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PubMed1984

Differential effects of hepatic cirrhosis on the plasma protein binding of drugs.

The binding of sulfisoxazole (sulfafurazole-INN) (100 micrograms/ml), diazepam (3 micrograms/ml) and digitoxin (0.025 micrograms/ml) has been studied in plasma from normal volunteers and from patients with hepatic cirrhosis. The free fraction of sulfisoxazole and diazepam in plasma was increased in these patients (22.9 +/- 3.0% and 6.5 +/- 0.7%) vs 6.6 +/- 0.6% and 3.1 +/- 0.2% in normal subjects, respectively), but binding of digitoxin did not greatly change (13.7 +/- 3.95% vs 13.9 +/- 2.27% in the control group). The increase in the free fraction of sulfisoxazole and diazepam correlated well with decreased serum albumin levels; but a change in albumin affinity, perhaps due to increased bilirubin levels, should also to be taken in consideration to explain this decreased drug binding in hepatic cirrhosis.

Blood Proteins↗
PubMed1980

[Which digitalis therapy is still justified today? (author's transl)].

Recent intoxication studies during digitalis therapy have shown that digoxin and digitoxin produce different pharmakokinetic results. The main difference is in the elimination pathways of the two substances. Whereas digoxin is almost exclusively excreted by the kidneys, digitoxin may be excreted both by the kidneys and by the intestine via the bile. New dosage guidelines have resulted from these studies. The problems of adjustment by means of instrumental parameters are presented and the need for individual dosage on the least effective dose principle is discussed.

Digitalis Glycosides↗
PubMed1981

[Haemorrhagic necrosis of the digestive tract consecutive to massive digitalis intoxication (author's transl)].

A 60-year-old man under digitalis treatment for hypertensive heart tried to commit suicide by absorbing a 15 mg dose of digitoxin. Severe intestinal bleeding occurred 12 hours later, followed by pseudo-occlusive syndrome and ischaemia of the distal lower limbs. On abdominal incision the whole gut was found to be invaded by haemorrhagic necrosis and perforated on three points. The patients subsequently died of peritonitis. The responsibility of digitoxin in these events was demonstrated by the absence of any other cause of ischaemia, such as heart failure, shock, arrhythmia, consumption coagulopathy or use of sympathomimetic drugs. This case shows that the vasoconstrictor effect of digitalis, experimentally demonstrated but clinically controversial, is a reality, and that digitalis compounds are contra-indicated in patients with haemorrhagic necrosis of the digestive tract.

Digitalis Glycosides↗
PubMed1980

[Effective concentration and dosage for cardiac glycosides].

The pharmacokinetic fundaments of the glycoside therapy with strophanthin, digoxin and digitoxin are described and compared with the traditional clinically oriented parameters total body stores, decay ratio and so on. Newly introduced is the parameter medium remaining duration in the circulation. A critical analysis of the hitherto cited values of the total body stores and the decay ratio established from the clinical effect shows that on the basis of pharmacokinetic calculations the corresponding values for digoxin and digotoxin need a great correction. The fully active quantity for digoxin lies between 0.5 and 0.8 mg and the subsiding share is 50%. The values for digitoxin lie at 0.9 mg and 9%. Furthermore the causes of the interindividual variability of the maintenance dose are discussed. According to the already existing international experiences an essential improvement of the therapy is possible, when the pharmacokinetically established effective constants are taken into consideration. Examinations of the inter- and intraindividual differences in the kinetics of the glycosides and the development of digoxin preparations with a high (i.e. constant) bioavailability may contribute to a further decrease of the frequency of toxic side-effects in future.

Biological Availability↗
PubMed1982

[Prognostic factors in acute digitalis poisoning].

The prognostic significance of various clinical and biochemical factors was investigated in 179 patients who had ingested more than 2 mg digitoxin. The mortality rate in this series was 17%. Supraventricular arrythmias had no influence on prognosis, but the death risk was higher in males and in patients with AV block. It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia. Two other factors--previous heart disease and vomiting--were also significant in patients without heart block. Calculated on the basis of 4 clinical factors, the mortality rate varied from 2 to 74%. The death risk in acute digitalis poisoning can therefore be easily assessed simply from clinical criteria.

Acute Disease↗
PubMed1982

[Incidence of side effects in digitalis therapy].

