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At least 649 records · Page 36Linked to original sources
PubMed1986

Pharmacology of platelet inhibitors.

Although many drugs have inhibitory effects on platelet function, none of them inhibits all of the mechanisms that may be involved in the various forms of thrombosis. Choice of suitable drugs is hampered by lack of full knowledge concerning the reactions that make the major contributions to the formation of arterial thrombi at sites of repeated vessel wall injury or on atherosclerotic lesions. Drugs such as aspirin that inhibit the arachidonate pathway in platelets can only be expected to be effective against thromboembolic events in which the generation of thromboxane A2 plays a major part. If thrombin and fibrin formation are dominant, oral anticoagulant agents or heparin should be beneficial; thus, experimental evidence indicates that with repeated vessel wall injury, the formation of platelet fibrin thrombi on the vessel wall is probably influenced more by inhibitors of thrombin generation than by the subendothelial constituents such as collagen. Agents like prostacyclin that raise platelet cyclic adenosine monophosphate (AMP) levels in platelets by stimulating adenylate cyclase are potent inhibitors of the reaction of platelets to all aggregating and release-inducing stimuli, but these agents are not suitable for long-term administration. The effect of dipyridamole on platelet cyclic AMP levels is weak, and this drug may act through other effects on platelets or on other cells. Indeed, several of the drugs that have been tested in clinical trials may exert their effects through unrecognized mechanisms. Many combinations of drugs have been used to affect platelets or platelets and coagulation. This practice has been based on the theory that because several mechanisms may be involved in thrombus formation, combinations of drugs that inhibit different mechanisms may be beneficial.

Anti-Bacterial Agents↗
PubMed1996

Photodegradation of indo-1 and its effect on apparent Ca2+ concentrations.

BACKGROUND: Fluorescent indicators that show alterations in excitation and/or emission spectra in response to changes in [Ca2+] are widely used for quantitative cytosolic [Ca2+] measurements. There are several reports of changes in apparent [Ca2+] due only to illumination, however. These results have been attributed either to photodamage to the cells or to photodegradation of the indicator. Light-induced alteration in the behavior of the dye or cells would severely hamper the interpretation of experimental data. We examined this phenomenon in indo-1 loaded cells using confocal laser scanning microscopy. RESULTS: Illumination of indo-1 loaded GH3 cells leads to a decrease in apparent basal [Ca2+] and decreased peaks after depolarization with KCl. When cells were double loaded with indo-1 and fluo-3, the effect of UV illumination was noticed only with the former dye. UV irradiation of indo-1 in simple buffers caused overall photobleaching and conversion to a fluorescent but Ca2+-insensitive species. The latter effect cannot be canceled by ratiometric calibration and is due to loss of carboxymethyl groups from the anilino nitrogens. This photodegradation was inhibited by extracellular administration of 10 to 100 microM Trolox, a water-soluble vitamin E analog. CONCLUSIONS: Photodegradation processes like that observed for indo-1 are likely to be possible for all cation indicators that contain bis(carboxymethyl)anilino moieties, which include essentially all fluorescent indicators for Ca2+ and Mg2+ currently in biological use. If unrecognized, this photochemical dealkylation leads to an underestimation of the analyte concentrations depending on the intensity and duration of illumination. The problem can be avoided by including cell-permeant antioxidants such as Trolox in the bathing solution. The ultimate solution would be to redesign the indicators to minimize photodegradation in the absence of antioxidants.

Aniline Compounds↗
PubMed1988

Inhibitors of membrane transport system for organic anions block fura-2 excretion from PC12 and N2A cells.

