Interaction between digoxin and propafenone

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.     

Interaction between indomethacin and heavy metal ions in aqueous solution.

The interaction between indomethacin anions and heavy metal ions, such as cadmium, zinc and copper(II) ions, was studied in aqueous solution by polarographic techniques. Indomethacin anions form complexes with these heavy metal ions: the complex formed with cadmium ions is sparingly soluble, while more soluble and also stronger complexes are formed with zinc and copper(II). At high concentrations, where indomethacin anions undergo self-aggregation, these last compounds are solubilised. This property is briefly discussed and compared to that of bile salts. In the presence of calcium ions, indomethacin forms a poorly soluble salt and no evidence was detected for the formation of complex species.     

Interaction between methotrexate and indomethacin on a human normal haemopoietic cell line.

1. The interaction between methotrexate and indomethacin has been examined, at a physiological folate concentration (20 nM), on a human normal lymphoblast-like cell line (RPMI 1788) in vitro. 2. Indomethacin (1 microgram ml-1) increased the reduction of lymphoblast growth caused by methotrexate (10-80 ng ml-1). 3. Indomethacin (0.1 and 1 microgram ml-1) potentiated the cytotoxicity of methotrexate (20 and 40 ng ml-1) after 4 days in culture. 4. Indomethacin (0.4 micrograms ml-1) reduced the accumulation of tritium in lymphoblasts incubated with [3H]-methotrexate after 30 min; therefore initial drug accumulation was not responsible for the potentiation seen after 4 days. 5. If indomethacin increases the killing of human cancer cells by methotrexate in vivo, with a smaller potentiation on lymphoblasts, this combination may be beneficial in treating human malignancy.     

The effect of ibuprofen on serum digoxin concentrations

This study was undertaken to determine the effects of ibuprofen (Motrin), in daily doses of at least 1600 mg, on steady-state digoxin concentrations. A total of 12 ambulatory patients (10, female; 2, male), with a mean age of 66 years (38-81 yr), completed the study. An initial baseline serum digoxin level was obtained, with follow-up levels at 7 days and, whenever possible, 28 days after ibuprofen initiation. Serum creatinine concentrations were not significantly different from baseline to 7 or 28 days of ibuprofen therapy. Results show a statistically significant (p less than 0.05) increase in digoxin levels after seven days of ibuprofen. The mean increase was 59 percent (range, 10.7-325.4 percent), with 10 of the 12 patients displaying increased seven-day levels. Digoxin levels drawn 28 days after ibuprofen initiation were not statistically different from baseline or seven-day digoxin levels.     

Interaction of indomethacin and sulindac with labetalol.

The effects of sulindac and indomethacin on the blood pressure response to labetalol were determined in well-controlled predominantly obese hypertensive patients (n = 26). A stabilized dose of labetalol alone was administered on weeks 1 and 3, and either indomethacin or sulindac was administered with labetalol on week 2, with cross-over to the other drug on week 4. Indomethacin and sulindac increased the sitting and standing systolic blood pressure (BP) to a statistically significant extent compared with placebo. The effects of indomethacin on systolic BP, diastolic BP, and weight were not significantly different from those with sulindac. Indomethacin but not sulindac produced minor increases in diastolic BP and weight compared with placebo.     

Effect of ibuprofen and indomethacin on human plasma melatonin

Ibuprofen reduced human plasma melatonin (MT) after 2 h when administered orally (400 mg) at 2400 h. Increasing plasma concentrations correlated well with increasing inhibition of serum MT levels during this time. Maximum plasma ibuprofen coincided with minimum plasma MT in 3 out of 4 volunteers. Although two volunteers exhibited a partial recovery in MT levels, concentrations after 6 h were significantly less than 0600 h values in drug-free volunteers. Administration of ibuprofen (400 mg) at 1800 h delayed the nocturnal surge of plasma MT. When a slow release preparation of indomethacin (75 mg) was administered at 1800 h, the dark phase rise of plasma MT was completely prevented. Thus the longer acting cyclooxygenase inhibitor exhibited a longer lasting inhibition of plasma MT concentration.     

Interaction between chloroquine and indomethacin in airways smooth muscle in vivo

The indomethacin-induced enhancement of airways smooth muscle contractility to histamine reported earlier in vitro has now been demonstrated in conscious guinea-pigs. Chloroquine, an anti-malarial drug with phospholipase A2 inhibitory activity, antagonized histamine and also reversed the indomethacin-induced enhancement. These observations indicate that histamine-induced bronchospasm in vivo is modulated by the arachidonate system and that chloroquine-type phospholipase A2 inhibitors may ameliorate such bronchospasm. These findings also explain the observed clinical benefits of chloroquine in chronic asthmatics.     

Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin.

The potential pharmacokinetic interactions between argatroban and acetaminophen, lidocaine, or digoxin were examined. Three randomized crossover studies were conducted. In the first study, 11 subjects completed three sessions (with a five-day washout period between sessions), receiving two 500-mg acetaminophen caplets at 0, 6, 12, 18, and 24 hours; i.v. argatroban 1.5 micrograms/kg/min from hours 12 to 30; or a combination of both. In the second study, 12 subjects completed three sessions (with a five-day washout period between sessions), receiving lidocaine hydrochloride injection 2 mg/kg/hr for 16 hours (after receiving a loading dose of 1.5 mg/kg over 10 minutes), i.v. argatroban 1.5 micrograms/kg/min for 16 hours, or a combination of both. In the third study, 12 subjects completed two sessions (with a seven-day washout period between sessions), receiving oral digoxin 0.375 mg/day for 15 days and either i.v. placebo or argatroban 2 micrograms/kg/min on days 11 through 15. Primary pharmacokinetic values in each study included area under the drug concentration versus time curve and steady-state concentrations of argatroban and the concomitantly administered drug. Lack of a pharmacokinetic interaction (individually defined for each study) was demonstrated in each study. Argatroban, regardless of acetaminophen or lidocaine administration, prolonged activated partial thromboplastin time values approximately 1.6-1.8 times the baseline values. No deaths, unexpected adverse events, or clinically significant changes in safety laboratory values occurred. No pharmacokinetic interaction was detected between argatroban and acetaminophen, lidocaine, or digoxin. Argatroban is well tolerated during coadministration with these drugs. In practice, argatroban coadministered with these frequently prescribed drugs should require no dosage adjustments.     

A crossover clinical trial of piroxicam, indomethacin and ibuprofen in rheumatoid arthritis.

A single-blind, crossover trial was carried out in 24 patients with definite or classical rheumatoid arthritis to compare the effectiveness and tolerability of piroxicam (20 mg once daily) with that of indomethacin (25 mg 3-times daily), ibuprofen (400 mg 3-times daily) and placebo. Each drug was given in random order for a period of 1 week. Pain, joint tenderness and morning stiffness decreased and grip strength increased with piroxicam compared to placebo; no statistically significant difference could be found between piroxicam and the two other active agents. A reduction in joint circumference could not be demonstrated with piroxicam or ibuprofen but most patients did not have reducible swelling in their finger joints. Piroxicam was just as effective as the other two drugs overall, but fewer side-effects were noted with piroxicam.     

Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen

STUDY OBJECTIVES: To study the concentration-effect relationships of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin, diclofenac, and ibuprofen; to investigate whether standard doses of these drugs inhibit prostaglandin concentrations to a similar extent, determined by measuring the concentration of a surrogate marker of prostaglandin E 2 (PGE 2 ); and to determine the extent to which dose increases produce analogous increases in prostaglandin inhibition. DESIGN: Single-dose, randomized, crossover trial with a 1-week washout period. SETTING: University biopharmaceutics and pharmacokinetics laboratory. SUBJECTS: Eight healthy adult volunteers younger than 35 years old. INTERVENTION: Subjects were administered two different standard doses of regular formulations (not enteric coated) of each NSAID on separate occasions. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected for determination of drug and 13,14-dihydro-15-keto-PGE 2 (PGEM; the surrogate marker of PGE 2 ) concentrations at regular intervals after administration of each NSAID dose. Statistically significant linear correlations were found between the percent reduction in PGEM concentration and the concentrations of diclofenac, indomethacin, and ibuprofen in plasma (R 2 = 0.992-0.999). The PGEM plasma concentrations correlated inversely with NSAID plasma concentrations, indicating maximum inhibition when the highest NSAID plasma concentrations were achieved. Statistically significant differences in the percent inhibition of PGEM concentrations were observed between the two doses for each NSAID (p<0.05), but not between subjects for each NSAID. Doubling the dose (100% increase) of diclofenac and indomethacin produced a 60-65% increase in maximum inhibition of PGEM concentrations, whereas a 50% increase in dose produced a 44% increase in the maximum effect of ibuprofen. CONCLUSION: Prostaglandin inhibition, as measured by changes in PGEM concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PGEM plasma concentrations appears to be a promising marker for estimation of relative potency of NSAIDs.     