In a literature research program concerning side effects during digitalis therapy 75 publications had been evaluated. Comparing 15 drug monitoring studies with different types of drugs, cytostatics, antibiotics and analgetics most frequently led to side effects. Digitalis glycosides ranged on the place 3-9. Adverse reactions rates up to 20% had been observed in hospitalized patients. The average of all data, however, was near 10%. Because of their generally low-risk rate of intoxication ambulant patients--with 96-97% glycoside prescriptions the dominant part of digitalis recipients--evidently had a lower incidence of adverse reactions. In this group of patients the rate of side effects ranged about 3% for digoxin and digitoxin, respectively. Comparative clinical studies with digoxin and digitoxin showed no signs of differences in the rate of adverse reactions between these two digitalis glycosides.

Ambulatory Care↗
PubMed1980

Hypotensive effects of cardiac glycosides in spontaneously hypertensive rats.

The effects of cardiac glycosides on systolic arterial pressure (SAP) and heart rate (HR) were studied in spontaneously hypertensive (SH) and normotensive (NT) Wistar rats. Ouabain (2 mg/kg), given by i.p. injection to unanesthetized rats, produced a significant decrease in SAP in both SH and NT rats with little concomitant HR change. Baroreceptor denervation abolished the response. To analyze the effects more completely, experiments were done on acutely anesthetized rats. Ouabain was administered i.p. 30 min after induction of anesthesia with alpha-chloralose (60 mg/kg i.p.). alpha-Chloralose alone produced a significant SAP decrease in both SH and NT rats and bradycardia in SH but no significant HR change in NT rats. Ouabain i.p. further reduced SAP in SH but had no effect on NT rats. When given by i.a. bolus injection (250 microgram in 0.1 mg of heparin-saline) to anesthetized (pentobarbital, 40 mg/kg i.p.) rats with intact left carotid sinus nerves, ouabain produced a transient but significant reduction in SAP of SH but NT rats or SH rats with sinoaortic denervation. Digitoxin, given by stomach tube (4--5 mg/kg) for 1 week, decreased SAP in SH but not NT rats. Digitoxin produced significant SAP increases in SH rats with sinoaortic denervation. Arterial baroreceptor discharge is increased by cardiac glycosides. The present results suggest that the reflex hypotensive effects of digitalis drugs are due, at least in part, to sensitization of baroreceptors and that SH rats may be more sensitive to these drugs possibly because of altered intrinsic baroreceptor properties.

Animals↗
PubMed1981

[Prognostic factors in acute digitalis poisoning (author's transl)].

The prognostic significance of various clinical and biochemical factors was investigated in 179 patients who had absorbed more than 2 mg of digitoxin. The mortality rate in this series was 17%. Supraventricular arrythmias had no influence on prognosis, but the death risk was higher in males and in patients with A-V block. It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia. Two other factors, previous heart disease and vomiting, were also significant in patients without heart block. Calculated on the basis of 4 clinical factors, the mortality rate varied from 2 to 74%. The death risk in acute digitalis poisoning can therefore be easily assessed from simple clinical criteria.

Acute Disease↗
PubMed1994

Identification of an amino acid substitution in human alpha 1 Na,K-ATPase which confers differentially reduced affinity for two related cardiac glycosides.

The ouabain-resistant cell line H1C1 displays a 30-fold differential of reduced sensitivity to the structurally related cardiac glycosides digoxin and digitoxin (Baker, R. M. (1976) in Biogenesis and Turnover of Membrane Macromolecules (Cook, J.S., ed) pp. 93-103, Raven Press, New York). Since these ligand congeners differ only by the presence of a hydroxyl group at C-12 of digoxin we predicted that the H1C1 phenotype must reflect a mutation which alters the binding site of the cardiac glycoside receptor (Na,K-ATPase). Complementary DNA encoding the alpha 1 Na,K-ATPase was prepared from H1C1 cell total RNA by reverse transcription-coupled polymerase chain reaction and these cDNAs were cloned. Sequence analysis of the reverse transcriptase-polymerase chain reaction clones revealed several independent isolates containing a G > A transition at nucleotide 332 of the propeptide coding sequence, generating the amino acid substitution C108Y. The ability of this substitution to confer differential sensitivity for digoxin and digitoxin was tested and confirmed by expressing a human alpha 1 C108Y-Na,K-ATPase in wild type HeLa cells and assaying for inhibition of cell growth and inhibition of Na,K-ATPase activity. Phenylalanine or alanine substitutions of this cysteine also confer this pattern of ligand discrimination. Ouabain-resistant Na,K-ATPase substitutions, at positions other than Cys-108 failed to exhibit differential sensitivity indicating that this ligand discrimination is unique to Cys-108 substitutions rather than a general property of cardiac glycoside-resistant mutants. It is proposed that differential resistance of the C108Y receptor for these ligands is a consequence of altering two features of the ligand-receptor interaction; one, a disruption of a common hydrogen bond resulting in general loss of affinity for cardiac glycosides and the other, formation of a new H-bond between the C-12 hydroxyl of digoxin and the receptor, specifically augmenting the stability of this ligand-receptor complex.

