Intraoperative control of the state of the arrested heart

Monitoring the function of the operated on heart over time based on the principle of recording the effort of the myocardium at rest was tried under the clinical conditions after preliminary experiments on the hearts of rats and dogs. The study included 11 patients operated on for aortal, mitral and multi-valvular prosthetics under pharmacological cardioplegia. Such monitoring enables an objective appraisal of the heart status, Besides, it makes it possible to decide on whether repeated administration of cardioplegic solutions is required, to specify the times of reoxygenation and to prognose the pattern of the heart function recovery after operation is over. The data obtained helped detect some disadvantages of the generally accepted method of pharmacological cardioplegia.     

Efficacy of balneotherapy on pain, function and quality of life in patients with osteoarthritis of the knee

The aims of this study were to evaluate whether balneotherapy with mineral sulphate-bicarbonate-calcium water could determine substantial symptomatic improvement, and to detect any changes in the quality of life (QoL) of patients with symptomatic knee osteoarthritis (OA). This was a prospective randomized, single blind controlled trial. Sixty outpatients with primary bilateral knee OA, according to ACR criteria, were included in the study and randomized to one of two groups: group I (30 patients) was treated with a daily sulphate-bicarbonate-calcium mineral water bath; group II (30 patients), the control group, continued their regular outpatient care routine. At baseline, after 15 days and after 12 weeks, patients were evaluated by Visual Analogue Scale (VAS) for spontaneous pain, Lequesne and Womac Index for gonarthrosis, SF-36, Arthritis Impact Measurement Scale (AIMS) and symptomatic drugs consumption. We observed a significant improvement of all parameters at the end of the cycle of balneotherapy which persisted throughout the follow-up period, whereas in the control group no significant differences were noted. This symptomatic effect was confirmed by the significant reduction of symptomatic drugs consumption. The differences between the two groups were significant for all considered parameters already from the 15th day and persisted during follow-up. Tolerability of balneotherapy seemed to be good, with light and transitory side effects. Our results confirm that the beneficial effects of balneotherapy in patients with knee OA last over time, with positive effects on the painful symptomatology, a significant improvement on functional capacities and QoL. Balneotherapy can represent a useful backup to pharmacological treatment of knee OA or a valid alternative for patients who do not tolerate pharmacological treatments.     

Effets secondaires d’un stress par Régadénoson en scintigraphie myocardique chez les patients traités par Ticagrélor

IntroductionAs an anti-aggregant that has demonstrated its superiority in the management of acute coronary syndrome, Ticagrelor is an inhibitor of adenosine recapture by red blood cells. Regadenoson, an adenosine agonist, is a preferred cardiac pharmacological stress in patients with a history of spastic bronchopathy. A synergistic effect of both drugs is therefore theoretically expected if they are combined during myocardial scintigraphy. In 2015, European Association of Nuclear Medicine did not rule on the use of Regadenoson in patients previously treated with Ticagrelor. The objective of this work is to study the frequency of adverse events in these patients during Regadenoson stress.Materials and methodsWe retrospectively included patients who underwent a myocardial scintigraphy with pharmacological stress by Regadenoson between February 2016 and February 2019. We compared the frequency of expected side effects of Regadenoson in patients treated with Ticagrelor and not treated with Ticagrelor. The data were analysed using a logistic regression model including patient characteristics and side effects.ResultsSeventeen treated patients were included for 49 untreated patients. There was no significant difference in the frequency of each adverse event between treated and untreated patients. However, a higher number of side effects have been reported in treated patients than in untreated patients. No major adverse event was reported.ConclusionIn order to rule about the use of Regadenoson in patients treated with Ticagrelor, a larger study is needed to support the hypothesis of more noted minor side effects and which of them should be more encountered.     

Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.     

Effector modeling of the effect of ligands of GABA receptor complex. Modification of conformation states of the complex by combined administration of benzodiazepines and barbiturates

The dynamics of the anticonvulsive effect (antagonism to the pharmacological effects of korazol, bicuculline, and picrotoxin) of sodium barbital, phenazepam, diazepam and their structural analogues was studied at their individual and combined administration. The indices of the combined pharmacological effect of barbiturates and benzodiazepines are not the summation of the pharmacologic effects of the compounds. The mutual influence of the effects of exogenic ligands--convulsive agents and anticonvulsive compounds was studied which can be considered as a result of the hyperbolic modification of three states of the GABA-receptor complex.     

