Search PubMed⌕ Search

Biomedical subjects

H Patscheke

Publications and source records attributed to H Patscheke.

At least 37 records · Page 2Linked to original sources
PubMed1992

Transport of anti-glycoprotein IIb/IIIa-antibodies into the alpha-granules of unstimulated human blood platelets.

The redistribution of the antibody-glycoprotein (GP) IIb/IIIa complex was investigated with the immuno-gold labeling technique in order to trace its transport in resting platelets. Washed platelets were incubated in the presence of aspirin and a prostacyclin analogue (iloprost) with three different monoclonal antibodies (Gi3, J15 and P2) against GPIIb/IIIa. The examination of ultrathin serial sections showed that the surface labeling was internalized into the surface connected membrane system (SCS). Labels were found within the alpha-granules after 40 min and the number of labels increased during longer incubation periods (max. 120 min). The transport possibly involved coated membranes. The alpha-granules were neither found to be altered during this process nor were any morphological signs of platelet activation detectable. The anti-GPIIb/IIIa complex remained membrane-associated during the transfer. These observations indicate that the membrane-GPIIb/IIIa complex was stable and transported from the surface into the alpha-granules of resting platelets. Since this transport was not influenced by iloprost or by aspirin it may be interpreted as constitutive endocytosis.

Antibodies, Monoclonal↗
PubMed1992

Regulation of the concentration of free arachidonic acid in homogenates of human platelets.

With the intention to study the regulation of the availability of free arachidonic acid through the enzymes of the Lands cycle, we established a model system in homogenates of human platelets. Phospholipase A2, arachidonoyl-CoA synthetase and lysophosphatidyl acyltransferase proved to be simultaneously active and a steady turnover of arachidonic acid was the consequence. EGTA suppressed the deacylating activity that acted on endogenous membrane phospholipids and prevented eicosanoid formation from previously esterified exogenous arachidonoyl-CoA. The reacylating enzymes took part in the control of eicosanoid biosynthesis by re-esterification of liberated arachidonic acid. Blockade of the reacylation by apyrase made arachidonic acid completely available for further metabolization into 12-HETE and thereby induced an increase in the eicosanoid release.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1991

Role of internalization in platelet activation induced by collagen fibers--differential effects of aspirin, cytochalasin D, and prostaglandin E1.

Washed human platelets were stimulated with fibrillar collagen and platelet aggregation was prevented by non-stirring conditions. In these samples, electron microscopy revealed three fractions of platelets: 1) a majority without contacts to the collagen fibers, 2) with focal contacts to collagen, and 3) a small fraction of platelets with internalized collagen. All platelets had undergone shape change, and exhibited an internal contraction and granule release. However, only those with internalized collagen were completely degranulated. The internalized collagen was found to be in close contact to the contractile sphere in the platelet center, as it was demonstrable with computer assisted 3-D reconstruction from serial sections. Aspirin inhibited neither the adhesion to collagen nor its internalization by internal contraction. Also it did not impair the shape change and degranulation in the platelet fractions that internalized collagen. However, aspirin blocked the shape change and internal contraction of the other platelets and inhibited the [3H]serotonin release. Cytochalasin D 0.1 microM also suppressed the internalization of collagen, the shape change, the formation of a contractile gel, the degranulation, and the [3H]serotonin release in all platelets, whereas the number of platelets that adhered to collagen remained unchanged. The same effects were produced by prostaglandin E1. If the platelets were stimulated with the TXA2 mimetic, U46619, cytochalasin D at 0.1 microM had no effect; but at 20 microM it strongly enhanced the degranulation and the [3H]serotonin release, although the platelets remained discoid. It is concluded that collagen triggers a focal activation of an adherent platelet at the site of its initial contact to collagen.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1990

Primary stimuli of icosanoid release inhibit arachidonoyl-CoA synthetase and lysophospholipid acyltransferase. Mechanism of action of hydrogen peroxide and methyl mercury in platelets.

