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PubMedDate not supplied

Effects of gallium chloride on changes in action potentials and contraction in guinea pig ventricular muscle.

The electrophysiological effects of gallium chloride (Ga ) and its activity on arrhythmias induced by digitalis were investigated in guinea pig papillary muscle. KCl microelectrodes were used to record transmembrane electrical activity from Purkinje cells from the papillary muscle of guinea pig hearts during superfusion and electrical stimulation in vitro at 37 degrees C. Myocardial contractility was continuously monitored. Ga was superfused alone in cumulative concentrations(4.5 . 10(-5) to 3.6 . 10(-4) M). Arrhythmias were induced by a superfusion of Digitoxin (7.5 . 10 (-7) M). A superfusion of Ga (4.5 . 10(-5), 9 . 10(-5), 1.8 . 10(-4) M and 3.6 . 10(-4) M) was started 20 min later and maintained for 70 min. Ga alone produced a dose dependent reduction of action potential duration and contractility. Ga potentiated the decrease in the amplitude and duration of the action potential induced by Digitoxin. The incidence of arrhythmias was immediately reduced by two concentrations of Ga (4.5 . 10(-5) and 9 . 10(-5) M) in the digitalized papillary muscles. It is concluded that Ga inhibits calcium movements and has negative inotropic and antidysrhythmic effects.

Action Potentials↗
PubMed1997

[A specific antidote for the treatment of digitalis poisoning in uremic patients].

Two chronic haemodialyzed patients with digitalis intoxication are reported. One of them took digoxin 0.25 mg three times daily for an unknown period and the other took digitoxin 0.1 mg twice daily for two weeks. The symptoms of intoxication were mainly concealed by uremic syndrome. The diagnosis was established by noticed sinus bradycardia, first- and second-degree atrioventricular block in ECG and the determination of sera levels of glycosides (serum digoxin concentration was 7.36 ng/ml, serum digitoxin concentration was 46.5 ng/ml) in both cases. Considering the probable long elimination period of digitalis and the potentially life-threatening situation the patients were given digoxin-specific antibody (Fab) fragments with potassium replacement therapy. The symptoms disappeared within a few hours after therapy, side effects and rebound toxicity did not develop. In connection with these cases the aim of this report is to publish a method which can reverse the life-threatening digitalis intoxication in patients suffering from renal failure as well. As to the above method, the authors have not found any similar case reports in the Hungarian medical literature.

Aged↗
PubMed1984

Rifampin drug interactions.

Rifampin, an antituberculosis agent, is usually administered for nine to 12 months with other antituberculosis drugs or drugs from other classes. A potential for drug interactions often exists because this drug is a potent inducer of drug metabolism. Rifampin causes a proliferation of the smooth endoplasmic reticulum and an increase in the cytochrome P-450 content in the liver. Rifampin's enzyme-induction effect is selective; therefore, it is not always clear which agents will be affected. Studies and case reports have demonstrated that rifampin accelerates the metabolism of several drugs, including oral anticoagulants, oral contraceptives, glucocorticoids, digitoxin, quinidine, methadone, hypoglycemics, and barbiturates. Rifampin interacts with other agents, but further study is needed to demonstrate the clinical importance of these interactions. In addition to inducing drug-metabolizing enzymes, rifampin may cause alterations in absorption and hepatic uptake. Future investigations will probably identify new rifampin drug interactions.

Anticoagulants↗
PubMed2000

A novel high-pressure liquid-liquid extraction process for downstream processing in biotechnology: extraction of cardiac glycosides.

This investigation examines phase equilibrium phenomena that can be used to create two water-like solvents for liquid-liquid extraction in downstream processing in biotechnology: a completely miscible, binary liquid mixture of water and a hydrophilic organic solvent (e. g., an alcohol) reveals a liquid phase split, when it is pressurized with a "near-critical" gas (i.e., a substance which at ambient conditions is a gas, near its critical temperature). This phase split results in two hydrophilic liquid phases. Making use of this phenomenon in process development first requires research on the phase split phenomenon and, second, research on the feasibility of biomolecule extraction and separation. In this study, basic fluid phase equilibrium phenomena are briefly described. Then, experimental results are reported for the partitioning of small amounts of cardiac glycosides (digitoxin and digoxin) on coexisting liquid phases in the high-pressure, three-phase, vapor-liquid-liquid equilibrium of the ternary system of "near critical" CO(2) + water + 1-propanol, at 313 K and 333 K. Finally, a process for extraction and separation of the aforementioned glycosides by means of the high-pressure phase equilibrium phenomenon is discussed.

