The effect of phytin, benzonal and their combination administered prophylactically on the pharmacodynamics of drugs metabolized in the liver in hypokinesia]

Hexenal, meprobamate, amidopyrine and ethylmorphine produced a significantly marked effect in animals under hypokinesia as compared with normal rats. When phytin, benzonal and their combination were used for preventive purposes, impaired pharmacodynamics of the tested drugs metabolizing in the liver disappeared. The investigations demonstrated that the preventive use of phytin in combination with benzonal is the most optimal in correcting the impairments of drug pharmacodynamics in hypokinesia.     

The liver monooxygenase system activity in the long-term compression syndrome and treatment with benzonal in prepubertal rats and rabbits

A compression syndrome was reproduced in rats and rabbits aged one month. Efficacy of the benzonal treatment in the postcompression period was evaluated by measuring the parameters of antipyrin pharmacokinetics, hexenal sleep duration, and the level of medium-molecular-weight (MMW) peptides in the blood serum. It was established that benzonal restored the detoxicating liver function (significantly reduced in animals with the compression syndrome) and eliminated the pronounced endotoxemia manifestations.     

Effect of phenobarbital, hexamidine and benzonal on the toxicity of dioxidine

It has been shown in experiments on rats that phenobarbital, hexamidine and benzonal administered in doses producing the induction of liver microsomal enzymes reduce the total toxic action of dioxydin and pathological alterations in the adrenals induced by dioxydin. A possible mechanism of the effect under consideration is discussed.     

Efficacy of enzyme-inducing agents in experimental tetrachloromethane poisoning

Liver monooxygenase system inductors benzonal, galonal, and galodif exceed phenobarbital and zixorin in therapeutic efficacy with respect to rats poisoned with tetrachloromethane. The former drugs increase the content and catalytic activity of cytochrome P-450, improve conjugation with reduced glutathione, prevent the cytolysis of hepatocytes, and stimulate the bile secretion and the liver excretion function.     

Effect of benzonal on the liver mono-oxygenase system of laboratory animals

The data are provided on benzonal as having the properties of the monoxygenase system inducer, evidenced by the shortening of hexenal sleep, increase of the intensity of the epr-signal of cytochrome P-450, activation of lipid peroxidation, carboxylesterase and arylesterase in the liver. The properties of benzonal described can be made use of for increasing the body resistance to the toxic action of xenobiotics.     

The advantages of benzonal as an inducer of the liver mono-oxygenase enzyme system compared to phenobarbital]

It is stated that phenobarbital used as the most potent inductor of the monoxygenase enzymic system of the liver in different pathologies has substantial side effects. In this connection the search of active inductive agents devoid of phenobarbital deficiencies is an important issue. Zixorene, a Hungarian drug developed to solve the problem, is weak as an inductor and has deficiencies of its own. A fitting substitute for phenobarbital is benzonal which is not inferior to phenobarbital in inductive activity but lacks its drawbacks. It is used both as a hypobilirubinemic agent and a drug restoring a disordered monohygenase system of the liver in different pathologies. Benhonal is metabolized in the gastrointestinal tract and the liver generating an active metabolite of phenobarbital. It is suggested that slow formation of phenobarbital in small quantities determines its more optimal interaction with the corresponding hepatic receptors resulting in the appearance of a marked inductive action while side effects are significantly decreased.     

Effect of anticonvulsant agents, inducers of microsomal oxidation, on the B-link of immunity and on the natural cytotoxicity of lymphoid organ cells in rats

Administration of phenobarbital, benzonal and benzobamil in a dose of 1/20 of LD50 to rats was shown to be followed by phase changes in the system of microsomal oxidation of the liver--activation in the first days after administration with the subsequent (in 1-3 months) decrease of the activity. The drugs activate the specific link of immunity directed at detoxication of the administered substances: increase the level of specific antibody-forming cells in the spleen and antibodies in the peripheral blood. Benzonal and bezobamil enhance the killing activity of cells of the thymus, phenobarbital and benzonal suppress the natural cytotoxicity of cells of the spleen and peritoneal exudate.     

Effect of benzonal on the absorptive-secretory function in the liver of immature rabbits in post-compression period of long-term compression syndrome

The absorptive-secretory function of hepatocytes using chromodiagnostic test by means of cardiogrin in rabbits at the age of 1 month in postcompression period of prolonged compression syndrome (PCS) was studied. It was established that the given function of hepatocytes was sufficiently and stably depressed for PCS. By effect of inductor of hepatocytes' monooxygenase system benzonal the disorders in parameters of cardiogreen pharmacokinetics are being distinctly removed. The velocity of blood stream in the liver was restored up to a level in health animals. It is supposed that an inclusion of benzonal into a complex of therapeutical remedies allows to enhance an effectiveness in PCS treatment during prepubescent period.     

抗炎免疫药物在消化系统的组织分布

综述了抗炎免疫药物在消化系统的组织分布,重点介绍其在肝脏、胃、肠等组织的分布.分析了其对消化系统药效学、药动学以及不良反应的影响.对进行抗炎免疫药物的临床疗效和安全性评价,指导抗炎免疫药物的合理应用具有一定意义.     