Amino Acid Sequence↗
PubMed1998

[Digitalis poisoning treated with a specific antidote].

Toxicity by digitalis is a common problem in everyday clinical practice. In this paper three cases of severe poisoning with digitoxin with maximal S-digitoxin levels of 115, 150 and 239 nmol/l are described. All patients received specific digoxin Fab-fragment intravenously. Administration of antidotes resulted in a favourable outcome in all three patients. So far, the use of digoxin-specific antibodies has been limited to a few cases of severe intoxication where life-threatening arrhythmias and hyperkalaemia were present. We discuss whether a more liberal indication should be accepted.

Anti-Arrhythmia Agents↗
PubMed1976

[Concentration of cardiac glycosides in the heart and brain (author's transl)].

In cats the concentration of cardio-active glycosides in the heart and brain were investigated with trititum-labelled substances. Steady-state conditions were achieved by repeated i.v. injections of ouabain, digoxin, beta-methyldigoxin, digitoxin, and oleandrin over 5 days. 5 h after the last application glycoside concentrations were measured in plasma, urine, heart, cerebrum and cerebellum. Furthermore the metabolic pattern in these compartments was determined. 1. The glycoside concentration in the heart per g wet weight ranges only from 0.93 (oleandrin) to 1.88% (ouabain) of the daily administered dose per kg. 2. The concentrations in the brain show much higher differences between the diverse glycosides: ouabain with a concentration of 0.02%/g wet weight in the cerebrum shows the lowest and oleandrin with 1.60% the highest value. 3. By calculating the mean relative weights for the hearts (3.9 g/kg) and the brains (11.1 g/kg) 3.7% of the daily administered ouabain activity were found in the whole heart and only 0.18% in the whole brain. In contrast to these data the content of heart and brain after giving the more lipophilic oleandrin was 3.6% and 17.7% (!), respectively. 4. Under steady-state conditions the glycosides ouabain, digoxin, beta-methyldigoxin and digitoxin in heart and brain are mainly unchanged whereas oleandrin is transformed at a higher rate to polar metabolites.

Animals↗
PubMed1981

Sodium fluxes in human fibroblasts: effect of serum, Ca+2, and amiloride.

Human fibroblasts that have been serum deprived for 4 hours have a digitoxin-insensitive Na influx of 9.5 +/- 1.0 (n = 4) mumol/g prot/min which is not significantly different from the influx of 9.4 +/- 0.6 (n = 3) mumol/g prot/min measured in cells arrested in the G1/G0 state by serum-deprivation for a period of four days. The Na influx in serum-deprived cells is rapidly stimulated (within one minute) simply by assaying the cells in medium containing 10% fetal bovine serum (FBS). The digitoxin-insensitive NA influx for cells in the presence of 10% FBS is 22.9 +/- 1.1 (n = 6) mumol/g prot/min. The stimulation of Na influx in serum-deprived cells can also be achieved by the addition of the purified mitogen, epidermal growth factor (EGF). Addition of EGF to serum-deprived cells gives a maximal stimulation of Na influx of approximately 1.6-fold, with the concentration for half-maximal stimulation being 7.5 ng/ml. The stimulation of Na influx results from the activation of an amiloride-sensitive pathway, which appears to be minimally active in serum-deprived cells. Kinetic analysis of Na influx experiments in the presence of 10% FBS and varying concentrations of amiloride indicate that at infinite concentrations of amiloride the Na flux would be reduced to 8.9 mumol/g prot/min, which is comparable to the level of Na flux measured in serum-deprived cells in the presence of 5 mM amiloride. Thus, amiloride can totally inhibit the serum-stimulated component of Na influx while inhibiting less than 10% of the Na influx in serum-deprived cells. The Na influx in serum-deprived cells can also be stimulated 2.5-fold by preincubating cells in the presence of the Ca+ ionophore A23187 to elevate the intracellular Ca content. This stimulation of Na influx by intracellular Ca+2 can be virtually eliminated by adding 1 mM amiloride.

Amiloride↗
PubMed1986

Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis).

