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Problems of rapid digitalization in severe congestive heart failure.

The pharmacodynamic effects (changes of systolic time intervals, STI, reaction of pulmonary arterial pressure) of digitoxin were studied in 7 patients with severe congestive heart failure in comparison with the corresponding plasma level. STI indicated glycoside-dependent changes, i.e. shortening of LVETc and QS2c and normalization of prolonged PEPc, while ICT shortening was less observed. In 2 patients with cor pulmonale a pulmonary oedema occurred accompanied with prolonged LVETc. During the early period of glycoside-dependent recompensation no significant correlation between STI shortening and glycoside plasma level was observed. Because of the retarded normalization of the haemodynamics of the pulmonary circulation and because of possible side-effects, rapid digitalization has to be reconsidered.

Adult↗

Problems of an optimum digitalis therapy.

In 25 digitalized patients with ischaemic heart disease who had survived a myocardial infarction for 2 to 4 weeks, the systolic time intervals (STI) and changes of glycoside plasma level were measured before and up to 5 hrs after oral intake of a maintenance dose of digitoxin (n = 18) or of digoxin (n = 7). Between the changes of STI and the increase in digitoxon and digoxin plasma level no significant correlations were found. Therefore it is concluded that neither shortening of STI during the test period nor PEP/LVET are reliable criteria of individualizing and optimizing the therapy with cardioactive glycosides.

Adult↗

Studies on drug metabolism and liver ultrastructure after conjoint treatment with pregnenolone-16alpha-carbonitrile and dl-ethionine.

Zoxazolamine paralysis, hexobarbital anesthesia and digitoxin convulsions were diminished in rats by 3 days of pretreatment with pregnenolone-16alpha-carbonitrile (PCN). Simultaneous injection of dl-ethionine did not block this effect of PCN. Dl-Ethionine decreased, while PCN or PCN + ethionene increased, zoxazolamine metabolism by the 9,000g supernatant fraction of the liver. Dl-ethionine neutralized the influence of PCN and phenobarbital on zoxazolamine metabolism in rats that were pretreated with PCN or phenobarbital for 1 day, and it inhibited the action of phenobarbital on hexobarbital anesthesia. PCN augmented the liver weight of animals given dl-ehtionine whereas dl-ethionine in itself did not. PCN produced SER proliferation in hepatocytes and dl-ethionine caused lipid accumulation, SER proliferation and myelin-figure formation. When administered conjointly, these compounds had an additive effect on the liver cell ultrastructure.

Animals↗

[Radioimmunological estimation of cardiac glycoside concentration in the plasma].

Radioimmunoassay is a simple method for estimating the concentration of cardiac glycosides in the blood. The technique is described. An condition of the accuracy of the estimation is that the drug levels in blood and tissue have reached equilibrium, since only then will the blood concentration accurately reflect the drug level in the tissues. The therapeutic plasma levels are 0.7 to 2.0 ng/ml for digoxin and 10-30 ng/ml for digitoxin. Indications for estimating the plasma glycoside levels are reviewed; they include suspected digitalis poisoning or intolerance, interaction of glycosides with other drugs and suspected negligence on the part of the patient to take the prescribed dose.

Albumins↗

Rifampin and rifabutin drug interactions: an update.

Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes. A few examples of well-documented clinically significant interactions include interactions with warfarin, oral contraceptives, cyclosporine, glucocorticoids, ketoconazole or itraconazole, theophylline, quinidine sulfate, digitoxin or digoxin, verapamil hydrochloride, human immunodeficiency virus-related protease inhibitors, zidovudine, delavirdine mesylate, nifedipine, and midazolam. Recent reports have demonstrated clinically relevant interactions with numerous other drugs, such as buspirone hydrochloride, zolpidem tartrate, simvastatin, propafenone hydrochloride, tacrolimus, ondansetron hydrochloride, and opiates. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Enhanced knowledge of known interactions will continue to develop, including research on the induction of specific cytochrome P-450 isoenzymes and on the importance of the P-glycoprotein transport system. New rifampin and rifabutin interactions will be discovered with further investigations.

AIDS-Related Opportunistic Infections↗

Antidotes for acute cardenolide (cardiac glycoside) poisoning.

BACKGROUND: Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited. OBJECTIVES: To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin. SEARCH STRATEGY: We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified. DATA COLLECTION AND ANALYSIS: We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate. MAIN RESULTS: Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. AUTHORS' CONCLUSIONS: There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.

Acute Disease↗

Binding of cosalane--a novel highly lipophilic anti-HIV agent--to albumin and glycoprotein.

