N. A. Klitgaard

Digoxin-verapamil interaction

To explore a possible interaction between digoxin and verapamil, a single‐dose kinetic study of digoxin was performed and then repeated after 10 days of verapamil treatment in eight healthy subjects. Verapamil diminished the apparent central distribution volume of digoxin from 0.83 ± 0.25 to 0.64 ± 0.17 l/kg (P < 0.05) and reduced total body clearance of digoxin from 3.28 ± 0.58 to 2.15 ± 0.66 ml/min/kg (P < 0.001) by impairing both renal and extrarenal clearance. Biological digoxin half‐life rose from 38.6 ± 8.5 to 50.5 ± 8.3 hr (P < 0.005). Reduction of renal clearance of digoxin may be due to inhibition of tubular secretion. The underlying mechanisms of extrarenal interaction are not known, but impaired hepatic degradation of digoxin induced by verapamil should be considered.

N-terminal pro-brain natriuretic peptide for discriminating between cardiac and non-cardiac dyspnoea

Evaluation of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) to confirm or disprove heart failure in community patients complaining of dyspnoea.

The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects

SummarySingle-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21±0.01 ng/ml (SE) to 0.34±0.01 ng/ml (p<0.01), and renal digoxin clearance had fallen from 197.57±17.37 ml/min to 128.20±10.33 ml/min (p<0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27±0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46±3.23% before to 69.78±3.69% (p<0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.

Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans

Tricyclic antidepressants relieve neuropathic pain, and the analgesic properties of tricyclic antidepressants are substantiated in human experimental pain models. It has been speculated that drugs with a selective inhibition of presynaptic reuptake of both serotonin and noradrenaline could have an analgesic effect comparable to the analgesic effect of tricyclic antidepressants.

Effect of Quinidine on Digoxin Bioavailability

SummaryTo evaluate the possible effect of quinidine on digoxin bioavailability, the steady state digoxin kinetics was examined with and without concomitant quinidine therapy, in 7 cardiac patients after simultaneous administration of oral digoxin and intravenous [3H]-digoxin. In the presence of quinidine, the absorption rate constant of digoxin (ka) increased from 2.72±1.04 to 3.53±1.34 h−1 (p<0.05), whereas lag time and peak time decreased from 0.16±0.10 to 0.05±0.04 h (p<0.05) and from 0.92±0.27 to 0.69±0.19 h (p<0.02), respectively. Predose plasma digoxin increased from 0.41±0.25 to 0.70±0.31 ng/ml (p<0.02), while peak plasma digoxin increased from 0.93±0.34 to 1.63±0.46 ng/ml (p<0.02). The systemic availability of digoxin increased from 68.48±13.35 to 79.09±14.89% (p<0.05) in the presence of quinidine. Quinidine had no effect on the biotransformation pattern of digoxin, as assessed by thin layer chromatography. Quinidine increases the rate and extent of digoxin absorption, and this interaction contributes significantly to the elevation in plasma digoxin during both its distribution and elimination phases.

Moclobemide and nortriptyline in elderly depressed patients. A randomized, multicentre trial against placebo

Moclobemide and nortriptyline were compared with placebo in a double-blind randomized multinational (Canada, Denmark and UK) trial comprising 109 patients of > 60 years of age with major depression (DSM-III-R). Patients were randomized to 7 weeks of treatment with doses of 400 mg/day moclobemide, 75 mg/day nortriptyline or placebo. It was necessary to adjust nortriptyline dosage in < 20% of patients to maintain serum levels within the postulated therapeutic window of 50-170 ng/ml. At end of treatment, the remission rates were 23% for moclobemide, 33% for nortriptyline and 11% for placebo. Anticholinergic and orthostatic events occurred more often with patients on nortriptyline than either moclobemide or placebo.