Icosanoid formation in platelets depends on the concentration of free arachidonate that is mainly liberated from membrane phospholipids by phospholipase A2. The concentration of free arachidonate is also controlled by the activities of the reacylating enzymes arachidonoyl-CoA synthetase and lysophospholipid acyltransferase. In human platelet microsomes we determined the high enzyme activities of 5.9 nmol.min-1.(10(9) platelets)-1 for the arachidonoyl-CoA synthetase and 37 nmol.min-1.(10(9) platelets)-1 for the lysophospholipid acyltransferase. The activities of these reacylating enzymes were strongly reduced by hydrogen peroxide (H2O2) and methyl mercury that are primary stimuli of arachidonate release in intact platelets. H2O2 inhibited the arachidonoyl-CoA synthetase with an IC50 of 3.3 mmol/l without affecting the lysophospholipid acyltransferase. Sulfhydryl group protection by 3-mercapto-1,2-propanediol did not overcome the inhibition but glutathione prevented the inhibition of the arachidonoyl-CoA synthetase by H2O2. This suggests that glutathione by virtue of the glutathione peroxidase reduces H2O2 rather than that it protects free sulfhydryl groups of the arachidonoyl-CoA synthetase. Methyl mercury left the arachidonoyl-CoA synthetase activity unaffected but inhibited the lysophospholipid acyltransferase activity with an IC50 of 3.4 mumol/l. The inhibition is probably evoked by the blockade of sulfhydryl groups of the lysophospholipid acyltransferase because it disappeared when 3-mercapto-1,2-propanediol was added at a concentration higher than that of methyl mercury. Thrombin as a physiological full agonist, Ca2+ less than or equal to 1 mmol/l, the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (TPA) and 1-oleoyl-2-acetylglycerol as model stimuli of protein kinase C neither influenced arachidonoyl-CoA synthetase nor lysophospholipid acyltransferase. It is concluded that the inhibitory effect of H2O2 and methyl mercury on the arachidonate-reacylating enzymes arachidonoyl-CoA synthetase or lysophospholipid acyltransferase, respectively, are responsible for their capacity to stimulate icosanoid release in intact cells. Thrombin and its intracellular messengers Ca2+ and diacylglycerol do not directly affect arachidonoyl-CoA synthetase and lysophospholipid acyltransferase.

Acyltransferases↗
PubMed1990

The origin of the membrane convolute in degranulating platelets. A comparative study of normal and "gray" platelets.

Thrombin-stimulated normal platelets contain a membrane system of dilated channels with openings to the exterior. Whether these membranes originate from the surface connected system (SCS), the alpha-granules or internalized portions of the plasmalemma has not yet been defined. The present study traces in series of ultrathin sections the rearrangement of these membranes during shape change, degranulation and internalization of surface membranes in washed normal and "gray" platelets upon the stimulation with thrombin (1 IU/ml). Cationized ferritin (CF) was used as a surface marker in order to recognize internalized portions of the plasmalemma. Within the first seconds after stimulation, both normal and gray platelets changed their shape by extrusion of the SCS membranes. Simultaneously they started to internalize surface membrane and formed surface membrane invaginations closely attached to the outer rim of the cytoskeletal sphere which developed during the internal contraction. CF was internalized in these invaginations. CF was not observed within the system of dilated channels of stimulated platelets, however. Thrombin-stimulated gray platelets showed a markedly reduced number of dilated channels or none at all. This observation may be due to the fact "gray" platelets are deficient in alpha-granules. It is concluded that the dilated system of membranes in degranulated normal platelets originates from membranes of the alpha-granules which have performed compound exocytosis.

Blood Platelet Disorders↗
PubMed1990

Current concepts for a drug-induced inhibition of formation and action of thromboxane A2.