1-Propanol↗
PubMed1982

Transformation of 12-deoxycardenolids with Streptomyces purpurascens.

Streptomyces purpurascens transforms primary and secondary 12-deoxycardenolids into digoxin, 7 beta-hydroxy-digitoxin and 7 beta-hydroxy-digoxin, respectively. A metabolic pathway is proposed for cardenolid transformations and the enzymes participating in it are investigated. The substrate concentration in the medium can be increased by using a water-miscible solvent of electron donor character. The newly developed procedure yields 0.5 g/1(-1) of digoxin in a five-day fermentation.

Amidohydrolases↗
PubMed1975

Systems approach to study of solute transport across membranes using suspension cultures of mammalian cells V: Uptake and release kinetics of cardiac glycosides by Burkitt lymphoma cells.

Mass transport studies with three cardiac glycosides in the Burkitt lymphoma cell system have provided significant examples of the factorization and quantification of the influences of serum-drug binding, membrane-drug binding, cell interior binding, and intrinsic membrane permeability upon the uptake and release kinetics of drugs in living cell systems. All of the data from the glycosides are in agreement with the general physical model involving the rapid equilibration of the solute within the cell after permeation through the rate-determining plasma membrane barrier. The transport of digitoxin was influenced by membrane and serum binding and that of digoxin was influenced by membrane binding. There was no binding of ouabain to the plasma membrane and serum. The variables in the uptake and release kinetic studies at pH 7.3 included the use of viable and heat-inactivated cells, fetal bovine serum levels, and temperature.

Burkitt Lymphoma↗
PubMed2004

A new selective population transfer experiment using a double pulsed field gradient spin-echo.

A new pulse sequence is proposed for the determination of scalar coupling correlation in small- and medium-sized organic compounds. The method uses a combination of the double pulsed field gradient spin-echo (DPFGSE) and the selective population transfer (SPT) techniques and is shown to be useful in the analysis of complex spectra with many overlapped signals. The usefulness of this method in the structural elucidation of natural substances is demonstrated using strychnine and digitoxin as examples.

Digitoxin↗
PubMed2003

Acaricidal effects of cardiac glycosides, azadirachtin and neem oil against the camel tick, Hyalomma dromedarii (Acari: Ixodidae).

The cardiac glycoside, digitoxin, from Digitalis purpurea L (Scrophulariaceae), a cardiac glycosidal (cardenolide) extract from Calotropis procera (Ait) R Br (Asclepiadaceae), azadirachtin and neem oil from Azadirachta indica A Juss (Meliaceae) were tested for their effects against larvae and adult stages of the camel tick, Hyalomma dromedarii Koch (Acari: Ixodidae). The contact LC50 values of the first three materials against adults were 4.08, 9.63 and >40.7 microg cm(-2), respectively, whereas the dipping LC50 values of the four materials were 409.9, 1096, >5000 and >5000 mg litre(-1), respectively. Contact and dipping LC50 values of the extract and azadirachtin against larvae were 6.16, >20.3 microg cm(-2) and 587.7 and >2500 mg litre(-1), respectively. Azadirachtin had no effects on egg production or feeding of adults up to 5000 mg litre(-1); however at 2500 mg litre(-1), it caused significant reduction in feeding activity of larve, prolonged the period for moulting to nymphal stage, and caused 60% reduction in moultability. Results of the two cardiac glycoside materials are comparable with those of several commercial acaricides. The risks and benefits associated with the use of cardiac glycosides are considered.

Animals↗
PubMed2005

Electrospray ionization mass spectrometry as a tool for determination of drug binding sites to human serum albumin by noncovalent interaction.

