A phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493), a folate receptor targeted chemotherapeutic agent in humans with advanced solid tumors.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

Novel mechanism for temperature-independent transitions in flexible molecules: role of thermodynamic fluctuations.

A novel physical mechanism is proposed to explain the temperature-independent transition reactions in molecular systems. The mechanism becomes effective in the case of conformation transitions between quasi-isoenergetic molecular states. It is shown that at room temperatures, stochastic broadening of molecular energy levels predominates the energy of low-frequency vibrations accompanying the transition. This leads to a cancellation of temperature dependence in the stochastically averaged rate constants. As an example, a physical interpretation of temperature-independent onset of P2X{3} receptor desensitization in neuronal membranes is provided.

P2X3 receptor gating near normal body temperature.

P2X3 purinoreceptors expressed in mammalian sensory neurons are involved in nociception, mechanosensory transduction, and temperature sensation. Homomeric P2X3 receptors desensitize rapidly (<500 ms after activation by an agonist) and recover from desensitization very slowly (20-25 min at room temperature). They are susceptible to use-dependent inhibition by low nanomolar concentrations of ATP through developing the "high-affinity binding site" (HABS), which traps ATP molecules, thus keeping receptors in a desensitized state (Pratt et al., J Neurosci 25:7359-7365, 2005). Indeed, here we demonstrated directly that the desensitization of the receptor, after being activated by ATP, proceeds independently of the presence of agonist. We found that the temperature sensitivity of P2X3 receptors is abnormal: development of desensitization does not depend on temperature within the range between 25 and 40 degrees C, whereas the recovery from desensitization is greatly \accelerated with temperature increase (Q10 approximately 10). The sensitivity of HABS to low nanomolar ATP near normal body temperature (35 degrees C) is substantially lower than at 25 degrees C (IC50 is 3.2+/-0.3 nM at 35 degrees C and 0.79+/-0.09 nM at 25 degrees C). HABS itself is subjected to slow desensitization partially loosing its sensitivity to ATP: at 35 degrees C the response completely recovers in 10 min in the presence of 3 nM ATP, making the receptor operational in the presence of up to 30 nM ATP. Unusual combination of temperature sensitivity/insensitivity of P2X3 receptors may be related to their pivotal role in the processing of thermal sensitivity as revealed by recent knockout experiments.

Barium dithionate as an EPR dosemeter.

Electron paramagnetic resonance (EPR) dosimetry is growing in popularity and this success has encouraged the search for other dosimetric materials. Previous studies of gamma-irradiated barium dithionate (BaS(2)O(6) x 2H(2)O) have shown promise for its use as a radiation dosemeter. This work studies in greater detail several essential attributes of the system. Special attention has been directed to the study of EPR response dependences on microwave power, irradiation temperature, minimum detectable dose and post-irradiation stability.

Bridge mediated two-electron transfer reactions: on the influence of intersite Coulomb interactions.

Donor-acceptor two-electron transfer (TET) mediated by a linear molecular bridge is described theoretically. The particular case is considered where the TET takes place in the presence of a strong electronic intersite coupling within the bridge and against the background of fast vibrational relaxation processes. For such a situation the coarse-grained description of bridge-assisted electron transfer in molecular systems can be utilized [Petrov et al., J. Phys. Chem. B 106, 3092 (2002)]. In the present case it leads to kinetic equations and rate expression for TET reactions. Our recent treatment of completely nonadiabtic TET reactions [Petrov et al., J. Chem. Phys. 120, 4441 (2004)] including a reduction to single-exponential kinetics (with overall transfer rate K(TET)) is generalized here to the case of strong intrabridge coupling and the presence of intersite Coulomb interactions. The dependence of K(TET) on the bridge length which is determined by a separate stepwise and concerted contribution is discussed in detail. It is found that the intersite Coulomb interaction favors the TET if the donor and the acceptor are uncharged in their completely reduced states (with two excess electrons present).

Two-electron transfer reactions in proteins: bridge-mediated and proton-assisted processes.

Nonadiabatic two-electron transfer (TET) reactions through donor-bridge-acceptor (DBA) systems is investigated within the approximation of fast vibrational relaxation. For TET reactions in which the population of bridging states remains small (less than 10(-2)) it is demonstrated that a multiexponential transition process reduces to three-state kinetics. The transfer starts at the state with two excess electrons at the D center (D(2-)BA), goes through the intermediate (transient) state with one electron at the D center and one at the A center (D-BA-), and ends up with the two electrons at the A center (DBA2-). Furthermore, if the population of the intermediate state becomes also small the two-exponential kinetics can be transformed with high accuracy to single-exponential D-A TET kinetics. The related overall transfer rate contains contributions from stepwise and from concerted TET. The latter process is determined by a specific two-electron superexchange coupling incorporating the bridging states (D-B-A and DB-A-) as well as the intermediate state (D-BA-). As an example, the reduction of micothione reductase by nicotinamide adenine dinucleotide phosphate is analyzed. Existing experimental data can be explained if one assumes that the proton-assisted reduction of the enzyme is realized by the concerted TET mechanism.