The neuroblastoma-like cell line N2A and the pheochromocytoma-like cell line PC12 excrete about 20-25% of the intracellular fluorescent Ca2+ indicator fura-2 during 10 min of incubation at 37 degrees C. The drug probenecid, known to inhibit membrane systems for the transport of organic anions [Cunningham, Israili & Dayton (1981) Clin. Pharmacol. 6, 135-151], inhibited fura-2 excretion in both cell types. However, probenecid also had untoward effects on intracellular Ca2+ homeostasis in N2A and PC12 cells. We therefore tested the drug sulphinpyrazone, another known inhibitor of organic-anion transport systems. Sulphinpyrazone fully inhibited excretion of fura-2 at 250 microM, a concentration one order of magnitude lower than that of probenecid. At this concentration and for incubation times up to 20 min, sulphinpyrazone had no untoward effects on cell viability and metabolic functions. Fura-2 was also loaded into the cytoplasm of N2A cells by permeabilization of the plasma membrane with extracellular ATP. In this case as well, the dye was rapidly released from the cells and the efflux was blocked by sulphinpyrazone. These findings suggest that N2A and PC12 cells possess a membrane system for the transport of the free-acid form of fura-2. This transport system is probably responsible for the excretion of fura-2 from these cells. Incubation of N2A and PC12 cells with sulphinpyrazone may help overcome problems arising in the investigation of [Ca2+]i homeostasis in these cell types.

Animals↗
PubMed1998

Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells.

Two membrane glycoproteins acting as energy-dependent efflux pumps, mdr-encoded P-glycoprotein (P-gp) and the more recently described multidrug resistance-associated protein (MRP), are known to confer cellular resistance to many cytotoxic hydrophobic drugs. In the brain, P-gp has been shown to be expressed specifically in the capillary endothelial cells forming the blood-brain barrier, but localization of MRP has not been well characterized yet. Using RT-PCR and immunoblot analysis, we have compared the expression of P-gp and Mrp1 in homogenates, isolated capillaries, primary cultured endothelial cells, and RBE4 immortalized endothelial cells from rat brain. Whereas the mdr1a P-gp-encoding mRNA was specifically detected in brain microvessels and mdr1b mRNA in brain parenchyma, mrp1 mRNA was present both in microvessels and in parenchyma. However, Mrp1 was weakly expressed in microvessels. Mrp1 expression was higher in brain parenchyma, as well as in primary cultured brain endothelial cells and in immortalized RBE4 cells. This Mrp1 overexpression in cultured brain endothelial cells was less pronounced when the cells were cocultured with astrocytes. A low Mrp activity could be demonstrated in the endothelial cell primary monocultures, because the intracellular [3H]vincristine accumulation was increased by several MRP modulators. No Mrp activity was found in the cocultures or in the RBE4 cells. We suggest that in rat brain, Mrp1, unlike P-gp, is not predominantly expressed in the blood-brain barrier endothelial cells and that Mrp1 and the mdr1b P-gp isoform may be present in other cerebral cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Recent therapeutic advances in thrombotic thrombocytopenic purpura.

Whole plasma infusion, in our experience, has been highly effective in the management of patients with thrombotic thrombocytopenic purpura. The effectiveness of plasma infusion in the treatment of this severe disorder implies the deficiency of a factor in the patient's plasma. Furthermore, we have observed that when platelets are suspended in plasma obtained during active, untreated thrombotic purpura, aggregation occurs. This effect is neutralized by preincubation of the thrombotic thrombocytopenic purpura plasma with normal plasma. Thus, there is both a correlation with the clinical pathogenic mechanism, disseminated platelet aggregation, and with the therapeutic response to plasma infusion. Based upon our experience and the concept that thrombotic thrombocytopenic purpura is a plasma factor deficiency state, we recommend initial infusion of a full plasma volume equivalent over the first 24 hours. This should be done under an intensive care setting. After this initial plasma infusion, we advise the infusion of 3 units of plasma daily until a full remission is obtained. When the clinical situation has stabilized, we stop the daily plasma infusions and cautiously observe for recurrence of the manifestations of thrombotic thrombocytopenic purpura. If there is a recurrence, plasma is again infused in substantial quantity during the first 24 hours and then 3 units daily until a full remission is again evident. Whether the plasma requirement might be attenuated or the course of the disease shortened by the concomitant use of antiplatelet agents, corticosteroids or other means remains to be determined.

Adolescent↗