Effect of digoxin on the sensitivity to flickering light

1 The sensitivity to flickering light at various light frequencies (DeLange curve) was determined in 20 controls and 45 patients receiving maintenance doses of digoxin. 2 Flicker thresholds (mean percentage of maximal light modulation +/- s.d.; F 30 Hz) were 7.6 +/- 1.7 in controls and 9.4 +/- 1.7 in patients with optimal plasma digoxin levels (0.5-1.9 ng/ml), but they rose to 15.5 +/- 1.9 at subtoxic levels (2.0-3.0 ng/ml), and to 21.8 +/- 2.6 at toxic levels (above 3.0 ng/ml). 3 Flicker sensitivity was inversely correlated with plasma digoxin levels and returned to baseline values when the administration of digoxin was interrupted. 4 The DeLange curve seems to be a valuable tool to measure the toxic effects of digitalis on the visual system.     

Impairment of digoxin clearance by coadministration of quinidine

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.     

Iodine-125-digoxin radioimmunoassay: comparison of commercial kits

Iodine-125-digoxin radioimmunoassay kits available from Abbott Diagnostics (AD), Dade Division (D), Schwarz/Mann (SM), and Clinical Assays (CA) were evaluated with respect to assay quality. The kit accuracies did not differ significantly at 2.0 ng/ml and the interassay coefficients of variation ranged from 9% (AD) to 21.4% (CA) The accuracy for all kits above 4 ng/ml is questionable, and since serum-dilution values correlated well with undiluted serum values, the dilution method of dose quantitation is preferable for levels above 4 ng/ml. Although all the kits were adequate, for evaluating digoxin at the 2ng/ml level, the Abott kit seems to be of slightly better quality.     

Intralobar sequestration causing heart failure in a new born infant. Surgical correction

An investigation was conducted to determine the specificity of the digoxin antibody provided in a commercially available radioimmunoassay kit with respect to dihydrodigoxin. Over the concentration range of 0.5 to 8.0 ng./ml. dihydrodigoxin displaced the 125I digoxin derivative from the antibody to a degree that could be significant at clinically observed serum and urine digoxin concentrations.     

Simultaneous liquid chromatographic analysis for carbamazepine and carbamazepine 10,11-epoxide in plasma and saliva by use of double internal standardization

High-performance liquid chromatography (HPLC) was used for simultaneous quantitation of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-EP) in plasma and saliva. Because concentrations of CBZ can greatly exceed those of CBZ-EP after single doses, two internal standards, lorazepam and N-desmethyldiazepam were added to all samples. Following extraction with chloroform, the components are separated on a muBondapak CN column with a mobile phase composed of 30% acetonitrile in water. Total chromatography time in 10 min. Concentrations of CBZ and CBZ-EP as low as 18 and 56 ng/ml, respectively, can be detected using 0.5 ml of plasma or saliva. The maximum within-day and day-to-day coefficients of variation for both compounds are 6.3 and 7.0%, respectively. Specificity of the method was supported by a significant correlation (r = 0.99) between assay results of the present method and those of a previously published HPLC assay. Application of the method to protein binding and salivary measurements in a single-dose CBZ disposition study is demonstrated.     

The effectiveness of formaldehyde treatment in protecting dietary protein from rumen microbial degradation

The kinetics of digoxin have been investigated in healthy volunteers using an isotopic tracer technique. A three compartment open kinetic model has been proposed as the simplest model consistent with the plasma, urinary and faecal data obtained. The renal clearance of digoxin (mean +/- s.d.) was found to be 119+/-10 ml/min, which did not differ significantly from the glomerular filtration rate (110+/-14 ml/min). Digoxin extra-renal clearance (mean+/-s.d.) was found to be 47+/-7 ml/min. The model predicts that the tissue concentration attained after four 0.25 mg oral doses spread over 24 h can be achieved within a period of 4 h following a single oral loading dose of 1 mg. Maintenance doses can be derived from a simple formula based on the glomerular filtration rate, extra-renal clearance and bioavailability of the digoxin preparation used.     

Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin     

Combined pharmacological and traction treatment in cases of painful syndromes of the cervical spine with degenerative and deformative changes

A simple, specific, and sensitive radioimmunoassay was developed for the determination of the diuretic bumetanide in plasma and urine. Antiserum to bumetanide was obtained from rabbits immunized with an immunogen prepared by covalently coupling the glycine conjugate of bumetanide to bovine serum albumin. Following extraction of the sample at pH 5.5 with ether, radioimmunoassay of the residue from the ether extract allows for the determination of bumetanide with a limit of sensitivity of about 1 ng/ml using 0.1 ml of plasma or urine. The specificity of the radioimmunoassay was established by comparison with specific radiometric and spectrofluorometric techniques. The pharmacokinetic profile of bumetanide in eight human subjects receiving single 2-mg oral doses of the drug was elucidated using the radioimmunoassay. The peak plasma levels ranged from 39 to 50 ng/ml at 1-4 hr after administration and declined with a mean apparent half-life of 1.17 hr. The mean plasma clearance rate was calculated to be 255 ml/min. During the first 24 hr, a mean of 43% of the bumetanide dose was excreted in the urine as intact drug.     

Validation of a telephone questionnaire for Parkinson''s disease

Unfractionated as well as low-molecular-weight heparins (LMWH) are known to cause an increase in blood levels of tissue factor pathway inhibitor (TFPI). To study the effect of a newly developed supersulfated LMWH (IK-SSH, Iketon Farmaceutici) on TFPI concentrations in human plasma, the compound was injected into volunteers at doses of 0.14, 0.33 and 0.66 mg/kg intravenously or 0.33, 0.66 and 1.0 mg/kg subcutaneously. At certain known times blood was drawn and plasma levels of both total and free TFPI were measured using enzyme-linked immunosorbent assay methodology. Baseline plasma concentrations of TFPI were 72.2+/-3.1 ng/ml for total and 10.8+/-0.8 ng/ml for free TFPI. Intravenous or subcutaneous injection of IK-SSH led to a strong and long-lasting rise in TFPI levels which were increased more than 5-fold for total TFPI and more than 30-fold for free TFPI. Maximum TFPI levels were reached 5-10 min after intravenous and 60 min after subcutaneous administration. IK-SSH caused prolongation of ex-vivo clotting times in the APTT and Heptest assay, whereas thrombin time was not affected. Anticoagulant actions of IK-SSH showed a significant correlation to plasma concentrations of TFPI and they are thought to be based at least partially on the release of TFPI from vascular sites.     

Usefulness of simultaneous determination of alpha-fetoprotein and des-gamma-carboxy prothrombin in hepatocellular carcinoma

Serum gamma-fetoprotein (AFP) and plasma des-gamma-carboxy prothrombin (DCP), a protein induced by vitamin K absence or antagonist II (PIVKA-II) levels, were measured in 197 patients with primary hepatocellular carcinoma (HCC). DCP levels were determined by conventional enzyme immunoassay kit (E-1023) and a newly developed high-sensitivity kit using the avidin-biotin complex method. Cut-off levels of AFP and DCP by the E-1023 kit and of DCP by the high-sensitivity kit were put at 100 ng/ml, 0.1 arbitrary unit (AU)/ml, and 0.004 AU/ml, respectively. Positive rate of AFP and DCP by the E-1023 kit and the high-sensitivity kit for HCC was 48%, 44%, and 57%, respectively. The positive rate by combination assay with AFP and DCP by the high-sensitivity kit increased up to 73%. There was no correlation between serum levels of AFP and those of plasma DCP. A significant correlation between tumor size and DCP levels was observed, but not with AFP. The postoperative disease-free survival rates of patients in the group with elevated levels of AFP and DCP were lower than those with normal levels of AFP and DCP. There were various patterns of change in the AFP and DCP levels at the time of recurrence compared with preoperative patterns. The combination assay of AFP and DCP levels is useful for the diagnosis, prognosis, and postoperative monitoring for recurrence of HCC.     