Zingiberis rhizoma: A comprehensive review on the ginger effect and efficacy profiles

Zingiberis rhizoma is used as a broadspectrum antiemetic. We, therefore, conducted a comprehensive review of the literature to summarize the pharmacological and clinical effects of this popular plant material. Although clinical and experimental studies suggest that ginger has some antiemetic properties, clinical evidence beyond doubt is only available for pregnancy-related nausea and vomiting. Meta-analyses could not demonstrate the postoperative antiemetic effectiveness, and effect in motion sickness or nausea/vomiting of other ethiology. It also remains to be confirmed that proprietary ginger preparations are clinically useful to alleviate osteoarthritic or other pain, although there is no doubt that ginger constituents interfere with the inflammatory cascade and the vanilloid nociceptor. Ginger exerts in vitro antioxidative, antitumorigenic and immunomodulatory effects and is an effective antimicrobial and antiviral agent. Animal studies demonstrate effects on the gastrointestinal tract, the cardiovascular system, on experimental pain and fever, antioxidative, antilipidemic and antitumor effects, as well as central and other effects. The most relevant human pharmacological studies require a confirmatory study to exclude interaction of ginger preparations with platelet aggregation. Pharmacokinetic data are only available for [6]-gingerol and zingiberene. Preclinical safety data do not rule out potential toxicity, which should be monitored especially following ginger consumption over longer periods.     

Neurotoxicity and other pharmacological activities of the snake venom phospholipase A2 OS2: the N-terminal region is more important than enzymatic activity

Several snake venom secreted phospholipases A2 (sPLA2s) including OS2 exert a variety of pharmacological effects ranging from central neurotoxicity to anti-HIV activity by mechanisms that are not yet fully understood. To conclusively address the role of enzymatic activity and map the key structural elements of OS2 responsible for its pharmacological properties, we have prepared single point OS2 mutants at the catalytic site and large chimeras between OS2 and OS1, a homologous but nontoxic sPLA2. Most importantly, we found that the enzymatic activity of the active site mutant H48Q is 500-fold lower than that of the wild-type protein, while central neurotoxicity is only 16-fold lower, providing convincing evidence that catalytic activity is at most a minor factor that determines central neurotoxicity. The chimera approach has identified the N-terminal region (residues 1-22) of OS2, but not the central one (residues 58-89), as crucial for both enzymatic activity and pharmacological effects. The C-terminal region of OS2 (residues 102-119) was found to be critical for enzymatic activity, but not for central neurotoxicity and anti-HIV activity, allowing us to further dissociate enzymatic activity and pharmacological effects. Finally, direct binding studies with the C-terminal chimera, which poorly binds to phospholipids while it is still neurotoxic, led to the identification of a subset of brain N-type receptors which may be directly involved in central neurotoxicity.     

Do pharmacological methods for the quantification of agonists work when the ternary complex mechanism operates?

It is well established that many receptors couple to G-proteins in order to subserve their pharmacological or physiological effects. In those systems it is possible that a ternary complex mechanism operates in which initiation of an effect depends on the concentration of agonist-receptor-G-protein complex formed. Such systems may be considered to obey a receptor-transducer model (Black & Leff, 1983, Proc. R. Soc. B220, 141). A theoretical analysis of this model is presented which seeks to determine how the operation of the ternary complex mechanism affects the quantification of agonists by conventional pharmacological methods. Previous analyses have concluded that pharmacological models may or may not accommodate the ternary complex mechanism depending upon the relationship between the relative concentrations of receptor and transducer units, [R0], and [T0] respectively. The present study extends these in two ways. It considers the impact of the ternary complex mechanism on agonist quantification under a more complete range of conditions relating [R0] and [T0], and it does so with regard to the analysis of partial agonists (by the comparative method) as well as of full agonists (by the method of receptor inactivation). The following predictions are made: (i) reliable estimates of affinity and efficacy can be made using the comparative method under the conditions [R0] much greater than [T0] and [R0] much less than [T0] whereas the inactivation method only works under the former condition; (ii) errors occur in the estimation of affinity and efficacy by both methods when [R0] = [T0] although better estimates are produced by the comparative method; (iii) when errors occur in the absolute estimation of affinity and efficacy, the orders of affinity and efficacy determined by the comparative method will generally be correct but this is not the case for the inactivation method; (iv) in general, the comparative method for agonist quantification appears to produce more reliable information for the purposes of receptor classification and medicinal chemistry than does the receptor inactivation method.     

TRPV6 and prostate cancer: cancer growth beyond the prostate correlates with increased TRPV6 Ca2+ channel expression

Life expectancy for patients suffering from prostate cancer is inversely correlated with the degree of extraprostatic metastasis. In order to find pharmacological tools to treat this aggressive growth it is important to define targets whose expression not only correlates with the malignancy of the cancerous cells, but that are also amenable to pharmacological intervention. In this review, we would like to focus on the potential role of a distinct class of ion channels that may be involved in this process.     

