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Biomedical subjects

P Mehta

Publications and source records attributed to P Mehta.

At least 181 records · Page 10Linked to original sources
PubMed1986

Calcium blocker diltiazem inhibits platelet activation and stimulates vascular prostacyclin synthesis.

The effects of slow channel calcium blocker diltiazem on platelet aggregation and on the generation of vasoactive prostanoids, thromboxane A2 and prostacyclin were examined. Diltiazem, in therapeutic concentrations (50-200 ng/ml), inhibited human platelet activation induced by cumulative subthreshold concentrations of calcium ionophore A 23187 plus ADP or epinephrine. However, platelet activation induced by cumulative effects of ADP plus epinephrine was inhibited by diltiazem only in very high concentrations (greater than 5 micrograms/ml). These data indicate that platelet aggregation mediated only through calcium flux is inhibited by diltiazem in therapeutic concentrations. In other experiments, diltiazem significantly potentiated prostacyclin release from human umbilical veins. These effects of diltiazem may contribute to efficacy of this compound in ischemic heart disease.

Benzazepines↗
PubMed1986

Antiemetics in children receiving cancer chemotherapy: a double-blind prospective randomized study comparing metoclopramide with chlorpromazine.

This is the first prospective randomized study comparing commonly used antiemetics in children receiving cancer chemotherapy. We compared metoclopramide (MCP) with chlorpromazine (CLP), both administered in conventional doses, in 50 cancer patients aged 6 to 18 years who were receiving emetic chemotherapy. CLP proved significantly better than MCP in reducing both the frequency of vomiting (P less than .05) and the duration of nausea and vomiting (P less than .025). Extrapyramidal reactions (EPRs) were more common in MCP-treated patients. We conclude that, in the standard doses used, CLP is a better overall antiemetic than MCP for children receiving intensive chemotherapy. However, further prospective pediatric studies of antiemetic combinations are needed.

Adolescent↗
PubMed1986

Cumulative effects of quinidine and aspirin on bleeding time and platelet alpha 2-adrenoceptors: potential mechanism of bleeding diathesis in patients receiving this combination.

We observed quinidine-induced prolongation of bleeding time without thrombocytopenia in three subjects. In addition, we noticed a cumulative prolongation of bleeding time by a combination of quinidine and aspirin. We postulated that because both quinidine and aspirin inhibit epinephrine-induced platelet aggregation, a cumulative effect of the two drugs might be responsible for the hemostatic defect. In studies using normal human platelets, we confirmed a marked reduction in epinephrine-induced platelet aggregation by the combination of these two agents. To further study the potential mechanism of this cumulative effect, platelet lysates were incubated with the alpha 2-adrenoceptor antagonist tritiated yohimbine in the presence of quinidine and aspirin. On the basis of the radioligand binding data, the dissociation constant (KD) of alpha 2-adrenoceptors was observed to increase in the presence of quinidine as well as aspirin. The combination of these two agents caused a marked increase in the KD of platelet alpha 2-adrenoceptors without alteration in the number of receptor sites. These data suggest that the cumulative effects of quinidine and aspirin on platelet alpha 2-adrenoceptor KD may relate to the significant reduction in epinephrine-induced platelet aggregation. This phenomenon, coupled with other well-known effects of aspirin on the platelet release reaction and arachidonate metabolism, may lead to bleeding problems in some patients receiving this combination.

Aspirin↗
PubMed1986

Polyamine stimulation of protein phosphatase-2A from rat liver using a non-protein phosphoester substrate.

The polyamines, spermine and spermidine, activate a high molecular weight form of phosphorylase a phosphatase isolated from rat liver. This broad specificity protein phosphatase (type 2A) was partially purified, using both protein and non-protein phosphoester substrates. Spermine and spermidine activated isolated protein phosphatase-2A1 (apparent Mr 210,000) approximately 2-fold, when p-nitrophenyl phosphate (PNPP) was used as substrate. Freeze-thawing, which activated the phosphatase activity against a variety of phosphoprotein substrates, also increased the extent of stimulation of PNPP phosphatase activity by spermine (8 to 9-fold with Ka of 93 microM) and spermidine (6 to 7-fold with Ka 280 microM). Kinetic analysis indicated that the activation of phosphatase by polyamines was accomplished by an increase in Vmax of the enzyme, by a mechanism independent of that achieved by other cations. The data indicate that polyamines, at physiological concentrations, can activate a form of protein phosphatase widely distributed in mammalian tissues, and thereby influence cellular protein phosphorylation.

