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By using methods of fluorescent and spine (electron paramagnetic resonance) probes it was shown that cardiac glycosides (digoxin, digitoxin, convallatoxin, corelborine and strophanthin) effectively interact with biomembrane lipids enhancing conformational motility of lipids and cause additional binding of calcium ions with the membrane.
The in-vitro influence of drugs on the chemokinesis and chemotaxis of neutrophils was investigated in order to prevent additional drug-induced motility impairment of cells in cases of already existing host defense disorders and for an eventual specific treatment of motility defects. Granulocyte motility is unimpaired by penicillin, ampicillin, carbenicillin, streptomycin, nystatin, and cyclophosphamide. The chemokinesis and chemotaxis of neutrophils are inhibited by erythromycin, oxytetracycline, doxycycline, chloramphenicol, hydrocortisone, g-strophanthin, digoxin, and digitoxin and in higher concentrations also by sulfonamides, gentamycin, prednisolone, methylprednisolone, dexamethasone, and phenylbutazone. Chemotaxis is selectively or rather more inhibited than chemokinesis by amphotericin B, griseofulvin, vinblastine++, trifluoperazine, and promethazine. Granulocyte motility is, however, stimulated by ascorbic acid, potassium thiocyanate, levamisole, lithium, and metofenazate.
A high-affinity monoclonal antidigoxin antibody, produced by somatic cell fusion, was amplified by the formation of ascites. Purification from ascites was accomplished by affinity chromatography by passing the ascites over a digitoxin-amine-agarose column. Affinity-purified antidigoxin antibody was coupled to a pellicular microbead at concentrations of 10, 25, 50, and 100 mg/g bead. The immobilized antibody was characterized for binding affinity, for specificity to other cardiac glycosides, and for binding capacity. There were no changes in the binding affinity observed for the immobilized antibody when compared to that of the antibody grown in culture media. Binding capacities for the immobilized antibody were decreased from calculated theoretical values. Saturating the microbead with increasing concentrations of antibody lowered the binding efficiency of the antibody from 32 to 22% of theoretical values. Attempts to improve the binding capacity by immobilizing antibodies to the microbead at the immunoglobulin carbohydrate by periodate oxidation were unsuccessful. These data demonstrate that antidrug antibodies immobilized on solid supports remain functional and may have the capability of removing drug from biological fluids passed over the support.
In experiments on rabbits various effects of steroidal agents (hydrocortisone, deoxycorticosterone, beta-lipoproteids, cholesterol, saponins, digitoxin, strophanthin) on the development of sensitization and allergization at their administration during sensitization and before the resolving dose of the antigen were shown.
This paper describes the evaluation of a heterogeneous enzymeimmunoassay (EIA, subtype ELISA) for the determination of digoxin in serum. Results are compared with those obtained from a radioimmunoassay (New England Nuclear, 125I-Digoxin). The limit of detection is 0.3 microgram/1 (0.4 nmol/1). The range of the test is from 0.3 unto 5.0 microgram/1 (0.4--6.4 nmol/1). Within-batch precision ranged from 7 to 11%, between-batch precision from 8--14%. Pure digoxin, added to solutions of albumin and pooled sera, gave recoveries between 87 and 106%. 116 sera from patients taking digoxin exclusively yielded no systematic difference compared to the results of a radioimmunoassay (RIA) (equation of the bivariate regression CELISA = 0.954 . CRIA + 0.14 (microgram/1) (0.18 nmol/1). Nevertheless marked differences between both tests were observed in individual cases. Digitoxin yielded in vitro and in vivo a cross-reactivity of 7 to 14% depending upon the concentration. In 68 sera from patients, taking digoxin plus spironolactone, we found results that were on average 0.48 microgram/1 (0.64 nmol/1) higher with the ELISA than with the RIA (p less than 0.01%). With respect to practicability the ELISA test for digoxin is very similar to the analogous RIA both using the solid phase technique.
The correlation between various maintenance doses of digoxin and digitoxin was made object to a clinical research on 342 patients with heart failure. Comparison between 1728 examined plasma levels from 47 other hospitals was carried out. It was referred to the accurate indications, contraindications, interactions, and to the dosage of digitalis glycosides.
In isolated, spontaneously beating guinea-pig atria the uptake, liberation and inotropic effect of [3H]16-acetyl-gitoxin were studied. At a concentration of 53.5 nmol/l 16-acetyl-gitoxin caused an increase in contractile force of 21% within 45 min. Within 60 min, 190.7 pmol per g tissue were taken up. The tissue-to-medium radioactivity ratio (T/M ratio) was 4.7. In the wash-out experiments, 40% of the accumulated radioactivity was liberated into the medium within 30 min, while the glycoside-dependent increment of inotropy ceased to continue. The kinetic properties of 16-acetyl-gitoxin were found to resemble more closely those of digitoxin than those of ouabain.
