[Pharmacokinetics and pharmacodynamics of verapamil in healthy volunteers after single oral and sublingual administration]. / Pharmakokinetik und Pharmakodynamik von Verapamil bei gesunden Versuchspersonen nach einmaliger oraler und sublingualer Applikation.

5-[3,4-Dimethoxyphenethyl)-methylamino]-2-(3,4-dimethoxyphenyl)-2- isopropylvaleronitril (verapamil, Isoptin) was administered p.o. (80 mg) and via the sublingual route (20 mg as the hydrochloride) in 6 healthy volunteers. After p.o. administration the mean peak serum concentration of 125.6 ng/ml was attained on average 80 min later. The half-life for the distribution phase (t1/2a) was 0.95 h and for the elimination phase (t1/2 beta) 6.08 h. After sublingual administration the mean peak serum concentration of verapamil was 26 ng/ml attained on average after 71.7 min. The mean t1/2a was 0.73 h and the mean T1/2 beta 4.39 h. There was an 18.4 min delay after oral administration and 0.8 min delay after sublingual administration before verapamil was detected in the serum. The relative bioavailability of verapamil sublingually was 2.7 (p.o. = 1.0). There were close correlations between the verapamil concentration in serum and the prolongation of the PQ-interval (0.725 sublingually; 0.853 p.o.). Approximately three times higher concentrations of verapamil were required when given by the oral route to produce the same prolongation of the PQ-interval obtained with sublingual administration. The variability of several important pharmacokinetic parameters of verapamil was reduced by sublingual application in comparison to the oral route. The coefficient of variation for the peak concentration, time to peak and t1/2 beta were 49.7%, 25.0% and 26.4%, respectively, after sublingual administration in comparison to 120.6%, 54.7% and 68.9%, respectively, when given p.o.

Arachidonic acid-induced chemiluminescence of human platelets: contribution of the prostaglandin and lipoxygenase pathways.

Two signals of chemiluminescence are observed when platelets are exposed to arachidonic acid in the presence of luminol. Three groups of agents interfere with these luminescence responses. Inhibitors of cyclooxygenase, known to augment the turnover of arachidonic acid by lipoxygenase, inhibit the first and enhance the second signal of luminescence. Sodium azide, diamide, NEM, and the endoperoxide analogues U 44069 and U 46619 interfere with the second luminescence signal but not with the first one nor with the generation of MDA. These agents may represent selective inhibitors of the lipoxygenase pathway. Phenidone, nordihydroguaiaretic acid, quercetin, silybin, phenylthiazolyl-thiourea, and aminotriazole inhibit both luminescence signals promoted by arachidonic acid. Measurement of luminescence may provide a tool to follow the time course of arachidonic-acid turnover by prostaglandin synthetase and lipoxygenase in whole cells.

Response of platelets exposed to potassium tetraperoxochromate, an extracellular source of singlet oxygen, hydroxyl radicals, superoxide anions and hydrogen-peroxide.

When potassium tetraperoxochromate (K3CrO8) is added to platelet suspension media it decomposes to the oxygen species hydrogen peroxide, superoxide radicals, hydroxyl radicals, and singlet oxygen. K3CrO8 induces a reversible shape change and aggregation of human platelets and, in the presence of Tris or sucrose, also the release of serotonin. Its effect on shape change and aggregation is due to the long-lived species hydrogen peroxide and is abolished by indomethacin and acetylsalicylic acid. Superoxide radicals, which are formed from K3CrO8 in HEPES-containing media do not evoke a platelet response. The release of serotonin depends on an interaction of hydroxyl radicals with Tris or sucrose and is associated with excessive formation of thiobarbituric acid-reactive material from platelets. Other scavengers of hydroxyl radicals such as mannitol, dimethylsulfoxide, EDTA or histidine prevent the release and the formation of thiobarbituric acid chromogen. Interaction of hydroxyl radicals with Tris or sucrose most likely results in the generation of short-lived intermediates which may act on platelets to produce thiobarbituric acid chromogen and to promote serotonin release. These effects on platelets are not inhibited by acetylsalicylic acid or indomethacin. Therefore the highly reactive hydroxyl radical and singlet oxygen, when generated extracellularly, do not mediate their effects via the enzyme-catalyzed prostaglandin pathway, in contrast to those evoked by the less reactive hydrogen peroxide.

Aggregation of activated platelets with Walker 256 carcinoma cells.

Walker 256 carcinoma cells form irreversible aggregates with rat platelets activated by ADP or serotonin. Since serotonin induces platelet shape change but not platelet aggregation the degree of activation indicated by the disc-sphere transformation is sufficient for platelets to interact with these tumor cells. This is confirmed by experiments with spheroid washed platelets which form irreversible mixed aggregates with Walker 256 carcinoma cells without a stimulus being required. This type of tumor cells could react with platelets in vivo, provided the platelets are activated by disturbed blood flow or contact with subendothelium. Our observations can explain why other authors found no interaction between Walker 256 carcinoma cells and non-activated platelets in vitro even though platelets contributed to the formation of bloodborne metastases of this tumor.

Superoxide-independent platelet response to xanthine oxidase.

Xanthine oxidase (1--5 microgram/ml) from cow's milk induces shape change, aggregation, and the release reaction of human washed platelets. Xanthine oxidase plus xanthine produce superoxide radicals, which reduce nitro blue tetrazolium. Superoxide dismutase, allopurinol, or ommission of xanthine inhibits the reduction of nitro blue tetrazolium but has no influence on the platelet response to xanthine oxidase. In contrast, small amounts of plasma or apyrase from potatoes abolish the effect on platelets, but not the enzyme activity of xanthine oxidase. Comparison of two xanthine oxidase preparations shows that higher specific enzyme activity corresponds to a lesser effect on platelets. The results suggest that platelet and enzyme activities reside in different components of xanthine oxidase preparations.