New insights for pelvic radiation disease treatment: Multipotent stromal cell is a promise mainstay treatment for the restoration of abdominopelvic severe chronic damages induced by radiotherapy

Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell (MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation. We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.     

Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver

Androgen and oestrogen receptors have been demonstrated in mammalian liver, but since it is generally accepted that they are probably non-functional at endogenous steroid concentrations, it is not apparent how they mediate physiological influences on this organ. Nor is it certain to what extent pharmacological actions of sex hormones reflect overstimulation of physiological routes or whether alternative mechanisms become available once threshold values have been reached. In this presentation an attempt has been made to answer some of these questions using data obtained from a study of the regulation of the activities of microsomal 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH) and 5 alpha-reductase in rat liver. Androgens exert their primary physiological and pharmacological influences at the level of the hypothalamus. Oestrogens can elicit three different types of effect-physiological, antiandrogenic and pharmacological--of which the first two involve primary effects on the pituitary. Hepatic oestrogen receptors only become activated when oestrogen concentrations reach pharmacological levels. Progestins probably have no physiological influence on the livers of non-pregnant rats. Their pharmacological actions may either be traced back to secondary androgenic (e.g. medroxyprogesterone acetate, levonorgestrel) or oestrogenic (e.g. norethynodrel, lynestrenol) properties, involving the routes described above, or to independent effects on the central nervous system (e.g. cyproterone acetate modulation of 5 alpha-reductase activity).     

经颅磁刺激:生理、心理、脑成像及其临床应用

非侵入性的经颅磁刺激 (TranscranialMagneticStimulation ,TMS)可以无痛地产生感应性电流来激活皮层 ,从而改变大脑内的生理过程。通过改变TMS的参数可以观测到不同的生理和心理效应。TMS对大脑的不同的调节方式体现在对感觉的调节、对认知功能和行为表现的促进或抑制上。TMS还可以与神经病学、精神病学和药理学研究相结合。无框架的TMS立体定位技术可以提高用于解剖定位的TMS以及用于指引脑外科手术的准确性。最后 ,中医针灸的理论也可以用于理解TMS在脑内调节作用的频率效应     

SCE in lymphocytes of patients treated with single, large doses of diazepam

When using the SCE test for evaluation of exposure in vivo to potential mutagens/carcinogens, it is necessary to consider possible confounding factors. In studies of possible mutagenic effects of pharmacological treatment the effect of concomitant administration of other agents such as sedatives may have to be considered. In order to assess whether diazepam per se influences SCE we have examined SCE in peripheral lymphocytes in 34 persons before and after oral administration of a single large dose of diazepam. 18 men and 16 women undergoing minor surgery of the hand received diazepam 0.2 mg kg-1 body weight orally on the day of operation, and venous blood samples were drawn on the day before the operation and again 2-5 h after the administration of diazepam. Both within cigarette smokers and non-smokers there was no statistically significant change of SCE following diazepam. It was concluded that there was no indication, from the SCE test, of an immediate mutagenic effect of a single large dose of diazepam and that such medication is not a confounding factor in studies by the SCE test.     

Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice

The pharmacological profiles of the endocannabinoid anandamide and exogenous cannabinoids (e.g., Delta9-tetrahydrocannabinol) are similar, but not exactly the same. One notable difference is that anandamide's in vivo effects in mice are not blocked by the brain cannabinoid (CB1) receptor antagonist SR141716A. The degree to which the rapid metabolism of anandamide to arachidonic acid might be involved in this unexpected lack of effect was the focus of this study. Mice were tested in a tetrad of tests sensitive to cannabinoids, consisting of spontaneous locomotion, ring immobility, rectal temperature and tail flick nociception. Anandamide and arachidonic acid produced a similar profile of effects, but neither drug was blocked by SR141716A. When hydrolysis of anandamide was inhibited by an amidase inhibitor (phenylmethyl sulfonyl fluoride; PMSF), however, SR141716A significantly attenuated anandamide's effects but did not completely block them. Similarly, the effects of the metabolically stable anandamide analog O-1812 were attenuated by SR141716A. The role of oxidative metabolism in anandamide's effects in the tetrad was also investigated through pharmacological modulation of cyclooxygenase and lipoxygenase, two major classes of enzymes that degrade arachidonic acid. Whereas the non-selective cyclooxygenase inhibitor ibuprofen blocked the in vivo effects of arachidonic acid, it did not alter anandamide's effects. Other modulators of the cyclooxygenase and lipoxygenase pathways also failed to block anandamide's effects. Together, these results offer partial support for a pharmacokinetic explanation of the failure of SR141716A to antagonize the effects of anandamide; however, they also suggest that non-CB1, non-CB2 receptors may be involved in mediation of anandamide's in vivo actions, particularly at higher doses.     

Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria

There is an emerging consensus that pharmacological opening of the mitochondrial ATP-sensitive K(+) (K(ATP)) channel protects the heart against ischemia-reperfusion damage; however, there are widely divergent views on the effects of openers on isolated heart mitochondria. We have examined the effects of diazoxide and pinacidil on the bioenergetic properties of rat heart mitochondria. As expected of hydrophobic compounds, these drugs have toxic, as well as pharmacological, effects on mitochondria. Both drugs inhibit respiration and increase membrane proton permeability as a function of concentration, causing a decrease in mitochondrial membrane potential and a consequent decrease in Ca(2+) uptake, but these effects are not caused by opening mitochondrial K(ATP) channels. In pharmacological doses (<50 microM), both drugs open mitochondrial K(ATP) channels, and resulting changes in membrane potential and respiration are minimal. The increased K(+) influx associated with mitochondrial K(ATP) channel opening is approximately 30 nmol. min(-1). mg(-1), a very low rate that will depolarize by only 1-2 mV. However, this increase in K(+) influx causes a significant increase in matrix volume. The volume increase is sufficient to reverse matrix contraction caused by oxidative phosphorylation and can be observed even when respiration is inhibited and the membrane potential is supported by ATP hydrolysis, conditions expected during ischemia. Thus opening mitochondrial K(ATP) channels has little direct effect on respiration, membrane potential, or Ca(2+) uptake but has important effects on matrix and intermembrane space volumes.     

利用微型生物指示评价污水处理厂运行的研究进展

目前基于理化指标和出水水质来调控污水处理厂运行工况存在一定滞后性,且建立的控制策略不利于系统长期稳定地运行.活性污泥工艺运行状态对微型生物的种群结构具有显著影响,可利用微型生物种群结构来指示和评价污水处理厂运行,且有利于建立面向种群优化的控制系统.在介绍微型生物分类、鉴定、计数的基础上详细阐述了微型生物种群结构与污水处理厂运行状态的相关性与内在联系,力求为今后利用微型生物种群结构特性来指示,评价污水处理厂的运行奠定基础.并对此方面的研究方向进行了展望.     

Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide

Arsenic trioxide induces differentiation and apoptosis of malignant cells in vitro and in vivo, but the mechanisms by which such effects occur have not been elucidated. In the present study we provide evidence that arsenic trioxide induces activation of the small G-protein Rac1 and the alpha and beta isoforms of the p38 mitogen-activated protein (MAP) kinase in several leukemia cell lines. Such activation of Rac1 and p38-isoforms results in downstream engagement of the MAP kinase-activated protein kinase-2 and is enhanced by pre-treatment of cells with ascorbic acid. Interestingly, pharmacological inhibition of p38 potentiates arsenic-dependent apoptosis and suppression of growth of leukemia cell lines, suggesting that this signaling cascade negatively regulates induction of antileukemic responses by arsenic trioxide. Consistent with this, overexpression of a dominant-negative p38 mutant (p38betaAGF) enhances the antiproliferative effects of arsenic trioxide on target cells. To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia. Arsenic trioxide suppressed the growth of leukemic myeloid (CFU-GM) progenitors from such patients, whereas concomitant pharmacological inhibition of the p38 pathway enhanced its growth-suppressive effects. Altogether, these data provide evidence for a novel function of the p38 MAP kinase pathway, acting as a negative regulator of arsenic trioxide-induced apoptosis and inhibition of malignant cell growth.     

Activation of the mitogen- and stress-activated kinase 1 by arsenic trioxide

Arsenic trioxide (As2O3) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As2O3 induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines. Such activation requires upstream engagement of p38 MAPK, as demonstrated by experiments using pharmacological inhibitors of p38 or p38alpha knock-out cells. Arsenic-induced apoptosis was enhanced in cells in which MSK1 expression was decreased using small interfering RNA and in Msk1 knock-out mouse embryonic fibroblasts, suggesting that this kinase is activated in a negative feedback regulatory manner to regulate As2O3 responses. Consistent with this, pharmacological inhibition of MSK1 enhanced the suppressive effects of As2O3 on the growth of primary leukemic progenitors from chronic myelogenous leukemia patients. Altogether, these findings indicate an important role for MSK1 downstream of p38 in the regulation of As2O3 responses.