[The effect of phenobarbital and cimetidine on the elimination kinetics and distribution in the heart and liver of propranolol in rats with acute and chronic inflammations]. / Vliianie fenobarbitala i tsimetidina na kinetiku éliminatsii i raspredelenie v serdtse i pecheni propranolola u krys s ostrym i khronicheskim vospaleniem.

Intravenous administration of propranolol (10 mg/kg) to rats with turpentine-induced inflammation and adjuvant-induced arthritis results in the reduction of the systemic clearance (Cltot.p), volume distribution (Vd,ss) and free fraction (fu). At the same time the area under the pharmacokinetic curve (AUC) increases and the half-life period (t1/2 beta) remains the same. In the phenobarbital-treated rats with acute inflammation Cltot.p increases, AUC and t1/2 beta decreased. Administration of cimetidine resulted in the opposite effect. In rats with adjuvant arthritis phenobarbital and cimetidine administration did not affect the propranolol elimination kinetics. In the phenobarbital-treated rats with inflammation Vd,ss significantly decreased and virtually did not change in cimetidine treated rats. The fu of propranolol increased markedly after the cimetidine treatment in all rats with inflammation, whereas phenobarbital treatment appeared effective only in rats with acute inflammation. The tissue-to plasma concentration ratio (Kp) of propranolol decreased in the liver of rats both with acute and chronic inflammation, whereas in the heart the effect was observed only in rats with chronic inflammation. The tissue to plasma concentration ratio of unbound propranolol (Kpu) decreased only in the liver of rats with acute inflammation. In the phenobarbital-treated rats with adjuvant arthritis Kp of propranolol in the liver increased and in the heart decreased, whereas cimetidine-treatment did not change Kp of propranolol in heart and decreased it in the liver. The Kpu of propranolol decreased only in the heart of rats with acute inflammation after phenobarbital treatment, whereas after cimetidine administration this parameter decreased in the heart and in the liver of rats regardless of the character of inflammation.

[Age, sex, genetic and exogenous factors as determinants of plasma protein binding of drugs]. / Vozrastnye, polovye, geneticheskie i ékzogennye faktory kak determinanty sviazyvaniia lekarstvennykh veshchestv belkami plazmy krovi.

The data on relations of individual variations in the plasma protein binding of drugs to age, sex, genetic monitoring, and some environmental factors among which food and lifestyle (smoking, alcohol and coffee consumption, exercise, etc.) are of much importance. Individual variability in the plasma protein binding of drugs may be of great significance for pharmacokinetics and pharmacodynamics.

[The relationship between antipyrine kinetics, the seromucoid content and the xanthine oxidase activity in the plasma of rats with acute and chronic inflammation]. / Izuchenie sviazi mezhdu kinetikoi antipirina, soderzhaniem seromukoida i aktivnost'iu ksantinoksidazy v plazme krys s ostrym i khronicheskim vospaleniem.

The relationship between changes in seromucoid levels, xanthine oxidase activity in plasma, and drug metabolism in rats with turpentine-induced inflammation and adjuvant-induced arthritis was studied. For antipyrine, systemic clearance decreased, the volume distribution remained the same, and the half-life increased in turpentine- and adjuvant-treated rats. In both cases seromucoid level and xanthine oxidase activity in plasma increased. Treatment of rats with dexamehasone before turpentine-induced inflammation raised the level of seromucoid. However, dexamehasone treatment of rats with adjuvant disease significantly decreased the level of seromucoid. Moreover, dexamehasone administration did not significantly protect against the effects of inflammation on the hepatic microsomal drug-metabolizing enzyme system and activity of xanthine oxidase in plasma. Thus, pharmacokinetics of different drugs can significantly change in some types of inflammation in animals and humans, particularly by dexamehasone administration.

[Blood plasma proteins and drug transport across the hemato-encephalic barrier]. / Belki plazmy krovi i transport lekarstvennykh veshchestv cherez gematoéntsefalicheskii bar'er.