Urinary and plasma metabolites of thromboxane A2 (TxA2) indicate an increased TxA2 synthesis in a number of diseases, whereby TxA2 is assumed to contribute to the underlying pathomechanisms by its profound effects on platelet aggregation and smooth muscle contraction. In some clinical situations the increment in TxA2 biosynthesis is accompanied by an increased formation of prostacyclin (PGI2) which is one of the most potent inhibitors of platelet activation and smooth muscle contraction. Therefore, drugs are being developed which suppress the formation or action of TxA2 without interfering with its functional antagonist PGI2. Low doses of acetylsalicyclic acid (ASA) preferentially inhibit cyclooxygenase activity in platelets and the synthesis of TxA2 in vivo. However, neither low doses (approximately 300 mg/day) nor very low doses spare the formation of PGI2 completely. Despite its limited selectivity, very low dose ASA (approximately 40 mg/day) provides an attractive perspective in TxA2 pharmacology. Although thromboxane synthase inhibitors selectively suppress TxA2 biosynthesis PGH2 can accumulate instead of TxA2 and substitute for TxA2 at their common TxA2/PGH2 receptors. Thromboxane synthase inhibitors can only exert platelet-inhibiting and vasodilating effects if PGH2 rapidly isomerizes to functional antagonists like PGI2 that can be formed from platelet-derived PGH2 by the vessel wall. TxA2/PGH2 receptor antagonists provide a specific and effective approach for inhibition of TxA2. These inhibitors do not interfere with the synthesis of PGI2 and other prostanoids but prevent TxA2 and PGH2 from activating platelets and inducing smooth muscle contractions. Most of the available TxA2/PGH2 receptor antagonists produce a competitive antagonism that can be overcome by high agonist concentrations. Since in certain disease states very high local TxA2 concentrations are to be antagonized, non-competitive receptor antagonists may be of particular interest. Some recent TxA2/PGH2 receptor antagonists produce such a non-competitive type of inhibition due to their low dissociation rate constant. As a consequence, agonists like TxA2 or PGH2 only reach a hemiequilibrium state at their receptors, previously occupied by those antagonists. A combination of a thromboxane synthase inhibitor with a TxA2/PGH2 receptor antagonist presents a very high inhibitory potential that utilizes the dual activities of the synthase inhibitor to increase PGI2 formation and of the receptor antagonist to antagonize PGH2 and TxA2. Such combinations or dual inhibitors, combining both moieties in one compound, prolong the skin bleeding time to a greater extent than thromboxane synthase inhibitors and even more than low dose ASA or TxA2/PGH2 receptor antagonists.

Aspirin↗
PubMed1990

Ultrastructure of the interaction between human platelets and polymerizing fibrin within the first minutes of clot formation.

In the presence of fibrinogen, thrombin induces the aggregation of platelets, the formation of fibrin, and the retraction of the fibrin network. Since these phenomena are initiated in the first minutes after stimulation, the platelet-fibrin interaction in the early stages of clot formation was investigated. To avoid the formation of high fibrin masses, which may obstruct the morphological evaluation, suspensions of washed platelets were diluted with homologous platelet-poor plasma and stimulated with thrombin. The incubation was stopped by fixation after different times and the clots were studied in series of ultra-thin sections. Between 30 and 60 s after stimulation, polymerizing fibrin was found to be situated predominantly within the contact spaces in aggregates of degranulating platelets. Assembling fibres were seen also in plasmalemmal invaginations located in the close vicinity of the constricting contractile cytoskeleton. Between 5 and 10 min after stimulation, fibres with increasing thickness were observed between the platelets and were internalized into deep-surface invaginations, which remained attached to the outer rim of the contractile cytoskeleton. Surface areas without connection to the cytoskeleton revealed no binding or internalization of fibres. Clots obtained after addition of cytochalasin (36 microM) showed no retraction. Fibrin was found to be bound on the whole surface of discoid and degranulated platelets but no internalization occurred. These results suggest that the association of the clustered fibrin(ogen)-receptor complexes to the contractile cytoskeleton and the formation of a constricting sphere leads to the retraction of the clot by internalization of the fibres.

Adenosine Diphosphate↗
PubMed1990

Pathophysiological role of thromboxane A2 and pharmacological approaches to its inhibition.