Pharmacokinetics of 10‐OH‐carbazepine, the main metabolite of the antiepileptic oxcarbazepine, from serum and saliva concentrations

After administration of 600 mg of the antiepileptic oxcarbazepine to 7 healthy volunteers, serum and stimulated saliva samples were collected for the next 72 h. Concentrations of 10‐OH‐carbazepine, the main metabolite of oxcarbazepine, were determined by an HPLC method. The time‐concentration curves showed a median Tmax of 8 h followed by a plateau until 24 h indicating saturable kinetic processes. Based on the curves, the pharmacokinetic parameters were calculated. The half‐life of 10‐OH‐carbazepine in saliva, 13.8 ± 3.7 (SD) h, was significantly shorter than in serum, 19.3 ± 6.2 (SD) h. The half‐life of 10‐OH‐carbazepine in serum was inversely correlated to the free fraction, estimated by the ratio saliva/serum concentrations. Calculation of the free fraction by this method showed that 53.1 ± 14.4 (SD) % of 10‐OH‐carbazepine is unbound in serum. There was a good correlation (r = 0.914) between serum and saliva concentrations of 10‐OH‐carbazepine from 8–72 h after administration of oxcarbazepine. This finding indicates that saliva concentrations may prove useful, as has been shown for carbamazepine, in therapeutic monitoring of oxcarbazepine treatment.

Simultaneous quantitative determination of the HIV protease inhibitors indinavir, amprenavir, ritonavir, lopinavir, saquinavir, nelfinavir and the nelfinavir active metabolite M8 in plasma by liquid chromatography

A simple HPLC method that quantitates all six currently available protease inhibitors and the nelfinavir active metabolite M8 in one assay is presented. A 500-microliter plasma sample was treated by liquid-liquid extraction with a mixture of heptane and ethyl acetate. After evaporation, the residue was redissolved in sodium dihydrogenphosphate and acetonitrile and washed twice with heptane. Chromatography was performed with an analytical C(18) column. Ultraviolet detection at 210 and 239 nm was used. The present method is associated with high accuracy and low imprecision in the concentration range of 25-5000 ng/ml of all six protease inhibitors and M8. This makes it suitable for monitoring purposes.

Insulin Increases Renal Magnesium Excretion: A Possible Cause of Magnesium Depletion in Hyperinsulinaemic States

The effects of insulin upon renal magnesium excretion were examined. Urinary magnesium excretion rates were measured in seven healthy volunteers (three men, four women) before and during a euglycaemic, hyperinsulinaemic clamp. Insulin was infused at 120 pmol m−2 min−1 and at 240 pmol m−2 min−1. Compared to baseline, the renal magnesium excretion increased 30 % during the infusion of insulin at a rate of 120 pmol m−2 min−1. During infusion of insulin, 240 pmol m−2 min−1, renal magnesium excretion increased 50 % compared to baseline. There were no changes in either glomerular filtration rates, plasma magnesium, urinary volume or general changes in the renal handling of divalent ions as judged by an unchanged urinary excretion rate of calcium (0 % during infusion of insulin, 120 pmol m−2 min−1, and 8 % increase during infusion of 240 pmol m−2 min−1 (NS)). During the 120 pmol m−2 min−1 insulin infusion rate, plasma insulin rose from 46.1 pmol l−1 to 158.8 pmol l−1 and during the 240 pmol m−2 min−1 insulin infusion rate, mean plasma insulin concentration was 361.4 pmol l−1. Thus, physiological concentrations of insulin induce a specific increase in the renal excretion of magnesium. This might partly explain the magnesium depletion observed in various hyperinsulinaemic states, diabetes mellitus, atherosclerosis, hypertension, and obesity.

Effect of nifedipine on digoxin kinetics in healthy subjects

Verapamil has been shown to reduce total‐body digoxin clearance by 35% due to impairments of both renal and extrarenal clearances. Our study was undertaken to evaluate the influence of the related calcium antagonist nifedipine on single‐dose digoxin kinetics. Nifedipine increased extrarenal clearance of digoxin from 1.09 ± 0.30(SD) to 1.45 ± 0.23 ml/min/kg (P < 0.05) and reduced the total urinary recovery of the drug from 69.2% ± 5.9(SD) to 64.3% ± 5.2 (P < 0.05). There were no significant changes in renal digoxin clearance, distribution, or biological half‐life or in digoxin distribution volumes during nifedipine coadministration.