The systolic time intervals (STI) corrected for changes in the heart rate, electromechanical systole (QS2c) and left ventricular ejection time (LVETc), and the ECG-derived PQ-time and QT-interval were measured in five female and four male healthy subjects. Each volunteer took 0.15, 0.30, 0.45, 0.60, 0.75 or 0.90 mg pengitoxin over six days, with a glycoside-free interval of two or three weeks between two doses. The glycoside plasma level was measured radioimmunologically. Linear correlations were found between the shortening of QS2, LVET, and QT (delta QS2c, delta LVETc, delta QTc) and the plasma level of 16-acetyl-gitoxin. The PQ-time showed a flat dose-dependent increase. The shortening of STI observed after therapeutic and subtoxic doses of pengitoxin was in accordance with that after intake of digitoxin and digoxin in corresponding doses. The efficacy of pengitoxin estimated by shortening of STI justifies the administration of daily maintenance doses between 0.30 and 0.45 mg.
Description of multifocal (chaotic) atrial tachycardia in a newborn, which reverted to sinus rhythm after treatment with digitoxin.
A report is presented of the clinical experience in the treatment of severe digitalis poisoning in nine young children aged 1 month to 4 years with digitalis antibody fragments (Fab). In 8 cases, accidental poisoning was involved, and in one case there was overdosage during the course of treatment. Digoxin preparations had been taken by 8 of the cases, 6 times in liquid form, and in one case digitoxin. Reliable signs for the ingestion of digitalis with high concentrations in the serum and the appearance of life-threatening disorders of rhythm or conduction were taken as the indication for the use of Fab. The Fab dose was 80 to 480 mg per case treated and was adjusted according to the quantity of glycoside ingested. All of the children recovered completely. Regression of the arrhythmias and improvement of the clinical condition were seen during or shortly after administration of the Fab infusion. In the serum there was a rapid fall in the level of free digoxin and a simultaneous marked rise in that of bound inactive digoxin. The digoxin was excreted in the urine in the bound form. Tolerance was good. No allergic reactions to foreign protein or later reactions in the form of serum sickness were observed.
This study is based on a double blind interlaboratory comparison between radioimmunoassay and E.L.I.S.A. digoxin determination. The correlation between digoxin values found with these two methods is good (r = 0.96 for therapeutic and toxic ranges 1,0 ng/ml - 5,5 ng/ml). The results indicate good repeatability, reproducibility and precision. The determination by E.L.I.S.A. can be performed with sera or plasma. The presence of haemolysis makes no appreciable difference in results. No variation is observed when different kits are used from an identical lot. However digoxin gives an important cross reactivity with digitoxin in Enzymeimmunoassay. Therefore it is necessary to know exactly the digitalis glycoside before the determination in order to avoid significant error.
Intravenous infusions of arrhythmogenic and lethal doses of ouabain and digoxin in anesthetized guinea pigs were not influenced by pretreatment with 1 g/kg D-penicillamine. The respective doses of proscillaridin and digitoxin, however, were significantly decreased by D-penicillamine. As could be demonstrated with proscillaridin this effect of D-penicillamine was dose-dependent between 0.25 and 1.0 g/kg. Obviously the strong plasma-protein binding of D-penicillamine leads to a displacement from binding sites of such cardiac glycosides which are also strongly bound to plasma proteins and thus reduces toxic doses of cardiac glycosides. Because of the extremely different doses of D-penicillamine in the animal experiments compared to those used therapeutically in man the present findings are irrelevant for clinical practice.
The care of the elderly covers a wide spectrum: 1, The prophylaxis of the relatively healthy olds. 2, The somatic, psychic and social care of the handicapped aged. 3, The treatment of special illnesses in old age. The gerotherapy must consider the characteristics of the biological age and the degree of the multimorbidity. I. General principles of therapy. The guide-lines of gerohygiene (diet, physical and mental activity, limitation of alcohol and sexuality, regular medical check-ups for registration of risk factors) have to be taken into consideration. The existing multimorbidities in high age should not be treated simultaneously in a polypragmatic way, but according to the prevailing illness with the least possible medicine. II. Special principles of therapy. In the early stage of heart insufficiency in long-lived persons low doses of Digoxin should be used. For aged with kidney insufficiency Digitoxin is preferable. Even in over 90 year old heart patients with the life threatening AV-block the implantation of the intracardial pacemaker is indicated. The myocardial infarction in very old patients developes mostly atypical and should not be treated with coumarin. The more severe hypertension in old age can be treated with low doses of beta-blocking substances in combination with a potassium saving diuretic and low doses of cardiac glycosides. Finally, the frequent sleep disturbances and their therapy in old age are mentioned. The brain function of elderly people depends on the quality of cardiac output and circulation.