The blood-brain barrier being a dynamic membrane interface between the blood and the brain is of great importance for the formation of the pharmacokinetics and pharmacodynamics of neurotropic drugs. One of the main factors influencing diffusion of drugs into the central nervous system is the degree of their binding by plasma proteins. It was supposed that only the unbound fraction of drugs is pharmacologically active. However in some papers the plasma-protein-mediated transport into the rat brain of endogenous compounds and drugs was demonstrated. This indicates that the measuring of the free fraction of a drug in vitro can lead to the underestimation of its concentration in the target organ.

[The relationship between antipyrine kinetics and the change in the seromucoid content of rat plasma under the influence of the immunomodulator levamisole]. / Sviaz' mezhdu kinetikoi antipirina i izmeneniia soderzhaniia seromukoida v plazme krys pod vliianiem immunomoduliatora levamizola.

The relationship between levamisole-induced changes in seromucoid levels and drug metabolism was studied. In the single dose study rats received levamisole hydrochloride (25 mg/kg by gastric intubation 24 hours before antipyrine administration in a dose of 10 mg/rat intravenously). This resulted in a decrease of antipyrine clearance and an increase of half-life. In contrast, the multiple administrations (5 mg/kg for 2 days in a week for 3 weeks) had no significant effect on the pharmacokinetics of antipyrine. However, in both cases seromucoid levels were elevated. It is concluded that the research on the effect of levamisole on drug metabolism and drug binding to plasma proteins in man is needed.

[Endogenous metabolites as modulators of the transport of drugs by serum albumin]. / Endogennye metabolity kak moduliatory transporta lekarstvennykh veshchestv syvorotochnym al'buminom.

The ability of serum albumin to bind reversibly on its surface drugs and to transport them in the process of distribution and elimination has been well established. Some endogenous metabolites, particularly unesterified fatty acids, bile acids, L-tryptophan and bilirubin which are formed both under physiological conditions and in pathological states of the organism, e.g., in uremia can displace drugs from their areas of binding on albumin molecule. The detection of endogenous metabolites and the study of the mechanism through which they displace drugs from the specific areas on plasma proteins is the urgent task of pharmacology.

[Role of maternal and fetal plasma proteins in transplacental transport of drugs]. / Rol' belkov plazmy materi i ploda v transplatsentarnom perekhode lekarstvennykh veshchestv.

One of the factors influencing the rate of drug transport through the placenta is their binding by maternal and fetal plasma proteins. Concentrations of the components binding the drug on both sides of the placenta influence significantly its distribution in the fetomaternal pair. It is emphasized that in plasma of a fetus or newborn there is observed the free fraction increase for most drugs--beta-adrenoblockers, local anesthetics, narcotic analgesics, antiarrthythmic and antiepileptic agents. As for salicylates, diazepam and valproic acid, one can note their accumulation in the fetal blood during labour to which side effects often observed in newborns after treatment with these drugs may be related. Free fatty acids of plasma influence the binding of drugs by maternal and fetal plasma proteins. In the published clinical papers on the drug binding by proteins of plasma of the fetomaternal pairs the transport role, in addition to serum albumin and acid alpha 1-glycoproteid, of alpha 1-fetoprotein as well is not taken into consideration. The drug transport by this protein can account for the contradiction of views on the role of maternal and fetal plasma proteins in the transplacental transport of drugs.

[Effect of various factors on the absorption of dimedrol, diprazine (pipolphen) and suprastin on rat small intestine in vitro]. / Vliianie razlichnykh faktorov na vsasyvanie dimedrola, diprazina (pipol'fena) i suprastina iz tonkogo kishechnika krysy in vitro.

In the experiments on male albino rats absorption of dimedrol, pipolphen and suprastin from the small intestine was studied in vitro by the method of "turned sacks". It was shown that immunization of the animals with ovalbumin in combination with Freund's incomplete adjuvant does not influence significantly absorption of the antihistaminic agents in the rat small intestine in vitro. During anaphylactic shock absorption of pipolphen and to a lesser degree of suprastin tends to increase. The structure of the absorbing surface of the intestinal mucosal epithelium is of importance for absorption of dimedrol and to a lesser degree of pipolphen. Absorption of the antihistaminic agents in the rat small intestine in vitro depends on the activity of the drug metabolizing enzymes that especially distinctly shows up for pipolphen. Induction of the metabolizing enzymes by phenobarbital contributes to an active elimination of the agents from the incubation medium. Absorption of dimedrol and suprastin is implemented through an active transport whose energy supply for dimedrol is related to a greater extent to anaerobic processes of oxidation and for suprastin both to aerobic and anaerobic processes.