[A sociomedical portrait of tuberculosis control service workers]. / Mediko-sotsial'nyi portret rabotnikov protivotuberkuleznoi sluzhby.

The social and medical causes of occupational tuberculosis were analyzed by using the results of questionnaire surveys in 300 workers of tuberculosis controlling service. Low salaries, high working load, unbalanced nutrition, poor rehabilitation on vacation are the most important risk factors leading to high rates of both somatic and occupational morbidity in the staff of antituberculosis service.

Macrophage arachidonate release via both the cytosolic Ca(2+)-dependent and -independent phospholipases is necessary for cell spreading.

We have observed that phospholipase A2 (PLA2) activation and arachidonate (AA) release are essential for monocyte/macrophage adherence and spreading. In this study, we addressed the relationship between AA release and cell adherence/spreading in murine resident peritoneal macrophages, and the roles of specific PLA2S in these processes. The PLA2-specific inhibitors, (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL, specific for the Ca(2+)-independent PLA2 (iPLA2)) and methyl arachidonoyl fluorophosphonate (MAFP, specific for the Ca(2+)-dependent phospholipase (cPLA2)) inhibited AA release and cell spreading in a correlated fashion but only modestly decreased cell adherence. Cell spreading was normalized by the addition of AA to PLA2-inhibited cells. AA release during spreading was also inhibited by Ca2+ depletion or protein kinase C (PKC) inhibition, and was accompanied by increased (but transient) phosphorylation of cPLA2-Inhibition of macrophage spreading, however, only partially inhibited AA release. Moreover, constitutive AA release was seen in fully spread macrophages which was inhibited by BEL, but not MAFP or Ca2+ depletion. BEL also reversed the phenotype of fully spread cells. These data suggest that macrophage spreading requires the release of AA by the iPLA2 (which appears to be constitutively active) and cPLA2 (which appears to be stimulated by adherence/spreading). Maintenance of macrophage spreading, in contrast, appears to be principally dependent on the iPLA2.

[The attitude of health personnel and population toward the economic reform in public health system. (The results of a survey in Chelyabinsk)]. / Otnoshenie meditsinskikh rabotnikov i naseleniya r provedeniyu ekonomicheskoy reformy v zdravookhranenii. (Rezul'taty sotsiologicheskogo issledovaniya po Chelyabinsku.

Sociologic survey of the knowledge of the population and medical workers about the new economical relations in public health system, including medical insurance, showed that both the population and medics understand the necessity of public health reformation, introduction of new economic relations, and medical insurance. The major part of the population is ready to pay for medical service, but cannot afford it.

[The modelling of the cavitation processes during the focusing of the shock wave in an electrodynamic lithotriptor]. / Modelirovanie kavitatsionnykh protsessov pri fokusirovanii udarnoi volny v élektrodinamicheskom litotriptore.

The paper reports an experimental technique and the results obtained in the study of cavitation arising in focusing the shock wave of electrodynamic lithotriptor. The aim of the above study was to specify mechanisms of soft tissue lesions during destruction of nephroliths with lithotriptor impulses. Cavitation regions were found along the axis of the generator focusing system and at its outgoing sites as a result of the boundary expansion wave. This phenomenon by the body margin is attributed to transformation of a positive pressure impulse into the tension impulse. As the shock wave pressure impulse is much more significant than the pressure impulse of the boundary expansion wave it is most probable that cavitation-induced lesions appear at the site of the wave exit from the body.

The effect of permeant ions on single calcium channel activation in mouse neuroblastoma cells: ion-channel interaction.

1. Single low-threshold inactivating (LTI or T-type) Ca2+ channels of undifferentiated neuroblastoma cells (clone N1E-115) were investigated using the patch-clamp technique. 2. Single-channel conductance, gi, for Ca2+, Sr2+ or Ba2+ as a permeant cation was similar (7.2 pS). Mean channel open time, tau op, was also practically independent of the divalent ion species; it decreased from 0.7 to 0.3 ms between -40 and 0 mV. 3. Modification of the calcium channel selectivity by lowering the external Ca2+ concentration to 10(-8) M produced an increase in gi for Na+ and Li+ ions and a shift of potential-dependent characteristics in the hyperpolarizing direction. Voltage sensitivity and absolute values of tau op were also changed. These changes were dependent on both permeant monovalent ion type and concentration. 4. At high [Na+]o, tau op was almost potential independent (congruent to 0.3 ms). Decrease in [Na+]o and substitution of Li+ for Na+ increased tau op and the steepness of its potential dependency. 5. The divalent and monovalent cations that were tested had much smaller effect on the mean intraburst shut time, tau cl(f), which was nearly independent of membrane potential (congruent to 0.6 ms). By contrast, mean burst duration was strongly potential dependent and noticeably affected by permeant ion type. 6. All kinetic changes were analysed in terms of a four-state sequential model for channel activation. According to this model the channel enters the open state through three closed states. Transitions between closed states can be formally related to the transmembrane movement of two charged gating particles (m2 process). The interaction between ion flux and a sterical region of the Ca2+ channel selectivity filter may, depending on ion transfer rate and ionic radius, lead to a local increase of the dielectric constant, resulting in redistribution of the electric field and changes in potential dependency of tau op.