Animals↗
PubMed1986

Effects of thromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation.

There is evidence that tumors may stimulate platelet aggregation, causing release of thromboxane A2. Thromboxane A2 may potentiate tumor metastasis by stimulating tumor cell growth and proliferation and by enhancing platelet-tumor cell aggregate formation. Despite potential significance of thromboxane A2 in tumor metastasis, agents which inhibit thromboxane A2 synthesis have not been uniformly effective in reducing tumor metastasis. We, therefore, evaluated the effects of a thromboxane A2 receptor antagonist SQ-29,548 compared to those of a thromboxane A2 synthetase inhibitor OKY-046 on osteogenic sarcoma-induced platelet aggregation and thromboxane A2 release. Osteogenic sarcoma cells added to platelet-rich plasma caused complete and irreversible platelet aggregation as well as thromboxane A2 release. Preincubation of platelet-rich plasma with SQ-29,548 (2 to 20 nM) decreased platelet aggregation induced by tumor cells, but it had no effect on thromboxane A2 release. In contrast, preincubation of platelet-rich plasma with OKY-046 (0.1 to 10 microM) had no effect on platelet aggregation despite a decrease in thromboxane A2 synthesis. These results suggest that thromboxane A2 receptor blockers, rather than synthetase inhibitors, may prevent tumor cell-induced platelet aggregation.

Blood Platelets↗
PubMed1985

Lack of efficacy of nafazatrom, a novel anti-thrombotic compound, in patients with coronary artery disease.

Nafazatrom (Bay G 6575) is a novel antithrombotic compound, which acts by stimulation of prostacyclin as well as by inhibition of lipoxygenase enzymes. To determine its effects on exercise performance in coronary artery disease patients, a double-blind study was conducted. Twenty patients with coronary artery disease underwent an exercise stress test before and 2 hours after administration of placebo or nafazatrom (1.2 gm). Before the drug administration, there was evidence of enhanced platelet activity, as reflected by elevated resting plasma beta thromboglobulin and thromboxane B2 concentrations. Plasma 6-keto-PGF1 alpha levels were undetectable in most patients. All coagulation tests were in the normal range. None of these parameters changed with exercise. Administration of placebo or nafazatrom before the exercise stress test did not significantly influence any of the coagulation or platelet function parameters or plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. This lack of effect was evident both at rest and upon exercise. Compared to placebo, nafazatrom did not significantly increase exercise tolerance time or exercise-induced symptoms. In conclusion, nafazatrom did not influence exercise performance in patients with coronary disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Prostacyclin and thromboxane A2 production by human cardiac atrial tissues.

We examined the generation of prostacyclin and thromboxane A2 in the right atrial tissues obtained from patients undergoing coronary bypass surgery. In all instances, the capability of atrial tissues to produce these potent prostaglandins was identified. The identity of prostacyclin and thromboxane A2 was confirmed by use of specific radioimmunoassays of stable metabolites and by use of specific thromboxane A2 synthetase and cyclo-oxygenase inhibitors.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Arachidonic acid and isolated human umbilical vein: concentration-limited prostacyclin generation and absence of direct toxic effects on endothelial integrity.

Previous studies show that administration of high doses of arachidonic acid to rabbits causes disruption of vascular integrity. To examine if similar changes would occur in isolated human vascular tissue, we treated human umbilical veins with arachidonic acid (0, 0.01, 0.1, 1.0 mM). Prostacyclin biosynthesis was quantitated in the supernatants and the endothelial integrity was evaluated by scanning electron microscopy. Prostacyclin synthesis was maximum at low concentrations (0.01-0.1 mM) with no additional increase with higher concentrations of arachidonic acid (1mM) confirming previous observations. There was no evidence for endothelial disruption with any concentration of arachidonic acid. This study shows that arachidonic acid has no direct effects on the vascular lining of isolated human umbilical vein, arachidonic acid-induced sudden death in experimental animals is not due to limitation of prostacyclin synthesis.

