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Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

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The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N' '-cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1, 4-dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K(+)-depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [(3)H](+)-isradipine and [(3)H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.

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Compound "C" which was synthesized in Institute of Organic Chemistry NA of Science unite in one molecule remnant of 4-aril-1,4-dihydropyridin kernek cause it as calcium channel block-up property and group of molecule pinacidil which determine if effect as activation potassium channels. This compound cause essential decrease arterial pressure and total periphery resistance of vessels. The decrease this figures of hemodynamic connect with reducing vessels tone. This is proved by substantial decrease contractile activity isolated strips of aorta and portal vein by compound "C". The mechanism reducing tone, as demonstrate investigations on isolated solitary smooth muscle mesenterial arteries, cause with increase potassium current, hyperpolarization of cell's membrane, and with depresses calcium current in L-type Ca(2+) channels.

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The papers summarizes the latest data on the pathogenesis of an inflammation reaction, with emphasis on the mechanism of action of antiinflammatory agents, including the drug regulation of the arachidonic acid cascade, and on the mechanisms of unassociated action on prostaglandins. It also discusses the prospects for using the existing antiphlogistics and the main trends in designing the new approaches to the pharmacological regulation of inflammation.

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The binding of sodium salicylate, sodium mefenamate, ortophen and piroxicam to membranes of erythrocyte ghosts and the effects of the drugs on the membrane microviscosity in carrageenan-induced inflammation were studied by the fluorescent probe method. It was shown that under inflammation the membrane microviscosity decreases and concurrently the affinity of the studied compounds to them increases. Antiphlogistics were found to enhance the membrane viscosity both in control and under inflammation. The possible mechanisms of the described effects of non-steroidal anti-inflammatory agents on biomembranes are discussed.

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In experiments on rats it was shown that ethonium pharmacokinetics at intragastric administration may be described within the framework of the two-compartment model with absorption. After administration ethonium cannot be directly absorbed although its absorption proceeds rapidly. The distribution between the central and peripheral compartments is slowed as well as the process of elimination from the blood flow.

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The action of nonsteroid antiinflammatory substances on the content in the inflammation focus of the inflammation reaction mediators, histamine, serotonin and kinines, and some aspects of their metabolism were studied. Sodium mephenaminate and butadion are shown to bring down the histamine content in the exudate of rats with experimental pleurisy. Sodium mephenaminate depresses the histamine synthesis (by inhibiting histidine decarboxylase in the pulmonary tissue), while butadion activates decomposition of this amine (by raising histaminase activity). All the study compounds (except sodium mephenaminate) force down the serotonin level in the exudate and inhibit 5-hydroxytryptophan decarboxylase. The content of kininogen in the exudate decreases only under the influence of butadion. Sodium mephenaminate and butadion mitigate the reaction of the dermal vessels to exogenous histamine and serotonin and chingamine does so only in response to histamine.

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The influence exerted by a number of non-steroid antiphlogistic agents on the fermentative mechanism responsible for the formation and decomposition of kininines in an inflammation focus and on the permeability of vessels in a skin changed under the effect of exogenous bradykininine was studied. Bradykininine, chigamin, sodium salicylate and mephenaminate are shown to inhibit "in vitro" the kininogenic and intensify the kininase activity of the exudate in rats with turpentine-induced pleuritis, while indometacin affects only the activity of kininogenases. Butadion, chingamin and sodium mephenaminate merely reduce the reactivity of the skin with respect to exogenous bradykininine.

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