[Clinical research on the tolerance for and the interferon-inducing activity of amiksin]. / Klinicheskie issledovaniia perenosimosti i interferonindutsiruiushchei aktivnosti amiksina.

Tolerance and interferon-inducing activity of amixine, an interferon inducer, was studied by the double-blind method clinically in healthy volunteers given tableted amixine orally in doses of 0.125-0.25 g by different schedules. According to clinical laboratory examinations and studies of indirect parameters of labor capacity amixine was found to be tolerable for man. The amount of interferon in the blood serum depended on the schedule of administration of the inducer, the optimal being 1-2 amixine tablets at least 2 days apart.

The influence of dynamics of ionic channel protein on its selectivity function.

Computer simulation was applied for modelling the sodium channel selective filter. The geometric parameters, electrostatic interactions and channel protein polar group dynamics were studied with respect to their effect on permeability and selectivity function. The most important parameters were shown to be the filter width, electrical charge on the binding site and the dielectric constant. Appropriate selection of all three parameter values permitted a qualitative description of the experimentally obtained data on Na+ channel selectivity. The dynamics of the dipolar groups in the channel protein molecule were treated in terms of the Debye model of dipolar relaxations. The dynamics of the dipoles exerted the most significant effect on channel permeability and selectivity. It is shown that when the dynamics occur on a scale slower than that of the motion of ions, the channel will exhibit a low degree of permeability and its selectivity will be lost. The model predicts the appearance of an effect arising from the saturation of electric current with increasing concentration of the permeant ion species. The saturation current decreases at slower rates of dipolar relaxation. Therefore, the effective operation of ion channels requires the channel protein to be capable of undergoing rapid motion.

[The information value of clinico-hematologic criteria for the early diagnosis of acute radiation sickness in pig-tailed macaques]. / Informativnost' kliniko-gematologicheskikh kriteriev rannei diagnostiki ostroi luchevoi bolezni u obez'ian makakov-lapunderov.

Ten pig-tailed monkeys (Macaca nemestrina) were subjected to 60Co radiation at a dose of 6.0-6.5 Gy and a dose rate of 1.2 Gy/min. Acute radiation sickness has developed in the monkeys causing their death on the 16-20 day. In spite of this, the initial reaction was weakly expressed and according to its manifestation it was impossible to evaluate severity and possible outcome of the lesion. At an early stage of the disease (6-24 hours) insufficient was uranin fluorescence in blood plasma, but more informative were the changes in adhesive properties of leukocytes the dynamics of lymphocytes (lymphopenia), reticulocytes (reticulocytopenia) and shifts in reticulograms (increased per cent of juvenile forms).

Activation kinetics of single high-threshold calcium channels in the membrane of sensory neurons from mouse embryos.

Activation kinetics of single high-threshold inactivating (HTI or N-type) calcium channels of cultured dorsal root ganglion cells from mouse embryos was studied using a patch-clamp method. Calcium channels displayed bursting activity. The open-time histogram was single exponential with an almost potential-independent mean open time tau op = 1.2 msec. The closed-time histogram was multicomponent; at least three of the components were associated with the activation process. The "fast" exponential component with the potential-independent time constant tau fcl = 0.9 msec included all intraburst gaps, while two "slower" ones with potential-dependent time constants tau scl and tau vscl described shut times between bursts and between clusters of bursts. The burst length histogram was biexponential. The "fast" component with a relatively potential-independent time constant tau fbur = 0.6 msec described short, isolated channel openings while the "slow" component characterized real bursts with a potential-dependent mean life time. The waiting-time histogram could be fitted by a difference of two exponentials with time constants being the same as tau scl and tau vscl. The data obtained were described in the frame of a 4-state sequential model of calcium channel activation, in which the first two stages are formally attributed to potential-dependent transmembrane transfer of two charged gating particles accompanying the channel transitions between three closed states, and the third one to fast conformational changes in channel protein leading to the opening of the channel. The rate constants for all transitions were defined. The validity of the proposed model for both low-threshold inactivating (LTI or T-type) and high-threshold noninactivating (HTN or L-type) calcium channels is discussed.