The formation of the proischemic and prothrombotic thromboxane A2 (TXA2) and of its functional antagonist prostacyclin is increased in patients with unstable angina and myocardial infarction. Therefore, pharmacological interventions aim at an inhibition of the synthesis or action of TXA2 without interference with the desirable effects of prostacyclin. Clinical studies currently evaluate low-dose aspirin, thromboxane synthase inhibitors, TXA2/PGH2 receptor antagonists, and a combination of the latter two principles of action. The major advantages and disadvantages of these drugs are: 1. Aspirin irreversibly inhibits TXA2 and PGH2 synthesis in platelets, but also reduces the formation of the platelet-inhibiting PGD2 and prostacyclin--even under a low-dose regimen. 2. Thromboxane synthase inhibitors increase the formation of PGD2 and prostacyclin, but also enhance the accumulation of the potent platelet agonist PGH2. 3. Competitive TXA2/PGH2 receptor antagonists selectively inhibit the action of TXA2 and PGH2 and do not interfere with the eicosanoid metabolism, but their inhibitory effect can be overcome by very high local TXA2 or PGH2 concentrations. 4. Non-competitive TXA2/PGH2 receptor antagonists do not share this drawback. Therefore, they might combine the advantage of aspirin to exert an irreversible inhibition with the specificity of a TXA2/PGH2 receptor antagonist. However, these antagonists are in the stage of experimental studies. 5. The most potent of the clinically available principles of a platelet inhibition is the combination of a thromboxane synthase inhibitor with a competitive TXA2/PGH2 receptor antagonist. Agents that combine both principles of action in one compound are also under clinical investigation.

Angina, Unstable↗
PubMed1990

Thromboxane A2/prostaglandin H2 receptor antagonists. A new therapeutic principle.

Neither low- nor very-low-dose Aspirin suppresses thromboxane A2 biosynthesis without inhibiting the formation of its functional antagonist prostacyclin. Although thromboxane synthase inhibitors selectively inhibit thromboxane A2 biosynthesis and increase prostacyclin formation in vivo, thromboxane synthase inhibitors can lead to an accumulation of prostaglandin H2 that substitutes for thromboxane A2 at their common receptors in platelets and smooth muscle. In contrast to those inhibitors of thromboxane A2 biosynthesis, thromboxane A2/prostaglandin H2 receptor antagonists do not affect the synthesis of prostacyclin and other prostaglandins but prevent thromboxane A2 and prostaglandin H2 from activating platelets and inducing vasoconstriction. The available thromboxane A2/prostaglandin H2 receptor antagonists are competitive antagonists. However, some of them, such as daltroban, S-145, GR 32.191, and Bay U 3405, produce a noncompetitive antagonism in human platelets due to their low dissociation rate. As a consequence, agonists equilibrate with the antagonist-occupied receptor pool so slowly that they fail to induce platelet activation. This property of some antagonists strongly increases their potency and the duration of their inhibitory effect. Therefore, a low dissociation rate is an important measure of the effectiveness of a thromboxane A2/prostaglandin H2 receptor antagonist in addition to its receptor affinity. Another approach in thromboxane A2 pharmacology is a combination of thromboxane synthase inhibition with thromboxane receptor antagonism in one drug, such as ridogrel. Such dual inhibitors present a very high inhibitory potential and prolong the skin bleeding time to a greater extent than Aspirin, thromboxane synthase inhibitors, or thromboxane A2/prostaglandin H2 receptor antagonists.

Aspirin↗
PubMed1989

Hydrogen peroxide and methyl mercury are primary stimuli of eicosanoid release in human platelets.

Hydrogen peroxide (H2O2) and methyl mercury induced the liberation of arachidonate and its metabolites from human washed platelets. [14C]Eicosanoids were extracted from the supernatants of [14C] arachidonate-prelabelled platelets and analysed by thin layer chromatography and radioscanning. Thromboxane B2 (TXB2), 12(S)-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) were found as stable metabolites, together with unreacted arachidonate. In the presence of dazoxiben, a shift in eicosanoid metabolism was observed towards prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha), while in the presence of indomethacin there was a shift towards 12-HETE and unmetabolized arachidonate. The concentration pattern of those metabolites resembled that found with the physiological agonist, thrombin. H2O2 and methyl mercury also induced platelet shape change, aggregation and secretion. The EC50 values for the induction of shape change and aggregation were 27 and 850 mumol/l for H2O2 and 0.33 and 2.7 mumol/l for methyl mercury, respectively. The [3H]serotonin release required higher stimulus concentrations and amounted to 45% with 2 mumol/l H2O2 and to 16% with 3 mumol/l methyl mercury. These effects on platelet function were absent in platelets exposed to acetylsalicylic acid and prevented by indomethacin, the prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptor antagonist, daltroban, and the functional antagonist, iloprost. In contrast, none of these drugs suppressed the formation of [14C]eicosanoids, indicating that the platelet activation by H2O2 and methyl mercury essentially requires previous PGH2/TXA2 formation. As expected, the thromboxane synthase inhibitor, dazoxiben, did not prevent, but instead potentiated the activation by H2O2 and methyl mercury through accumulated PGH2.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acids↗
PubMed1989

Transient concentrations and agonist potency of PGH2 in platelet activation by endogenous arachidonate.