Most proteins in blood plasma bind ligands. Human serum albumin (HSA) is the main transport protein with a very high capacity for binding of endogenous and exogenous compounds in plasma. Many pharmacokinetic properties of a drug depend on the level of binding to plasma proteins. This work reports studies of noncovalent interactions by means of nanoelectrospray ionization mass spectrometry (nanoESI-MS) for determination of the specific binding of selected drug candidates to HSA. Warfarin, iopanoic acid and digitoxin were chosen as site-specific probes that bind to the main sites of HSA. Two drug candidates and two known binders to HSA were analyzed using a competitive approach. The drugs were incubated with the target protein followed by addition of site-specific probes, one at a time. The drug candidates showed predominant affinity to site I (warfarin site). Naproxen and glyburide showed affinity to both sites I and II. The advantages of nanoESI-MS for these studies are the sensitivity, the absence of labeled molecules and the short method development time.

Binding Sites↗
PubMed1981

Uptake, accumulation and release of ouabain by isolated rat hepatocytes.

We investigated uptake of ouabain into isolated rat hepatocytes and release of ouabain from preloaded hepatocytes, thus assessing separately the two membrane transport steps, involved in biliary elimination of the drug. The following results were obtained: Uptake of ouabain was saturable (Km = 263 + 61 microM, V = 3.3 + 1.0 nmol/mgprot. x min), energy-dependent, sensitive to dinitrofluorobenzene and temperature-dependent (E = 80 - 96 kJ/mol). It had no pH-optimum in the physiological pH-range and was independent of the extracellular cation composition. Uptake of ouabain was competitively inhibited by the cardiac glycoside digitoxin (Ki = 0.3 microM). Uptake was not inhibited in the presence of the glycosidic sugar l-rhamnose, but it was competitively inhibited by the steroid taurocholate (Ki = 6.3 microM). Ouabain was accumulated within hepatocytes 170-fold. The predominant fraction of intracellular ouabain being unbound. Release of ouabain from preloaded cells was energy-independent, independent of the Na+-concentration and not susceptible to inhibition by dinitrofluorobenzene or taurocholate. It is concluded, first that hepatocellular uptake of ouabain is mediated by a carrier for steroids and second that the pathway of release is distinct from that of uptake. We assume, that the high bile/plasma concentration-gradient of ouabain in vivo is generated during active uptake into the cell and not during release into bile.

Animals↗
PubMed1979

The binding of gitoxin to human plasma proteins.

The binding of gitoxin, digitoxin and digoxin to human plasma proteins was measured by ultracentrifugation and equilibrium dialysis. At concentrations in the range of therapeutic plasma levels, protein binding amounted, respectively, to 85, 92 and 20%, the last two values being consistent with data reported in the literature. The affinity of purified human albumin was not significantly different for the three cardiac glycosides tested. No other protein than albumin was found to bind gitoxin in human plasma.

Blood Proteins↗
PubMed1990

Aminoglutethimide enzyme induction: pharmacological and endocrinological implications.

Aminoglutethimide is an aromatase inhibitor that is successfully used for endocrine treatment of advanced breast cancer. This drug also stimulates the activity of hepatic mixed-function oxidases, increasing the metabolism of several drugs, including warfarin, digitoxin, antipyrine and theophylline. It also increases the plasma clearance rate of oestrone sulphate. As this oestrogen may be an important substrate for tumour cells, stimulation of oestrone sulphate metabolism may be a component of the mechanism of action of aminoglutethimide.

Aminoglutethimide↗
PubMedDate not supplied

Effect of the position of the cyano-group of cyanopregnenolones on their drug metabolic inducing activity.

The effect of the position of the cyano-group of several cyanopregnenolones on the body's resistance to drugs and on drug metabolism was investigated. Female rats were pretreated with 2 alpha-, 6-, 16 alpha-, 17 alpha-cyano- or 16 alpha-cyanomethyl-pregnenolone or with pregnenolone, and the (in vivo) resistance to zoxazolamine, digitoxin and indomethacin, as well as the in vitro drug metabolism (post mitochondrial fraction) of zoxazolamine and ethylmorphine were determined. It was found that the 16-derivative was the most active in this respect, the 2- and 17-cyanopregnenolones were less active but significantly potent compared to controls, while the 6-cyano, the 16-cyanomethyl derivatives and pregnenolone were essentially inactive. These differences were explained in terms of an effective or poor fit of the steroids to their receptor. The poor performance of pregnenolone-16 alpha-acetonitrile was attributed to electronic effects. A hypothesis of some structural features of the receptor site for its interaction with the cyanopregnenolone inducers was presented.