Single daily dose of digoxin for maintenance therapy of infants and children with cardiac disease: is it reliable?

Between July 1990 and September 1991, 30 infants and children, most of whom had a congenital heart defect and who had been treated at least during the previous 20 days by two daily doses of digoxin and were in a stable clinical condition, were selected at random. A maintenance dose of digoxin was administered at 24-h intervals for 7 days in the study group (n = 15); no change was made in the 12-h dosage interval in the control group (n = 15). When the serum digoxin concentrations were compared, no significant difference was found between pre- and poststudy values in the study group (1.0 +/- 0.6 and 0.8 +/- 0.3 ng/ml, respectively) or between the control and study groups (0.9 +/- 0.6 and 0.8 +/- 0.3 ng/ml, respectively) in terms of trough serum digoxin concentrations. Although the peak serum concentrations in the study group were increased significantly (2.3 +/- 0.8 ng/ml) compared with prestudy peak levels (1.6 +/- 0.7 ng/ml, p < 0.05) and with the level in the control group (1.5 +/- 0.8 ng/ml, p < 0.05), a toxic concentration was not reached, and toxicity symptoms were not observed clinically. Blood pressure, heart rate, and liver size did not change significantly in any patient during the study.     

Determination of plasma digoxin in newborn infants. Practical applications

Measurement of plasma digoxin concentrations in infants after three increasing dosage levels shows that the optimal dose of this glycoside in 20 microgram/kg/day, i.e. a loading dose of 20 microgram/kg followed every 8 hours by a maintenance dose of 7 microgram/kg. The plateau concentration achieved is 3.0 +/- 0,5 ng/ml 8 hours after the last administration. When digoxin levels exceed 5 ng/ml (overdosage, renal failure or low body weight), toxic manifestations occur.     

Plasma-digoxin concentration in patients at time of hospital admission (author's transl)

Plasma-digoxin and serum creatinine concentrations were determined on admission in 145 unselected patients previously digitalized as outpatients. Adequate digitalization was found in 62.7%, inadequate doses in 15.9% of patients. In the latter group the daily dosage reported by the patients failed to correlate with the plasma-digoxin concentration by radioimmunoassay. One-fifth of all patients had clinical evidence of digitalis intoxication. Of these, 69% had plasma-digoxin concentrations of more than 2.0 ng/ml and 31% less than 2.0 ng/ml. Mean digoxin concentration for all patients with signs of digitalis intoxication was 2.5+/-0.9 ng/ml. In patients simultaneously receiving spironolactone or canrenoate-K+ there was danger of falsely high values for digoxin because of interference of those drugs with the radioimmunoassay.     

A specific antidote for the treatment of digitalis poisoning in uremic patients

Two chronic haemodialyzed patients with digitalis intoxication are reported. One of them took digoxin 0.25 mg three times daily for an unknown period and the other took digitoxin 0.1 mg twice daily for two weeks. The symptoms of intoxication were mainly concealed by uremic syndrome. The diagnosis was established by noticed sinus bradycardia, first- and second-degree atrioventricular block in ECG and the determination of sera levels of glycosides (serum digoxin concentration was 7.36 ng/ml, serum digitoxin concentration was 46.5 ng/ml) in both cases. Considering the probable long elimination period of digitalis and the potentially life-threatening situation the patients were given digoxin-specific antibody (Fab) fragments with potassium replacement therapy. The symptoms disappeared within a few hours after therapy, side effects and rebound toxicity did not develop. In connection with these cases the aim of this report is to publish a method which can reverse the life-threatening digitalis intoxication in patients suffering from renal failure as well. As to the above method, the authors have not found any similar case reports in the Hungarian medical literature.     