Human platelets were prelabelled with [14C]arachidonate and stimulated with thrombin or methyl mercury. [14C]PGH2 and the more stable of the other [14C]eicosanoids formed were rapidly extracted with organic solvent cooled to -30 degrees C and analyzed by radio-TLC. TXB2 and PGH2 were also quantified by radioimmunoassay, the latter as its index metabolite PGE2. PGH2 reached its peak concentration of 12 nmol/l after 20-30 s when it amounted to approximately 2/3 of the TXB2 concentration. In the presence of the thromboxane synthase inhibitor dazoxiben, PGH2 peaked after 60 s and afterwards declined in favour of PGE2, PGD2 and PGF2 alpha. Thirty seconds after stimulation with thrombin 1 IU/ml or methyl mercury 20 mumol/l, PGH2 amounted to 35 or 28% of the cyclooxygenase products in the absence and to 66 or 63% in the presence of dazoxiben, respectively. The platelet-activating potency of PGH2 was evaluated with purified PGH2 in platelets pretreated with acetylsalicylic acid. The EC50 values of PGH2 were 0.69 and 19 nmol/l for shape change and aggregation, respectively. U 46619 produced the same effects at 4.1 and 23 nmol/l. PGH2-induced [3H]serotonin release did not exceed 25%, whereas U 46619 was able to induce approximately 50% [3H]serotonin release. Dazoxiben enhanced the aggregation induced by PGH2. Human serum albumin inhibited the aggregating effect of PGH2, suppressed the enhancing effect of dazoxiben and shifted the metabolism of PGH2 to the inhibitory PGD2. The TXA2/PGH2 receptor antagonist daltroban suppressed the agonistic effects of endogenous or added PGH2, demonstrating that the TXA2/PGH2 receptor was its site of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1989

Prostaglandin H2 in human platelet activation: coactivator and substitute for thromboxane A2.

(1) When platelets form TXA2 from endogeneous AA, PGH2 reaches concentrations very similar to those of TXA2 and high enough to produce strong platelet activation. Therefore, platelet activation by TXA2 appears to go along with an activation by PGH2. (2) PGH2 is a more potent stimulus of platelet shape change and aggregation than U 46619. (3) The agonism of PGH2 is limited by the formation of inhibitory prostaglandins, especially PGD2 at higher concentrations. That is why thromboxane synthase inhibitors in PRP and at a physiological HSA concentration do not augment platelet activation. (4) HSA promotes the formation of inhibitory PGD2 at the expense of agonistic PGH2.

Blood Platelets↗
PubMed1988

Irreversible inhibition of the TXA2/PGH2 receptor of human platelets by a photoaffinity ligand.

In order to tag the TXA2/PGH2 receptor of human platelets, we synthesized azido-BSP (= 4-[2-(4-azido-benzenesulfonylamino)-ethyl]phenoxyacetic acid), a photolabile derivative of the specific TXA2/PGH2 receptor antagonist sulotroban (= BM 13.177). If protected from UV light, azido-BSP competitively inhibited the shape change of human washed platelets stimulated by the TXA2 mimetic U 46619. Schild analysis revealed a pA2 = 6.7 (apparent KD = 0.2 mumol/l). Irreversible inhibition of the U 46619-induced platelet activation was achieved by irradiating for 5 min with UV light of 254 nm a platelet suspension containing azido-BSP. After subsequent washing, the platelets were stimulated with U 46619, ADP or PAF. Under these conditions azido-BSP inhibited the shape change, aggregation and [3H]serotonin release induced by U 46619 but not the shape change induced by ADP or PAF. The concentrations of azido-BSP which blocked the U 46619-induced [3H]serotonin release and the aggregation were 0.5 mumol/l and 1.0 mumol/l, respectively, whereas even 50.0 mumol/l of azido-BSP only partially inhibited the U 46619-stimulated shape change. Obviously, increasing numbers of thromboxane receptors have to be blocked in order to inhibit the [3H]serotonin release, the aggregation and the shape change. Even at an azido-BSP concentration equal to 250 times the apparent dissociation constant, enough receptor sites remained active to allow U 46619 to induce the shape change. In sulotroban was added prior to irradiation, the blocking effect of azido-BSP decreased with increasing concentrations of sulotroban. These results show that azido-BSP is a specific and high affinity ligand of the TXA2/PGH2 receptor and that it covalently links to the receptor under irradiation. Azido-BSP is a new tool to identify and characterize the TXA2/PGH2 receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