The relative toxicity of numerous cardiotonic steroids (viz. ouabain, digitoxin, digoxin, convallatoxin, SC4453, bufalin, gitaloxin, digoxigenin, actodigin, oleandrin, digitoxigenin, gitoxin, strophanthidin, gitoxigenin, lanatosides A, B and C, alpha- and beta-acetyl digoxin, alpha- and beta-methyl digoxin) and related compounds towards a number of independent cell lines established from human, monkey, mouse, Syrian hamster, and Chinese hamster have been determined. All cardiac glycosides and their genins, as well as the cardiotonic alkaloid cassaine, exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. These differences are species-related as all cell lines (both normal as well as transformed) from any one species, as well as cells from the closely related species (e.g., man and monkey or mouse, Chinese hamster, and Syrian hamster), showed similar sensitivity towards these drugs. The failure to see any significant differences in cellular toxicity for a larger number of other compounds which either bear limited structural resemblance to cardiac glycosides (viz. estradiol 17-beta-acetate, testosterone propionate, 21-acetoxy pregnenolone, beta-estradiol, digitonin, tigogenin, and tomatine) or interact with the Na+/K+ ATPase in a different manner (viz. veratridine, sanguinarine nitrate, penicillic acid, vanadium pentoxide, harmaline-HCI,5,5'-diphenyl hydantoin, quindonium bromide, and methyl quinolizinum bromide) provides strong evidence that the observed species-related differences are highly specific for cardiotonic steroids. Studies on the binding of [3H]ouabain show that, in comparison to human and monkey cell lines, no significant binding of the drug is observed in cells derived from the resistant species (i.e., mouse and Chinese hamster). The Na+/K+ ATPase from cells of the resistant species is inhibited at much higher concentrations of ouabain and digitoxin in comparison to the enzyme from human cells, and a good correlation is observed between these concentrations and those reported for inhibition of the enzyme from isolated heart muscles of the same species. These results provide strong evidence that the species-related differences in sensitivity to digitalis have a cellular basis and that the cultured cells from various mammalian species provide a useful model system for investigating the mechanism of action of cardiac glycosides.

Animals↗
PubMed1990

Pseudotumour cerebri-neurosurgical considerations.

Pseudotumour was diagnosed in six patients aged 3-38 years during an 8 years period. The diagnosis was based on headache, papilloedema, normal CT scan and cerebrospinal fluid (CSF) composition. Additional clinical symptoms were nausea, VIth nerve palsy, ataxia, blurred vision and frank visual reduction over time. Sagittal sinus thrombosis was ruled out by angiography or magnetic resonance imaging. In five of the six patients lumbar steady state infusion tests were performed to evaluate intracranial hydrodynamics and CSF resorbtion. All patients demonstrated a markedly increased opening pressure (range 13 to 48 mm Hg). CSF outflow resistance ranged from upper normal to pathologically increased levels (8-19 mm Hg/ml/min). Combined epidural intracranial pressure/middle cerebral artery blood velocity monitoring in 3 patients revealed a great number of B waves and a labile cerebral vasomotor state. Pharmacological treatment was tried with digitoxin, acetazolamide, furosemide and/or corticosteroids. Two patients did well on long-term treatment with digitoxin and furosemide, respectively. In the other four patients the clinical development was unsatisfactory on medical treatment alone. They were subsequently operated with implantation of a lumboperitoneal, cisternoatrial or cisternoperitoneal shunt. Shunting rapidly reversed clinical signs and symptoms, except for a partial persistent visual loss in an 18 years old boy who had experienced symptoms for 3 years resistant to pharmacological treatment.

Adolescent↗
PubMed1992

Cardiac effects of R 79595 and its isomers (R 80122 and R 80123) in an acute heart failure model. A new class of cardiotonic agents with highly selective phosphodiesterase III inhibitory properties.