The serum digoxin concentration: ten questions to ask

Although the role of digoxin therapy has been the subject of debate, the drug is generally accepted as effective in the treatment of heart failure due to systolic dysfunction and as therapy for atrial fibrillation and supraventricular tachyarrhythmias. Serum digoxin concentrations are commonly used to gauge patient response to digoxin. Digoxin pharmacokinetics are complex, and many factors can confound the interpretation of digoxin concentrations. The exact therapeutic range of serum digoxin varies in the literature but should be considered to be from 0.8 to 2.0 ng per mL, on the basis of population data regarding therapeutic response and toxicity. Renal function plays a major role in digoxin pharmacokinetics and is an important factor in determining digoxin doses. Many medications, including quinidine, amiodarone and verapamil, alter digoxin pharmacokinetics and can result in two- to three-fold increases in the serum digoxin concentration. Effective interpretation of the digoxin concentration requires consideration of the patient's renal function and clinical status, possible drug interactions, time of the assay and other variables.     

Neutralization of cardiac toxins oleandrin, oleandrigenin, bufalin, and cinobufotalin by digibind: monitoring the effect by measuring free digitoxin concentrations

Oleandrin plant poisoning is common in children and the plant extract is used in Chinese medicines. The toxicity is due to oleandrin and the deglycosylated metabolite oleandrigenin. Bufalin and cinobufotalin (toad cardiac toxins) are also widely used in Chinese medicines like Chan SU, and Lu-Shen -WU. Severe toxicity from bufalin after consumption of toad soup has been reported. Taking advantage of structural similarities of these toxins with digitoxin, we demonstrated that these compounds can be rapidly detected in blood by the fluorescence polarization immunoassay for digitoxin. The cross reactivities of these compounds with digoxin assay were much lower. For example, when a drug free serum was supplemented with 10 microg/ml of oleandrin, we observed 127.7 ng/ml of digitoxin equivalent but only 2.4 ng/ml of digoxin equivalent concentration. Digibind neutralized all cardiac toxins studied as evidenced by significant fall of free concentrations. When aliquots of serum pool containing 50.0 microg/ml of oleandrin were supplemented with 0, 10.0, 25.0, 50.0, 100, and 200 microg/ml of digibind, the mean free concentrations were 30.6, 23.3, 16.0, 10.7, 7.8 and 5.5 microg/ml respectively. Similarly, with 50.0 microg/ml of oleandrigenin (total concentration: 36.2 ng/ml), the free concentration was 14.5 ng/ml digitoxin equivalent in the absence of digibind and 5.4 ng/ml in the presence of 200 microg/ml of digibind. In another specimen containing 500 ng/ml bufalin (total concentration: 156.9 ng/ml), the free concentration was 8.6 ng/ml in the absence of digibind and none detected in the presence of 100.0 microg/ml digibind. Because such neutralization may also occur in vivo, digibind may be useful in treating patients exposed to these toxins.     

Measurement of gestagen concentration in feces using a bovine milk progesterone quantitative test EIA kit and its application to early pregnancy diagnosis in the sow

We attempted to measure the gestagen concentration in the feces of pigs by using a commercial bovine milk progesterone quantitative test EIA kit, and investigated the possibility of applying of this method of gestagen concentration measurement to early pregnancy diagnosis in the sow. Feces were collected from the rectum of the pig, and 0.5 g of the feces was placed in 20 ml of distilled water, stirred, and centrifuged. The supernatant was used as the fecal solution for measurement of gestagen. The procedure used for measuring gestagen in feces was the same as that for the measurement of progesterone in milk, except that a standard fecal gestagen solution (0.5-30.0 ng/ml) was prepared by the authors in the laboratory. The sensitivity of measurement using this method was 0.80 ng/ml, or 32.0 ng/g of fecal weight. The recovery was 105.2-105.6%. Intra-assay coeffecients of variation (CVs) were 2.8-8.5%. The interassay CVs were 7.4-10.2%. Gestagen concentrations in feces measured by the present method and progesterone concentrations in peripheral plasma, collected at the same time as the feces were highly correlated (r = 0.98, p < 0.001). The criteria for diagnosis of pregnancy based on the fecal gestagen level was positive for a gestagen level of > or = 200 ng/g and negative for a gestagen level of < 200 ng/g. When fecal gestagen measurements were applied to early pregnancy diagnosis in 149 sows, the accuracy of diagnosis from day 21 to day 25 after the last mating was 96.2% for positive cases (102/106) and 95.3% for negative cases (41/43). Thus, the results of this study show the quantitative measurement of the fecal gestagen concentration in the sow using a bovine milk quantitative test EIA kit is a practical method for early pregnancy diagnosis.     