Cosalane is a potent inhibitor of HIV replication with multiple sites of action. The purposes of this study were to (a) determine the extent and nature of cosalane binding to mucin, alpha(1)-acid glycoprotein (AAG), plasma, and human (HSA) and bovine serum (BSA) albumin, and (b) determine the primary site(s) of cosalane binding to HSA. Plasma protein binding of cosalane was studied by a gel filtration technique. Cosalane binding to HSA was also determined in the presence of salicylic acid. Competitive inhibition studies were conducted using warfarin, digitoxin, and diazepam to determine the primary HSA binding site(s) of cosalane. The drug was bound extensively to HSA and BSA and required 500-550 moles to saturate 1 mole of protein. Stoichiometries of cosalane binding to alpha(1)-acid glycoprotein (AAG) and mucin were between 30 and 50 mol/mol of either glycoprotein. The binding isotherm deviated from a rectangular hyperbola, suggesting self-association of the ligand. Salicylic acid decreased cosalane binding to HSA by one order of magnitude. Inhibition studies of cosalane to HSA revealed that the compound binds primarily to warfarin site with a K(i) of 1.24 +/- 0.24 nM. In summary, cosalane binds extensively to serum albumins and to a lesser extent to both AAG and mucin.

Animals↗

Roles of peritrophic membranes in protecting herbivorous insects from ingested plant allelochemicals.

Four mechanisms by which peritrophic membranes (PMs) potentially protect herbivorous insects from ingested allelochemicals are reviewed: adsorption, ultrafiltration, polyanion exclusion, and the capacity of PMs to act as antioxidants. Most of the research on the protective roles of PMs against ingested allelochemicals has focused on their impermeability to tannins. Adsorption of tannins by the PMs in grasshoppers may limit their permeability, but ultrafiltration of tannin complexes in the caeca is an alternative explanation. Polyanion exclusion does not explain the impermeability of caterpillar PMs to tannins (polyphenolate anions). Ultrafiltration remains the most likely mechanism by which tannins, and other tested allelochemicals, are retained in the endoperitrophic space. Although the pores in PMs are too large to impede the passage of most free allelochemicals, large allelochemical complexes are retained. Such complexes form in the gut fluid of caterpillars between tannic acid, proteins, lipids, and polyvalent metal cations, and also in the gut fluid of grasshoppers (Melanoplus sanguinipes) between some amphiphilic allelochemicals (digitoxin) and surfactant micelles. Further work is needed to examine the role of PMs as antioxidants in vivo, such as their potential to bind catalytically-active metal ions.

Animals↗

Development of a standard, freeze-dried serum containing the drugs assayed most often in French hospitals.

A quality control program for the therapeutic drug monitoring methodology used to determine serum levels of the fourteen drugs assayed most frequently by French hospital laboratories is described. The program has been adopted by the Societé Française de Biologie Clinique (SFBC), which provides participating laboratories with a statistical analysis of the performance data. The control samples developed for the program are prepared by spiking calf serum with, in one case, phenobarbital, phenytoin, carbamazepine, sodium valproate, amikacin, lithium carbonate, digitoxin and hydroquinidine, and, in the other case, caffeine, quinidine, digoxin, isoniazid and gentamycin. After freeze-drying the spiked serum, the drugs were shown to be stable for at least a year when stored at -20 degrees, +4 degrees and +22 degrees; at the end of this time, the samples were pathogen free. For checking therapeutic drug monitoring methods, the freeze-dried serum is diluted with distilled water (10 ml); these solutions are chemically stable, and remain pathogen-free, when stored in stoppered glass tubes at -20 degrees or +4 degrees for 4 weeks.

Drug Contamination↗

Pharmacokinetics of a novel surface-active agent, purified poloxamer 188, in rat, rabbit, dog and man.

Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.

Analysis of Variance↗

Investigation of enantioselective ofloxacin-albumin binding and displacement interactions using capillary affinity zone electrophoresis.

The direct chiral separation of ofloxacin by capillary affinity zone electrophoresis using serum albumins from different animal sources as chiral selector in the supporting electrolyte is described. In addition, the effects of displacers on the mobility and enantioselectivity of ofloxacin were studied. Firstly, the separation behaviour of the enantiomers of the ofloxacin (OFLX) and tryptophan (Trp) was compared. The influence of albumin types, including chemically modified bovine serum albumins (BSAs), and buffer types on the migration behaviour of enantiomers was investigated. The results showed that stereoselectivity of Trp is independent of the type of albumin used. However, chiral separation of OFLX depends on the biological species of albumin. Use of chemically modified BSA led to poorer resolution of enantiomers. Only with acetylated BSA could chiral separation of Trp be achieved. Using Good's buffer solutions (DIPSO and HEPES) as a supporting electrolyte affected the migration times of OFLX enantiomers. Finally, a variety of displacers were added to the buffer along with the protein, and the effects on separation behaviour were observed. The displacers included warfarin, ketoproten, diazepam, propranolol, benzoinphenylbutazone, digitoxin and octanoic acid. From the results obtained, it is concluded that capillary affinity zone electrophoresis using albumin as a chiral selector may allow screening of OFLX-displacer interactions.