中国药典2010年版一部收载中药的药性特点研究

目的了解中国药典2010年版一部药材所收载中药的药性特点,为临床用药安全和中药研发提供参考。方法统计分析中国药典2010年版一部中药材和饮片,了解药典记载的中药材和饮片四气五味等,归纳其药性特点。结果药典一部所收载的683味中药,温性药有25．84％,苦味药有43．47％,入肝经有51．40％,有毒药物有14．35％。结论本文结合现代中药药理学和药效学等研究,提出用统计学方法系统分析中药药性理论的科学内涵,概括中药药性理论的共性,促进中药药性理论的完善。     

抗真菌药物非临床药效学研究技术指南

本文是抗菌药物(包括抗细菌药物、抗真菌药物、抗结核菌药物等)非临床研究技术指南系列文章之一,是由中国药理学会化疗药理专委会组织国内从事相关研究的专家编写而成。本文主要针对真菌生物学特点,介绍了抗真菌药物非临床研究中药效学之体外药效学研究、体内药效学研究、体内PK/PD研究、抗真菌作用机制研究等方面的技术要点,其中省略了体外药效学研究中与抗细菌药物类同的内容。期望能为抗真菌药物非临床药效学研究提供参考。     

Effects of liver disease on pharmacokinetics. An update

Liver disease can modify the kinetics of drugs biotransformed by the liver. This review updates recent developments in this field, with particular emphasis on cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharmacology. The information currently available on specific isoforms involved in drug metabolism has increased tremendously over the latest years, but knowledge remains incomplete. Studies on the effects of liver disease on specific isoenzymes of CYP have shown that some isoforms are more susceptible than others to liver disease. A detailed knowledge of the particular isoenzyme involved in the metabolism of a drug and the impact of liver disease on that enzyme can provide a rational basis for dosage adjustment in patients with hepatic impairment. The capacity of the liver to metabolise drugs depends on hepatic blood flow and liver enzyme activity, both of which can be affected by liver disease. In addition, liver failure can influence the binding of a drug to plasma proteins. These changes can occur alone or in combination; when they coexist their effect on drug kinetics is synergistic, not simply additive. The kinetics of drugs with a low hepatic extraction are sensitive to hepatic failure rather than to liver blood flow changes, but drugs having a significant first-pass effect are sensitive to alterations in hepatic blood flow. The drugs examined in this review are: cardiovascular agents (angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antagonists, ketanserin, antiarrhythmics and hypolipidaemics), diuretics (torasemide), psychoactive and anticonvulsant agents (benzodiazepines, flumazenil, antidepressants and tiagabine), antiemetics (metoclopramide and serotonin antagonists), antiulcers (acid pump inhibitors), anti-infectives and antiretroviral agents (grepafloxacin, ornidazole, pefloxacin, stavudine and zidovudine), immunosuppressants (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene. According to the available data, the kinetics of many drugs are altered by liver disease to an extent that requires dosage adjustment; the problem is to quantify the required changes. Obviously, this requires the evaluation of the degree of hepatic impairment. At present there is no satisfactory test that gives a quantitative measure of liver function and its impairment. A critical evaluation of these methods is provided. Guidelines providing a rational basis for dosage adjustment are illustrated. Finally, it is important to consider that liver disease not only affects pharmacokinetics but also pharmacodynamics. This review also examines drugs with altered pharmacodynamics.     

Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation.

P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of multidrug resistance in cancer, only recently has the role of P-gp expressed in normal tissues as a determinant of drug pharmacokinetics and pharmacodynamics been examined. P-glycoprotein is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues. Many marketed drugs inhibit P-gp function, and several compounds are under development as P-gp inhibitors. Similarly, numerous drugs can induce P-gp expression. While P-gp induction does not have a therapeutic role, P-gp inhibition is an attractive therapeutic approach to reverse multidrug resistance. Clinicians should recognize that P-gp induction or inhibition may have a substantial effect on the pharmacokinetics and pharmacodynamics of concomitantly administered drugs that are substrates for this transporter.     

Drug dosage in the elderly: dermatological drugs

Drug pharmacokinetics and pharmacodynamics may be altered in the elderly. An important contribution is made by decreased renal function, but biotransformation in the liver may also play a role. Commonly prescribed dermatological drugs such as methotrexate and cetirizine are likely to be eliminated more slowly in the elderly and potentially hepatotoxic drugs such as itraconazole and acitretin should be used with caution. Altered drug distribution as a result of body composition changes can lead to prolonged half-life or higher plasma concentrations of many drugs. Higher prevalence of adverse drug reactions and multidrug regimens, and large interindividual variability in drug response make drug dosage and administration in the elderly challenging. New immunobiological agents such as alefacept, efalizumab and etanercept, which are approved for treatment of psoriasis, seem to be as well tolerated in the elderly as in younger patients. A recommended approach when prescribing drugs to the elderly would be to start with a small initial dose and to reduce the number of drugs administered simultaneously. It is crucial to simplify the drug regimen as much as possible in order to enhance drug management in the elderly. To improve pharmacotherapy in the elderly, we review age-related changes in pharmacokinetics that are likely to play a role in dermatological practice.     

