compounds were chromatographed in HPLC systems employing three reversed-phase columns and methanol-buffer solvents of various composition at acidic, neutral and alkaline pH. 3. Chemometrical analysis by the principal component method allowed for ordering of the compounds on a plane determined by the first two principal component axes. 4. Pharmacological tests were done for representatives of the series of compounds. 5. An in vivo antithrombotic assay on mice proved diversified bioactivity within the group of agents. 6. Attempts were undertaken to relate chromatographic behaviour to antithrombotic activity. 7. Based on the results obtained, an approach was proposed to reduce the number of pharmacological tests in selecting the most promising agents.