Increase in serum digoxin concentrations after indomethacin therapy in a full-term neonate.

Digoxin was administered to an 18-day-old infant who showed evidence of cardiac failure. When a Doppler echogram revealed a patent ductus, indomethacin was administered for medical management. Therapeutic digoxin doses then resulted in toxic serum concentrations of 8.2 ng/ml. Serum creatinine rose accordingly. Although this patient did not manifest signs of digoxin toxicity, practitioners should be alerted to the potential complications of these commonly used agents.     

Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha)

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorn's beneficial effects in the treatment of heart failure. However, these components may also affect P-glycoprotein function and cause interactions with drugs that are P-glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0-infinity, Cmax-Cmin, Cmin, and renal clearance for the D group were 79 +/- 26 mcg.h/L, 1.4 +/- 0.7 mcg/L, 0.84 +/- 0.2 mcg/L, and 74 +/- 10 mL/min versus 73 +/- 20 mcg.h/L, 1.1 +/- 0.1 mcg/L, 0.65 +/- 0.2 mcg/L, and 81 +/- 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, may be coadministered safely.     

Interaction between digoxin and nifedipine at steady state in patients with atrial fibrillation

The possible kinetic and hemodynamic interactions between digoxin and nifedipine were evaluated in nine patients with atrial fibrillation who were receiving chronic digoxin. After 2 control weeks, nifedipine (20 mg b.i.d.), in a new formulation with sustained release characteristics, was added to the therapeutic regimen for 2 weeks. Trough serum digoxin concentrations and peak nifedipine concentrations were determined repeatedly. On the same days, resting blood pressure and heart rate were measured. During nifedipine administration, serum digoxin levels increased by 15% from 0.87 +/- 0.38 to 1.04 +/- 0.37 ng/ml (mean +/- SD, p less than 0.05). This was accompanied by a reduction in systolic and diastolic blood pressure of 16 +/- 6 (p less than 0.01) and 12 +/- 5 mm Hg (p less than 0.001), respectively. In two patients, noncardiac side effects were reported. In two other patients, nifedipine was discontinued because of skin rash and severe headache, respectively. In conclusion, plasma digoxin levels were elevated slightly in the presence of nifedipine, but this probably has little clinical relevance.     

Pharmacokinetics of digoxin alone and in the presence of indomethacin therapy

The effects of maintenance indomethacin therapy on single dose digoxin pharmacokinetics and dynamics were studied in six healthy volunteers with normal renal function. Indomethacin did not alter the elimination half-life, systemic clearance or distribution of digoxin. No pharmacodynamic interaction as assessed by changes in the systolic time intervals QA2 and LVET was found. This study does not lend support for a significant digoxin-indomethacin interaction in man.     

Interaction of digoxin and montmorillonite: mechanism of adsorption and degradation.

IR, X-ray diffraction, and absorption studies showed that digoxin is adsorbed onto montmorillonite by a reversible adsorption mechanism at pH 2 and 6. Degradation studies indicated abnormally high acid hydrolysis rates for digoxin interacted with montmorillonite. Accelerated digoxin degradation is attributed to the ability of the clay surface to concentrate both digoxin and protons. The effective pH at the clay surface appeared to be 1.5 pH unites lower than the bulk suspension pH. Bisdigoxigenin was the major adsorbed degradation product. A similar catalytic effect also may occur with other neutral drugs that degrade by acid hydrolysis and should be considered in the formulation of clay-containing drug products or their coadministration with other drugs.     

The mechanism of the antihypoxic action of indomethacin, voltaren and ibuprofen

The antihypoxic effects of indomethacin, voltaren and ibuprofen were studied experimentally by the parameters of acid-base equilibrium of the blood and the ratio of lactic and pyruvic acids in the blood during chronic hemic and respiratory hypoxia. The results of the studies suggested that indomethacin, voltaren and to a lesser extent ibuprofen in the tested doses (10% LD50) exerted the antihypoxic action that consisted in the improvement of oxygen supply to tissues under conditions of its deficiency, the decrease of incompletely oxidized products of metabolism, the enhancement of hemoglobin synthesis and the ability of voltaren to influence the increase of the number of erythrocytes in the peripheral blood.