Antiarrhythmic properties of the anticonvulsant drug benzonal

In experiments on albino rats benzonal was found to exert an antiarrhythmic effect on models of chloride calcium-, aconitine- and strophantine-induced arrhythmias. In chloride calcium- and aconitine-induced arrhythmias its effect was qualitatively similar to that of diphenine, however it was inferior by the value of ED50 as compared with the latter. The advantage of benzonal over diphenine was its low toxicity.     

Drug interaction studies of therapeutic proteins or monoclonal antibodies

Drug interactions can alter the pharmacokinetics and/or pharmacodynamics of a drug. In pharmacokinetic drug interactions, the concentrations of 1 or more drugs are altered by another. This change in concentration in a given drug may be due to changes in absorption, distribution, metabolism, or elimination. The pharmacodynamic interaction can lead to additive, synergistic, or antagonistic effects of a drug. Drug interaction studies are regularly conducted with conventional drugs (small molecules), but very few drug interaction studies have been performed with macromolecules (therapeutic proteins or monoclonal antibodies). This is mainly because most macromolecules are not metabolized by the cytochrome P450 system, and their mechanism of elimination is complex. However, it has been shown in several studies that interferons can have an impact on the cytochrome P450 system that may alter the pharmacokinetics and pharmacodynamics of a conventional drug when given with interferons. Therefore, it is important to evaluate the effect of other classes of macromolecules (cytokines, interleukins, monoclonal antibodies) on drug-metabolizing enzymes. It is also imperative that the effects of conventional drugs on the pharmacokinetics and pharmacodynamics of macromolecules be conducted. The present review encompasses several drug interaction studies that were conducted with macromolecules and highlights the impact of these studies on the pharmacokinetics and/or pharmacodynamics of the involved drugs.     

Functional characterization of drug uptake and metabolism in the heart

INTRODUCTION: Evaluation of kinetics of uptake into the heart could be important for the efficacy and toxicity of cardioactive drugs. Although recent advances in molecular biology have identified cardiac uptake and efflux transporters as well as drug-metabolizing enzymes, little is known about their functional properties in situ. AREAS COVERED: The modeling of cardiac pharmacokinetics and pharmacodynamics (PK/PD) is overviewed with respect to experimental designs. Also covered is the role of myocardial uptake and binding processes for pharmacologic effect kinetics in relation to cardiac drugs. An update is given on the role of transport processes for the acute myocardial uptake of drugs and the impact on the time course of pharmacodynamic effects, as well as the interaction of drugs with CYP enzymes in myocytes. EXPERT OPINION: Depending on physicochemical properties, drugs are relatively rapidly taken up by the heart. It is important to realize that interstitial concentration is determinative when cardiac drugs act via cell membrane receptors. The role of uptake and efflux transporters in myocardial uptake of drugs is not yet clearly defined. Kinetic modeling of receptor-mediated pharmacodynamics may provide useful information on receptor binding and transduction processes. Inhibition or induction of cardiac CYP by drugs can cause changes in the metabolism of endogenous substances and thus influence cardiac function.     

围术期血容量变化对异丙酚代谢动力学影响的研究概况

血容量的变化不仅引起血流动力学的相应改变,也将导致机体内环境的变化,如血浆蛋白浓度的改变,这些变化都将影响药物在体内的转运和代谢,特别是高蛋白结合及高肝摄取药物,如异丙酚,从而影响药物疗效和（或）增加不良反应的发生。本文综述了近年来有关围术期血容量变化对异丙酚代谢影响的研究,以期有助于临床合理用药。     

Sex-related differences in the antinociceptive effect of some non-narcotic analgetics in rats: the role of biotransformation

Non-narcotic analgetics sodium diclofenac, indomethacin, naproxen, nimesulid, ketorolac, and celebrex (cytochrome P-450(2)c substrates) produce more pronounced and prolonged analgesic effect in pubertate female rats than in males. This can be related to the slower elimination of drugs from the female organism. The liver of females is characterized by a lower content of cytochrome P-450 and by less pronounced activity of amidopyrine-N-, indomethacin-O-, and naproxen-O-demethylase activity. No sex-related differences in pharmacodynamics were observed for meloxicam, and ethoricoxib, benzofurocaine, and amison, and acetylsalicylic acid, which are the substrates predominantly for CYP3A.     

抗抑郁药的药效学性别异质性研究进展

抑郁症存在高患病率、高致残率和高自杀率的特点,严重影响患者的生活质量。药物治疗为该病的首选治疗方式,在临床治疗过程中,抗抑郁药物的药效学存在着明显的性别差异,可能与男女之间的大脑结构、性格、激素水平存在差异有关,但具体原因和机制尚未有统一结论。本文对抗抑郁药物的药效学性别异质性及其产生原因进行综述。