R 79595 (N-cyclohexyl-N-methyl-2-[[[phenyl (1,2,3,5-tetrahydro-2 oxoimidazo [2,1-b]-quinazolin-7-yl) methylene] amin] oxy] acetamide) and its isomers represent a novel class of compounds with phosphodiesterase (PDE) inhibitory and cardiotonic (positive inotropic) actions. The cardiac effects of this class of compounds were investigated in the hexobarbital-depressed heart-lung preparation of the guinea-pig. After induction of heart failure (reduction of cardiac output to 25% of the initial value) cumulative addition of R 79595 or its isomers R 80122 (E-isomer) and R 80123 (Z-isomer) concentration-dependently reversed the cardiac depressant effects of hexobarbitone-Na. With regard to reconstitution of contractility and cardiac function R 80122 (E-isomer) was 10 fold more potent than R 79595 (1:1 mixture of the isomers) and nearly 100 fold more potent than R 80123 (Z-isomer). Furthermore, the cardiotonic action of the most potent isomer (R 80122) was compared to the effects of several positive inotropic reference compounds. The order of cardiotonic potency was as follows: (-)-adrenaline > R 80122 = adibendan > digitoxin > milrinone = enoximone > theophylline. Adibendan (EC50 value: 6.7 +/- 1.8 x 10.-8 mol/l), which showed cardiotonic effects in the same concentration range as R 80122 (EC50 value: 6.1 +/- 1.3 x 10(-8) mol/l), was significantly (p < 0.01) less effective than R 80122 with respect to the maximally induceable increase in cardiac output (CO). The cardiotonic effects of R 80122 could be observed in the low concentration range of 3 x 10(-8) to 1 x 10(-6) mol/l, whereas enoximone (EC50 value: 1.2 +/- 0.1 x 10(-5) mol/l) and milrinone (EC50 value: 8.9 +/- 3.5 x 10(-6) mol/l) elicited positive inotropic effects at 100 fold higher concentrations. Digitoxin was 10 fold less and theophylline was 300 fold less potent than R 80122 with regard to reconstitution of heart function. The cardiotonic effects of R 80122 were not accompanied by an increase in heart rate as found with milrinone, theophylline or (-)-adrenaline in this model. Furthermore, the PDE inhibitory effect of R 79595 and its E-isomer R 80122 were investigated in partially purified isoenzymes from guinea-pig ventricles. The IC50 values of R 79595 and R 80122 on PDE I-IV were compared to the IC50 values of adibendan, milrinone, enoximone and theophylline. The selectivity of an inhibitor for PDE III was evaluated by division of its IC50 values on PDE I, II and IV by the IC50 value on PDE III. R 80122 was the most potent and selective PDE III inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1977

Bilary and urinary excretion of five cardiac glycosides and its correlation with their physical and chemical properties.

Biliary and urinary excretion of five tritium-labelled cardiac glycosides, i.e. Ouabain, K-strophanthoside, Digoxin, Digitoxin and Deslanatoside C, were investigated in anaesthetized guinea-pigs 5 h after i.v. or enteral administration. Urinary excretion is the main route of elimination in the case of Ouabain and Deslanatoside C. Conversely, biliary excretion is predominant in the case of Digoxin and Digitoxin. K-strophanthoside is excreted both via bile and urine. In conscious guinea-pigs treated i.v. with the same cardiac glycosides the highest levels were observed in urine, bile, kidneys and liver. The relative values of those levels were in agreement with the excretion pattern observed in anaesthetized animals. An inverse linear relation (P less than 0.05) was encountered between biliary excretion rate and polarity of glycoside molecula. This correlation has been previously observed by other authors in other species, but not in the rabbit. This suggests that the correlation may not be considered generally applicable at present.

Animals↗
PubMed1983

On the pharmacokinetics of pengitoxin and its cardioactive derivative 16-acetyl-gitoxin.

The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng X ml-1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-infinity-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml X min-1 (7.0 to 18.6 ml X min-1) and 3.0 ml X min-1 (1.9 to 3.9 ml X min-1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.

Acetyldigoxins↗
PubMed1980

The effect of cathartic agents on transmucosal electrical potential difference in the human rectum.

Active ion transport in the colon is generating a transmucosal electrical potential difference (PD) of about 40 mV. Cathartic agents inhibit electrolyte and water net-absorption or cause net-secretion which should be reflected in a change of PD. In 83 normal subjects the effect of an isotonic eletrolyte solution (control) and different cathartic agents on rectal PD was tested: Laxatives (bisacodyl, rhein), bile acids (cholic and deoxycholic acid), fatty acids (oleic and ricinoleic acid) and cardiac glycosides (meproscillarin, digitoxin, digoxin). Bisacodyl, deoxycholic acid in high concentration, meproscillarin and digitoxin significantly decreased PD, while the other substances did not. Cathartics act on different transport mechanisms which together with different absorption characteristics of the proximal and distal colon may explain the difference in effecting the PD. Rectal PD measurement provides an easy and convenient tool to document effects of cathartic agents on electrolyte transport, otherwise difficult to obtain, and is applicable for clinical use.

Adult↗