The correction of the immune and microcirculatory disorders in patients with chronic hepatitis of alcoholic and viral etiologies

A simple, rapid and sensitive method for the clean-up and analysis of cefoxitin in serum and tissue is described. Serum (0.5 ml) and tissue (100 mg) samples after homogenization underwent high speed centrifugation. Chromatography was performed on a muBondapak C18 cartridge using a mobile phase of 0.005 M potassium dihydrogen phosphate-acetonitrile-glacial acetic acid (77.5:22:0.5, v/v/v) with a flow-rate of 2.0 ml/min. Ultraviolet detection occurred at 235 nm. The procedure produced a linear curve for the concentration range 100-5000 ng/ml. The assay produced accurate, repeatable and rapid results for both tissue and serum samples without the need for chemical extraction.     

An open, randomized study of ketoprofen in patients in surgery for Achilles or patellar tendinopathy

OBJECTIVE: To assess the concentration of ketoprofen, after topical plaster application, in various tissues in relation to plasma levels in 60 patients undergoing surgery for Achilles or patellar tendinopathy; and to analyze whether tissues act as a reservoir of ketoprofen, by evaluating tissue concentrations in relation to plasma concentration at various time points after removal of the plaster. No attempt was made to study the clinical effect of treatment per se. METHODS: In random order to patients applied 30 mg plasters once daily for 5 consecutive days (n = 30), or took a single oral dose 50 mg (n = 30) before surgery. Tissue samples of skin, subcutaneous fat, tendon sheath, and tendon, and plasma were collected intraoperatively at 0, 6 and 14 hours after removal of the 5th plaster, and at 2, 6, and 14 hours after oral intake. Ketoprofen concentration was determined by a validated GC/MS method. The low limit of quantification was 0.5 ng/ml plasma and 0.5 ng/50 mg tissues. RESULTS: High concentrations of ketoprofen were observed in fat, tendon sheath, and tendon after topical applications, whereas plasma levels of ketoprofen were low. CONCLUSION: Ketoprofen attains high concentrations in subcutaneous tissues after multiple topical applications. Subcutaneous tissues appear to act as a reservoir of ketoprofen.     

Development and use of specific polymerase reaction for the detection of an organism resembling Ehrlichia sp. in white-tailed deer

OBJECTIVE: To establish the pharmacodynamic and safety equivalence between 2 sustained-release forms of leuprorelin 11.25 mg and 3.75 mg, in the treatment of metastatic prostatic carcinoma. METHODS: 44 patients received subcutaneous injections of leuprorelin for 9 months (randomization: 2/l): either 11.25 mg every three months (n = 29) or 3.75 mg monthly (n = 15). Main criterion: centralized monthly assay of plasma testosterone (T). RESULTS: The equivalence of the 2 forms in terms of mean plasma testosterone was demonstrated (p = 0.002): 1 month: T = 0.19 +/- 0.03 ng/ml; 3 months: T = 0.27 +/- 0.04 ng/ml. Exploratory analysis did not reveal any significant difference between the groups for the number of patients castrated at each visit or for the number of patients with all T values < or = 0.5 ng/ml, or for clinical responses or safety. CONCLUSION: The 2 forms have a comparable efficacy and safety.