Animals↗

Mass spectrometric analysis of cardiac glycosides by the desorption/ionization technique potassium ion ionization of desorbed species.

The analysis of cardiac glycosides by the desorption/ionization (D/I) mass spectrometric technique potassium ion ionization of desorbed species (K+IDS) is presented. K+IDS mass spectra of digitonin, digoxin, digoxigenin, digitoxin and ouabain are discussed to demonstrate the capabilities of this D/I method. The K+IDS analysis consists of two steps: thermal desorption of neutral molecules representative of the analyte, followed by gas-phase addition of K+ ions to these species. Structural and molecular weight information of the cardiac glycosides is obtained with the K+IDS technique. The most intense peak in the K+IDS mass spectrum of an analyte, M, is frequently the [M]K+ ion. Interpretation of the K+IDS mass spectra is simple, since one thermal degradation mechanism dominates. This mechanism is a 1,2-elimination process. A variation of the original K+IDS technique, performed by changing the ionizing metal from K+ to Na+ (i.e. Na+IDS), is presented for the analysis of digoxin. The Na+IDS mass spectrum of digoxin contains more structural information than the K+IDS mass spectrum of that compound. This may lead to a means of controlling the types of information obtainable with this D/I technique by varying the cation that is thermionically generated. K+IDS analyses can be performed rapidly, no sample derivatization is necessary, no matrix is required and little instrument modification is necessary.

Cardiac Glycosides↗

Sodium fluxes in human fibroblasts: kinetics of serum-dependent and serum-independent pathways.

Sodium influx in serum-deprived human fibroblasts is by way of a pathway which shows saturation kinetics. A plot of initial Na influx versus [Na]0 ([Na]i approximately equal to 10 mM) gives a simple Michaelis-Menten type of curve with a K1/2 = 70.0 +/- 8.1 mM and a Vmax = 14.5 +/- 1.9 mumol/g prot/min. A similar plot of initial Na influx versus [Na]0 in the presence of 10% fetal bovine serum (FBS) gives a nonsaturating curvilinear response which appears to be biphasic. A plot of the serum-dependent Na influx versus [Na]0 (obtained by subtracting the curve in the absence of FBS from the curve in the presence of 10% FBS) shows that there is a linear relationship between serum-induced Na influx and external [Na]. At physiological Na concentrations, in the presence of FBS, the serum-induced Na influx is equal to the amiloride-sensitive Na flux, whereas in the absence of serum amiloride inhibits less than 10% of the Na influx. The effect of intracellular Na on Na flux was tested by preloading cells with Na in a digitoxin-containing medium prior to measurement of Na flux. A plot of steady-state Na exchange flux versus [Na]0 ([Na]i approximately equal to [Na]0) in the absence of serum gives a curve that appears to saturate at approximately 100 mM Na (flux = 100 mumol/g prot/min) and then declines with increasing [Na] (flux = 40 mumol/g prot/min at 150 mM). In contrast to Na influx in control serum-deprived cells, Na flux in Na-loaded cells in dramatically inhibited by the presence of amiloride. Since the peak Na exchange flux of 100 mumol/g prot/min is greatly in excess of the Vmax for Na influx in control serum-deprived cells and the enhanced Na flux is amiloride-sensitive, elevating intracellular Na must somehow activate the amiloride-sensitive Na transport system, which is normally only minimally active in the absence of serum.

Amiloride↗

Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation.

Inclusion complexes of the digitalis glycosides digitoxin, digoxin, and methyl digoxin with three cyclodextrins (alpha-, beta-, gamma-homologues) in water and in the solid state were studied by a solubility method, IR and 1H-NMR spectroscopy, and X-ray diffractometry. Solid complexes (in a molar ratio of 1:4) of the digitalis glycosides with gamma-cyclodextrin were prepared and their in vivo absorption examined. The rapidly dissolving form of the gamma-cyclodextrin complex significantly increased plasma levels of digoxin (approximately 5.4-fold) after oral administration to dogs.

Animals↗

Digitonin derivatives of low toxicity: potential solubilizers for lipophilic compounds.