Arachidonic Acid↗
PubMed1985

Increase in human platelet alpha 2-adrenergic receptor affinity for agonist in unstable angina.

Spontaneous increase in platelet activity and change in coronary vasomotor tone have been implicated in the pathogenesis of acute myocardial ischemia. To define the mechanism of platelet "hypersensitivity" in acute myocardial ischemia, we examined the status of platelet alpha 2-adrenergic receptors in patients hospitalized with severe unstable angina. With the use of the specific alpha 2-receptor antagonist 3H-yohimbine, we identified a 26% decrease in the receptor binding sites on platelet membranes from patients with unstable angina compared with controls (155 +/- 32 vs. 210 +/- 29 fmol/mg protein, P less than or equal to 0.005). The dissociation constants of 3H-yohimbine binding to platelet alpha 2-receptors were similar in both groups (3.3 +/- 1.1 and 4.1 +/- 1.6 nmol/L, P not significant). To study the alterations in the affinity of platelet alpha 2-receptors for the agonists, effects of 1-epinephrine on specific binding of 3H-yohimbine were examined. We observed a marked reduction in 1-epinephrine concentration for inhibition of antagonist binding by 50% in acute myocardial ischemia (IC50: 4.2 +/- 3.9 X 10(-8) vs. 6.7 +/- 3.4 X 10(-7) mol/L, P less than or equal to 0.01), indicating increase in platelet alpha 2-receptor affinity for the agonist. Platelet aggregation and thromboxane A2 generation in response to epinephrine were also significantly increased in the acute phase of myocardial ischemia. This study suggests enhanced affinity of platelet alpha 2-receptors to the agonist 1-epinephrine as a possible mechanism of platelet hypersensitivity in acute myocardial ischemia.

Acute Disease↗
PubMed1985

Influence of selective thromboxane synthetase blocker CGS-13080 on thromboxane and prostacyclin biosynthesis in whole blood: evidence for synthesis of prostacyclin by leukocytes from platelet-derived endoperoxides.

Increase in thromboxane A2 (TXA2) generation has been proposed as a mechanism of dynamic vaso-occlusion and in vivo platelet thrombus formation. We have examined the effects of CGS-13080, an imidazole derivative, on rabbit and human TXA2-prostacyclin (PGI2) "balance." In rabbits given CGS-13080, serum levels of TXB2 (stable metabolite of TXA2) were inhibited 81% at 2 hours and 56% at 24 hours (both P less than or equal to 0.01). Collagen-induced platelet aggregation was inhibited at 2 hours after CGS-13080 administration. In contrast, serum levels of 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) increased 587% compared with control values at 2 hours (P less than or equal to 0.01). Platelet and white blood cell counts were not significantly altered. In human blood incubated in vitro with CGS-13080, serum TXB2 was completely inhibited, whereas PGI2 generation was stimulated (both P less than or equal to 0.001). In other experiments, we demonstrated uptake of platelet-generated cyclic endoperoxides by leukocytes and generation of PGI2 in the presence of CGS-13080 but not indomethacin. Thus, CGS-13080 inhibits TXA2 and stimulates PGI2 production in rabbit and human blood. Increase in PGI2 generation with TXA2 inhibition may be of potential benefit in conditions characterized by platelet hyperactivity.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Decreased platelet aggregation but increased thromboxane A2 generation in polycythemia vera.

Patients with polycythemia vera have been described to have hemorrhagic as well as thrombotic tendencies. In a patient with polycythemia vera and angina pectoris, we observed markedly decreased platelet aggregation response to epinephrine but increased platelet and whole-blood thromboxane A2 generation compared with normal subjects. Electron microscopy mostly showed partially activated forms of platelets, which may account for decreased aggregation response in vitro and hemorrhagic tendencies. Young and large platelets found in this disease, however, can generate large amounts of vasoconstrictor and platelet proaggregatory prostanoid thromboxane A2 in response to endogenous thrombin, which may be a basis for thrombotic tendencies.

Angina Pectoris↗