The effects of ouabain and other cardiotonic steroids were examined to investigate whether changes in Na,K-adenosine triphosphatase (ATPase) activity modified the actions of palytoxin (PTX) in rabbit aortic vascular smooth muscle. The effects of these agents on rabbit aorta were compared with those on rat aorta, as it is known that the concentration of cardiac glycosides required to inhibit Na,K-ATPase of rat aorta is markedly higher than that of other species. PTX induced contraction in rabbit and rat aortas in a similar concentration range (10(-11) to 10(-8) M). PTX rapidly decreased tissue K content of these preparations. Ouabain (2 X 10(-5) M) inhibited both the contraction and the loss of tissue K in rabbit aorta but not in rat aorta. In rabbit aorta, convallatoxin (2 X 10(-5) M), which has one rhamnose as a sugar moiety like ouabain, and cymarin (2 X 10(-5) M), which has one cymarose, inhibited the PTX-induced contraction and the loss of tissue K, although ouabagenin, convallatoxigenin and cymarigenin (strophanthidin) (2 X 10(-5) M) did not. Other cardiotonic steroids, digoxin and digitoxin, which have 3 U of digitoxose as a sugar component, or the corresponding aglycones failed to inhibit the PTX-responses. On the other hand, all the cardiotonic steroids at concentration of 2 X 10(-5) M equally inhibited the reuptake of K and relaxation of norepinephrine-induced contractions induced by the readdition of K. Inhibition of Na-K pump by K-free solution potentiated rather than inhibited the PTX-induced contraction. These results suggest that the specific sugar moiety of cardiac glycosides is important for the inhibitory effect exerted by these compounds on the PTX-induced responses and that the inhibition is not related to the activity of the Na,K-ATPase.
A method has been developed for the isolation of sealed plasma membrane vesicles from rabbit white skeletal muscle. The final preparation was highly purified as indicated by enrichment of plasma membrane marker enzymes (i.e. ouabain-sensitive (Na+,K+)-ATPase, adenylate cyclase, and acetylcholinesterase). The absence of sarcoplasmic reticulum and mitochondria as contaminants was indicated by the low specific activity of marker enzymes, i.e. Ca2+-ATPase, succinate-cytochrome c reductase, and monoamine oxidase. Thin section and negative staining electron microscopy confirmed the absence of sarcoplasmic reticulum and mitochondrial contamination. The plasma membrane preparation consisted largely of sealed vesicles as observed by electron microscopy and as also demonstrated by latency of enzymic activities, which were unmasked by preincubation with detergent (sodium dodecyl sulfate). Membrane sidedness was estimated from latency of ouabain-sensitive (Na+,K+)-ATPase activity and acetylcholinesterase activity. The latency studies suggest that most of the vesicles are oriented inside out with respect to the orientation of the sarcolemma membrane in the muscle fiber. The inside-out plasma membrane vesicles actively accumulated sodium ions upon addition of ATP. The sodium ions were concentrated greater than 8-fold inside the vesicles and were released upon addition of the ionophore monensin. The sodium ions were taken up in the presence of K+ or NH4+ but not of choline. Uptake was inhibited by low concentrations of vanadate or digitoxin. The Na+ uptake was concomitant with Rb+ efflux. Therefore, the sodium ion transport and the resulting gradients formed appear to have been generated by the ouabain-sensitive (Na+,K+)-ATPase. Batrachotoxin, which opens Na+ channels in excitable tissues, prevents most of the Na+ uptake, suggesting the presence of toxin-activated Na+ channels in these plasma membrane vesicles.
NMR spectroscopy was used to establish the formation of digoxin and digitoxin complexes with calcium ions. Microcolorimetric titration demonstrated the formation of two types of digoxin complexes with magnesium at a ratio of 1:1 and 1:2. It was noticed in rat experiments that digoxin (2.5 mg/kg) raises the magnesium level in liver tissue, whereas in a toxic dose of 12.5 mg/kg it increases the calcium content in the heart muscle.
The effect of hepatic disease on the metabolism of drugs is reviewed. Drugs discussed include those acting on the central nervous system (phenobarbital, pentobarbital, amobarbital, diazepam, chlordiazepoxide, oxazepam, clorazepate, chlorpromazine, morphine, meperidine, phenytoin); those acting on the cardiopulmonary system (digoxin, digitoxin, lidocaine, theophylline); antineoplastic agents (azathioprine, 6-mercaptopurine, doxorubicin), antimicrobials (carbenicillin, ampicillin, nafcillin, chloramphenicol, clindamycin, lincomycin, rifampin, isoniazid, aminosalicylic acid) and antiinflammatory agents (phenylbutazone, prednisone). The effect of hepatic dysfunction on drug disposition is not consistent or predictable. The efficiency with which drugs are metabolized by the liver, the extent of drug plasma binding, and the etiology and stage of the hepatic disorder are each important in determining whether drug disposition will be altered.
A specific dosage schedule is designed for the case of multiple dosing with the aim of achieving the desired steady-state blood level in a predetermined time interval. The method is based on the administration of nonuniform doses at uniform dosage intervals during the saturation time. To calculate the doses a nonlinear equation must be solved. The theory is illustrated by a quantitative example (digitoxin).