Acetonitriles↗
PubMed1975

Digitalis toxicity: epidemiology and clinical use of serum concentration measurements.

Despite continuing advances in understanding of the basic pharmacology of the cardiac glycosides, digitalis intoxication remains a common clinical problem. Physician education programs and increasing use of serum or plasma concentration data have, however, been shown to be capable of substantially reducing the incidence of digitalis toxicity. Methodologic progress and availability of commercial radioimmunoassay kits have placed measurement of clinically relevant serum or plasma cardiac glycoside concentrations within the capability of most well equipped clinical laboratories. Extensive experience with serum digitalis levels now provides a basis for ongoing examination of the role of these measurements in clinical practice. Results of studies to date demonstrate that mean serum digoxin and digitoxin levels are significantly higher in patients with electrocardiographic evidence of toxicity compared with patients without such evidence. It must be emphasized, however, that because of overlap in serum digitalis levels between these two groups, sole dependence on these levels for established of a diagnosis of digitalis toxicity is not warranted. Multiple factors influence individual responses to cardiac glycosides, and serum concentration data must be interpreted in the over-all clinical context. Type and extent of underlying heart disease are important determinants of the clinical response to any given dose or concentration of cardiac glycoside. Knowledge of the serum digitalis concentration is likely to be helpful in the setting of suspected digitalis intoxication in the absence of an adequate history, or in the presence of fluctuating renal function, overt or suspected malabsorption, or uncertain bioavailability. More generally, such measurements may prove useful whenever an unanticipated response to digitalis is encountered, whether it be suspected toxicity or the absence of an expected therapeutic effect.

Creatinine↗
PubMed1977

Control of brain slice respiration by (Na+ + K+)-activated adenosine triphosphate and the effects of enzyme inhibitors.

The involvement of membrane (Na+ + K+)-ATPase (Mg2+-dependent, (Na+ + K+)-activated ATP phosphohydrolase, E.C. 3.6.1.3) in the oxygen consumption of rat brain cortical slices was studied in order to determine whether (Na+ + K+)-ATPase activity in intact cells can be estimated from oxygen consumption. The stimulation of brain slice respiration with K+ required the simultaneous presence of Na+. Ouabain, a specific inhibitor of (Na+ + K+)-ATPase, significantly inhibited the (Na+ + K+)-stimulation of respiration. These observations suggest that the (Na+ + K+)-stimulation of brain slice respiration is related to ADP production as a result of (Na+ + K+)-ATPase activity. However, ouabain also inhibited non-K+ -stimulated respiration. Additionally, ouabain markedly reduced the stimulation of respiration by 2,4-dinitrophenol in a high (Na+ + K+)-medium. Thus, ouabain depresses brain slice respiration by reducing the availability of ADP through (Na+ + K+)-ATPase inhibition and acts additionally by increasing the intracellular Na+ concentration. These studies indicate that the use of ouabain results in an over-estimation of the respiration related to (Na+ + K+)-ATPase activity. This fraction of the respiration can be estimated more precisely from the difference between slice respiration in high Na+ and K+ media and that in choline, K+ media. Studies were performed with two (Na+ + K+)-ATPase inhibitors to determine whether administration of these agents to intact rats would produce changes in brain respiration and (Na+ + K+)-ATPase activity. The intraperitoneal injection of digitoxin in rats caused an inhibition of brain (Na+ + K+)-ATPase and related respiration, but chlorpromazine failed to alter either (Na+ + K+)-ATPase activity or related respiration.

Adenosine Triphosphatases↗
PubMed1985

Interaction of cardiodigin, endogenous inhibitor of Na+,K+-ATPase, with antidigoxin and antidigitoxin antibodies.