Digitoxin was modified by condensation with propylene oxide or with 1,4-butanediol diglycidyl ether in aqueous alkali, yielding products in which some of the CH2OH groups of digitonin were converted to CH2OCH2CHOHCH3 or to CH2OCH2CHOHCH2O(CH2)4OCH2CHOHCH2OH groups, respectively. These modified digitonins were very soluble in water and chloroform and effectively solubilized lipophilic compounds into aqueous solutions; e.g., 2 mg of vitamin A or 0.6 mg of cholecalciferol could be dissolved per 1 mL of 5% aqueous solutions of modified digitonins. Compared with the toxicity of digitonin (LD50 4 mg/kg iv), the toxicity of modified digitonin was greatly reduced: doses of 500 mg/kg by intravenous infusion were not lethal for mice.

Adjuvants, Pharmaceutic↗

Computer analysis of mutations that affect antibody specificity.

The mouse hybridoma cell line 40-150 secretes antibodies with high affinity toward the cardiac glycosides digoxin and digitoxin. A spontaneous mutant, 40-150 A2.4, produces an antibody which carries a single residue mutation, Ser----Arg, in its heavy chain (H94) and has an altered specificity. A second-order mutant, 40-150 A2.4 P.10, produces two antibody molecules, one the same as 40-150 A2.4, the other lacking two residues at the N-terminus of its H chain, and having a specificity profile approaching that of 40-150 antibody. The N-terminus and the position H94 are distant from the antigen-binding site of the antibody; thus, the structural basis of the specificity changes was not immediately clear. Approximate structures of the 40-150 antibody and its mutants were constructed in the computer, based on atomic coordinates of the homologous mouse antibody McPC 603. Using the program CONGEN, the torsional space of the polypeptide backbone and side chains around position H94 was uniformly sampled, and the lowest energy conformations were analyzed in detail. The results indicate that when Arg-H94 is substituted for Ser, Arg-H94 can hydrogen bond to side chains of Asp-H101, Arg-L46, and Asp-L55. This results in a change in the surface of the combining site which may account for the affinity changes. Deletion of the two N-terminal residues increases solvent accessibility of Arg-H94. The solvation may cause a hydrogen bond between Arg-H94 and Asp-H101 to be lost, restoring the structure to one similar to that of 40-150.

Animals↗

Contractility of isolated bovine ventricular myocytes is enhanced by intracellular injection of cardioactive glycosides. Evidence for an intracellular mode of action.

The contractions of isolated bovine left ventricular myocytes were evaluated by optically measuring the extent of unloaded shortening (ES), the maximal rate of shortening (MRS) and the maximal rate of re-lengthening (MRL). Ouabain, digoxin or digitoxin were intracellularly injected by 2 sec long pressure pulses via the microelectrodes. Their i.c. concentration was estimated to be 2-5 nM. Within 1-4 min after the injection, ES, MRS and MRL increased by more than 2-fold. The contractility renormalized within the following 20 min. Injection of solutions without glycosides did not increase the contractility. An interaction of the injected glycoside with the e.c. ouabain receptor could be largely excluded because a) the amount of the released glycoside was too small for e.c. effects, b) 500 nM e.c. antidigoxin, c) 20 mM [K]o or d) covalent binding of digoxin to HSA did not prevent the increase in contractility due to the i.c. injections. Since contractility also increased when the injections were performed at Na-free conditions, [Na]i-load is not necessary for the effect of i.e. glycosides. The increased contractility due to the injected glycosides was not observed when the contractility prior to the injection was already potentiated, e.g. by greater than 3.6 mM [Ca]o or by stimulation at frequencies greater than 1.25 Hz. The results are interpreted by the hypothesis that the i.c. glycosides facilitate the release of activator calcium from the SR. The possible i.c. modes of action are discussed as well as the idea that e.c. applied glycosides internalize and mediate inotropy via the i.e. mechanism.

Animals↗

Azapropazone binding to human serum albumin.

Azapropazone, a new non-steroidal antiinflammatory drug, is strongly bound to human serum albumin. As revealed by Scatchard analysis, one high-affinity binding site with an association constant of about 1.2 x 10(6)M-1 and two low-affinity binding sites with association constants of about 0.05 x 10(6)M-1 were found. While the high-affinity binding site of azapropazone is clearly not identical with the diazepam or digitoxin binding sites of human serum albumin, contradictory evidence was found by optical measurements and displacement studies for the similarity of the azapropazone and the warfarin binding site of human serum albumin. At present, it is suggested that both drugs bind to different areas of the same binding site. Therefore, the pronounced effects of various disease states on the plasma protein binding of azapropazone can not be explained by a binding to an unusual binding site, but seem to be due to an extreme sensitivity of the azapropazone binding area to the putative endogenous binding inhibitors, present in the blood during those disease states.

Apazone↗