The exocytosis of human blood platelets. A fast freezing and freeze-substitution analysis.

Human platelets were stimulated with thrombin or collagen in order to induce the release of alpha-granules and dense bodies. The platelets were cryofixed in various stages of exocytosis and subsequently cryosubstituted in acetone containing 4% osmium tetroxide. The platelets embedded in araldite were analyzed in serial sections. The initial changes of the alpha-granules were characterized by an impressive swelling and a dispersal of the granular matrix. Swollen alpha-granules in different stages of exocytosis formed contacts. Between the attached membranes of the alpha-granules electron-dense connections were sometimes observed. In a later stage, the membranes formed a pentalaminar structure (apposition), typical for the prefusion state. After apposition, sequential fusion of single alpha-granules took place and fusions of single or of compound granules with the plasmalemma were observed. The formation of a pore on the platelet surface allowed the passage of granular constituents to the exterior. The dense bodies extruded their electron-dense contents in a similar way after fusion with the plasmalemma but, compared with the alpha-granules, after less extensive swelling. These findings suggest that swelling of the secretory organelles plays an important role for granule fusion and platelet exocytosis. There is some evidence that the characteristic "internal contraction" of cytoskeletal structures in stimulated platelets is not the driving force of the platelet release reaction. An involvement of membranes of the surface connected system in the secretory pathway could not be ascertained.

Blood Platelets↗
PubMed1986

Single dose pharmacokinetics and effects on platelet function of the thromboxane receptor blocker BM 13.177.

The pharmacokinetics and pharmacodynamic effect on platelet activation of a single 800 mg oral dose of BM 13.177 have been investigated in 8 male volunteers. BM 13.177 disappeared from plasma with a terminal elimination half-life of 0.85 h. 52% of the dose was excreted unchanged in urine. Assuming complete absorption, total clearance was calculated to be 741.3 ml/min and renal clearance to range from 310.4 to 396.9 ml/min. The pharmacodynamic studies were performed ex vivo/in vitro in studies were performed ex vivo/in vitro in platelets stimulated either with methyl mercury chloride or with U 46619. Methyl mercury chloride is a platelet activator that requires TXA2 formation from endogenous arachidonic acid, whereas U 46619 is a stable PGH2 analogue and thromboxane mimetic at the platelet TXA2/PGH2 receptor. A close correlation between the plasma concentration-time profile of BM 13.177 and inhibition of platelet shape change or aggregation was demonstrated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

The pharmacokinetic and pharmacodynamic profiles of the thromboxane A-2 receptor blocker BM 13.177.

The pharmacokinetics and pharmacodynamics of BM 13.177 were investigated in eight healthy men who received a single oral dose of 800 mg on the first day and seven equal doses in 8-hour intervals on the second to fourth days. Pharmacodynamic effects were measured ex vivo by the testing of platelet functions such as shape change, aggregation, and [3H]serotonin release. The maximum serum concentration of 6.6 or 6.7 mg/L was achieved within 1.6 hours after the first dose and within 1.5 hours after multiple doses, respectively. Afterwards, BM 13.177 was eliminated in urine with a terminal elimination t1/2 of 0.84 or 1.0 hours after single and multiple dosing, respectively. The inhibition of platelet function showed the same close correlation with the serum concentrations of BM 13.177 after single and after multiple doses. Apparently, BM 13.177 induces neither refractoriness to BM 13.177 nor desensitization of the platelet thromboxane receptor. Because BM 13.177 was also well tolerated without subjective or objective side effects, this drug appears to be useful in evaluating the clinical benefit of thromboxane receptor blockade.

Adult↗