The present study was undertaken to further characterize the immunoreactivity of cardiodigin, digitalis-like factor present in mammalian tissues. Guinea-pig heart extracts purified by reverse-phase low pressure and high pressure liquid chromatographies were analysed for their cross-reactivity with antidigitoxin and antidigoxin antibodies. The putative digitalis-like factor showed an affinity about 10 times higher for antidigoxin antibodies than for antidigitoxin antibodies. EC50 ratios (digoxin/digitoxin assay) determined at two purification steps were different from those of digoxin and digitoxin. These results show that cardiodigin presents molecular determinants recognizable by antidigoxin and antidigitoxin antibodies but that it is a chemical entity different from these well known cardioactive steroids.

Animals↗
PubMed1987

Human cell mutants affected in the interaction of the 12 beta-OH group of cardiac glycosides with the digitalis receptor.

The cross-resistance patterns of two different types of mutants of HeLa cells selected for resistance to the digoxin analog SC4453 (SCR mutants) in which the Na+/K+-ATPase is affected [A. Chopra and R. S. Gupta, J. biol. Chem. 261, 2034 (1986)], and towards numerous cardiac glycosides (CGs) and genins, were examined. One type of SCR mutant (designated as group C) was highly resistant to all CGs and genins investigated. In contrast, the other type of SCR mutant (group D) showed a high degree of cross-resistance towards selected CG derivatives (viz. digoxin, SC4453, digoxigenin, lanatoside C, alpha- and beta-methyldigoxin, dihydrodigoxin, alpha- and beta-acetyldigoxin, alpha,beta-diacetyldigoxin), all of which contained a free 12 beta-OH group in the steroid structure. Slight cross-resistance of the group D mutants was also observed for other compounds (viz. ouabain, ouabagenin, dihydroouabain) that contain a free 11 alpha-OH group in the molecule. However, these mutants exhibited no cross-resistance to other CG derivatives, which either lacked the above groups (viz. digitoxin, digitoxigenin, dihydrodigitoxin, digitoxigenin mono- and bisdigitoside, nerifolin, gitoxigenin, gitoxin, 16-acetylgitoxin, lanatosides A and B, cymarin, convallatoxin, oleandrin, strophanthidin, actodigin and bufalin) or in which the 12 beta-OH group was acetylated (viz. as in the case of 12-acetyldigoxin). Since the 12 beta-OH group is not required for CG-like activity, to account for these observations it is suggested that the genetic lesion in the group D mutant leads to the creation of a new binding site in the digitalis receptor, which specifically interacts with the 12 beta-OH group (the site presumably also interacts weakly with the 11 alpha-OH group) and either prevents or distorts the binding of the compounds to the drug binding site on the receptor. Further investigations with the different classes of CG-resistant mutants at the molecular level should prove very useful in identifying the drug receptor site and in understanding how these drugs interact with it.

Cardiac Glycosides↗
PubMed1990

Concentrative uptake of digoxin by slices of chicken renal cortex.

The purpose of this investigation was to define, under controlled in vitro conditions, the processes contributing to the uptake and accumulation of [3H]digoxin by incubated slices of chicken renal cortex. Progressive uptake was evident in time-course experiments with the slice-to-medium concentration ratio (S/M) reaching 5.25 after 120 min. No metabolism was evident. Increasing the ratio of unlabeled to labeled digoxin resulted in a concentration-dependent decrease in relative uptake of the label, suggesting saturability. Incubation under conditions of metabolic inhibition reduced digoxin S/M by about 50%, indicating that both energy-requiring and passive mechanisms contribute to the overall accumulation process. The structural nature of the uptake process was explored by incubating digoxin in the presence of potential inhibitors of transport. The organic cation quinine and the non-glycosidic steroids digoxigenin and spironolactone were without effect even at greater than 1000-fold excess compared to digoxin. Similarly, the sugar digitoxose had no inhibitory activity on digoxin accumulation by the slices. On the other hand, the glycosides digitoxin, digoxigenin-bis-digitoxoside and digoxigenin-mono-digitoxoside inhibited dogoxin uptake in a concentration-dependent manner. These results indicate a structural preference for an intact glycoside rather than for either the steroidal or sugar portion of the molecule alone. An inhibitory effect of ouabain and a stimulatory effect of reduced medium potassium concentration suggest a possible role for Na+,K(+)-ATPase in the uptake of digoxin by the renal cortex.

Animals↗