[Characteristics of dimedrol, pipolfen and suprastin absorption from the small intestine of rats in systemic anaphylactic shock]. / Osobennosti vsasyvaniia dimedrola, pipol'fena i suprastina iz tonkoi kishki krysy pri sistemnom anafilakticheskom shoke.

It was shown by the in situ method that absorption of dimedrol, pipolphen and suprastine from the small intestine of the rats immunized parenterally with ovalbumin against the background of intravenous administration of the resolving dose of ovalbumin significantly decreased in connection with the formation in the immunized rats of antiovalbumin antibodies. Administration of euphylline simultaneously with the resolving dose of ovalbumin to the immunized rats partially normalized absorbability of all three drugs.

[Dependence of the absorption through the human oral mucosa of antihistaminic (H1) preparations on their physicochemical properties]. / Zavisimost' vsasyvaniia cherez slizistuiu polosti rta cheloveka antigistaminnykh (H1) preparatov ot ikh fiziko-khimicheskikh svoistv.

Antihistaminic (H1) drugs pipolphen, suprastin and dimedrol are characterized according to absorption through human oral mucosa and distribution between phosphate buffer solution and organic solvents at various medium pH values. Their constants of ionization and coefficients of distribution in the n-octanol--phosphate buffer system, pH 7.4, as well as the bound fraction at the interaction of these drugs with human serum albumin were determined. The relationship between absorption through human oral mucosa of antihistaminic drugs and the hydrophobic character of their molecules and constants of ionization was found. An attempt was made to predict for them on the basis of the authors' own results and literature data possible pharmacokinetic and pharmacodynamic behavior in the organism.

[Action of antihistaminic agents in patients with various heart pathologies undergoing surgical treatment]. / Issledovanie deistviia protivogistaminnykh sredstv u bol'nykh s razlichnoi patologiei serdtsa pri khirurgicheskom lechenii.

Clinical observations and experimental studies enabled the authors to show that sensitivity of patients with rheumatic heart diseases to antihistaminic drugs is not always constant. It depends on pH value of the medium and blood concentration of calcium ions. It is advisable to include antihistaminic drugs in combination with colloid and crystalloid blood substitutes with regard to pH of the medium into the complex of agents for pre-, intra- and postoperative medication.

[Effect of histamine on dimedrol interaction with human serum albumin]. / Vliianie gistamina na vzaimodeistvie dimedrola s syvorotochnym al'buminom cheloveka.

It has been established by equilibrium dialysis and ultraviolet difference spectrophotometry that at pH 6.8 diphenhydramine interacts with human serum albumin more actively. It has been demonstrated that on the molecule of human serum albumin diphenhydramine interacts with two types of independent binding sites. The effects of pH and ionic strength of the medium, temperature, and cations on diphenhydramine binding with human serum albumin indicate that the drug is bound by hydrophobic interaction to the first type of the binding site and by van der Waals' forces to the second type of the binding site. Interaction of diphenhydramine with the second type of the binding site involves B conformation of human serum albumin. The presence of histamine increases diphenhydramine binding to human serum albumin via the second type of the binding site.

[Interaction of pipolfen and suprastin with human serum albumin depending on the pH of the medium and its calcium ion content]. / Vzaimodeistvie pipol'fena i suprastina s syvorotochnym al'buminom cheloveka v zavisimosti ot pH sredy i soderzhaniia v nei ionov kal'tsiia.

Experiments made with the use of equilibrium dialysis and differential spectrophotometry have shown that pipolfen and difenhydramine interact actively with human serum albumin at pH 6.8-7.4. Calcium ions have been demonstrated to activate the interaction of pipolphen and diphenhydramine with albumin.