Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin

Summary Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.Supported in part by Grant Oc 10/4 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-12279 from the United States Public Health Service     

Digitalis intoxication and treatment with digoxin antibody fragments in renal failure

Summary Severe digitalis intoxication today is preferentially treated by intravenous infusion of Fab fragments of digoxin antibodies (Digitalis Antidot BM). The kinetics of Fab fragments in the circulation are well known when kidney function is normal or slightly impaired. There are no data available, however, in complete renal failure. We observed a patient with life-threatening digitalis intoxication (serum digoxin, 3.7 ng/ml) and anuria, who was treated successfully by 160 mg Fab fragments i.v. Serum digoxin and Fab fragment concentrations could be followed for 229 h. The extrarenal clearance of Fab fragments was lower (5.6 ml/min) than in patients with normal kidney function (10.9 ml/min). This finding suggests that lower doses than usual might be sufficient for treating patients with severe digitalis intoxication and renal failure.Abbreviations AUC area under the curve - FAB fragments digoxin antibody fragments - h hour     

Kein Einfluß von Digitalis auf Sexual-und Nebennierenrindenhormone bei gesunden Probanden und bei Patienten mit Herzinsuffizienz

Summary Digoxin was studied to see whether it impairs adrenal function and feminizes male subjects by changing plasma sexual hormones; both have been reported on previously. In eight healthy male subjects neither estrone (38.7±7.7 vs 35.4±3.2 pg/ml) nor estradiol (35.8±6.4 vs 32.2±3.9 pg/ml) nor testosterone (6.32±0.74 vs 6.45±0.73 ng/ml) were found to be altered by digoxin administration (plasma levels 1.55±0.27 ng/ml) lasting 35 days. The same was true of free testosterone (147±24 vs 142±19 pg/ml) and free estradiol (657±77 vs 615±78 fg/ml). Even maximal stimulation of the adrenal and gonadal glands by adrenocorticotropic hormone (ACTH) and human chorionic gonadotropin (hCG) did not exhibit any digoxin-induced alterations in the synthesizing capacity of steroid hormones, as shown by plasma cortisol (increase from 128±18 to 389±18 ng/ml) and testosterone (from 5.96±0.90 to 10.33±1.19 ng/ml). Furthermore, seven subjects on digoxin were observed over a period of 150–210 days; they did not show any increase of estrogens. This was also found in three subjects when estrogen levels were elevated initially due to extreme obesity. Also, 35 patients who took -methyldigoxin (n=8), -acetyldigoxin (n=20) and digitoxin (n=7) from 1 to 9 (x:1.9) years demonstrated normal plasma concentrations of gonadal and adrenal steroids, irrespective of duration of application or the digitalis compound. However, our studies showed that sexual hormones are correlated to cardiac performance: with decreasing cardiac index, testosterone (r: 0.86;P<0.01) and estradiol (r: 0.68;P<0.05) decreased significantly. We conclude that digoxin does not exert any influence on plasma sexual steroids. Since no competition between digoxin and estradiol receptors was found, it may even be the digitalis compound of choice when feminization is expected due to other complications. Furthermore, on digoxin the adrenal gland is capable of synthesizing cortisol sufficiently.

Unterstützt durch die Deutsche Forschungsgemeinschaft (Kl 346)     

Pharmacokinetics of chloral hydrate poisoning treated with hemodialysis and hemoperfusion

In a severe case of chloral hydrate intoxication treated with combined hemodialysis and hemoperfusion the pharmacokinetics of the metabolites trichloroethanol (TCE), trichloroethanol glucuronide (TCE-Glu) and trichloroacetic acid (TCA) were studied. Indications of delayed absorption and some slowing of metabolism were found. At a blood flow rate of 200 ml/min clearances by hemodialysis and hemoperfusion, respectively, in ml/min were estimated to be 188 and 156 for TCE, 184 and 181 for TCE-Glu, 142 and 91 for TCA. Clearance by hemoperfusion declined with time. The half-lives of TCE and TCA were 3.2 and 4.3 hours during combined hemodialysis and hemoperfusion. After termination of treatment the half-life of TCE was 12.8 hours, whereas TCA was metabolized so slowly, that no reliable calculation could be performed. We conclude that hemodialysis and hemoperfusion are equally and highly efficient in the treatment of chloral hydrate poisoning, but hemoperfusion may increase the risk of gastric bleeding more than hemodialysis. Hemodialysis may therefore be preferable and should be tried in spite of low blood pressure.     

Use of extracorporeal circulation in the treatment of 2,4-dichlorophenoxyacetic acid poisoning

The paper presents the course of illness in four patients poisoned by the 2,4-dichlorophenoxyacetic acid. The first patient, 50 years old, attempted suicide by taking 400 ml of 40% solution of the 2,4-dichlorophenoxyacetic acid (2,4-D). He was hospitalized in a comatous state 6 hours after intoxication. He was treated by the extracorporal hemodialysis and the course of the illness was successfull. The second patient, 80 years old, drank up 100 ml of 40% solution of 2,4-D accidentally. He was admitted in a comatous state a few hours after intoxication. He was treated by hemodialysis and resin hemoperfusion (XAD-4) successfully. Before treatment, the serum 2,4-D concentration reached 177 mg/100 ml, with the 2,4-D clearance of 56.3 ml/min. The third patient, 24 years old, attempted suicide by taking 200 ml 40% solution of 2,4-D, but it remained questionable whether it was 2,4-D or paraquat intoxication. He was admitted to hospital 10 hours after intoxication. He was treated by hemodialysis and hemoperfusion methods (XAD-4) successfully. The serum 2,4-D concentration reached the amount of 122.5 mg/100 ml, and the clearance of 2,4-D was 85.4 ml/min. The fourth patient, 50 years old, drank 100-200 ml of 40% solution of 2,4-D accidentally. He was hospitalized in a comatous state 3 hours after intoxication. He was treated by the hemodialysis method successfully. The serum 2,4-D concentration before the treatment reached the amount of 37 mg/100 ml, and the clearance of 2,4-D was 96 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

Effect of quinine on plasma digoxin concentration and renal digoxin clearance

In order to explore the digoxin-quinine interaction, digoxin steady state pharmacokinetics was studied before and during quinine coadministration in seven healthy subjects. Quinine (250 mg/day) increased mean plasma digoxin concentration from 0.64 +/- 0.12 to 0.80 +/- 0.18 ng/ml (p less than 0.05) within one week. Urinary digoxin recovery rose from 154.0 +/- 18.8 to 181.5 +/- 22.6 micrograms/24 h (p less than 0.01), whereas renal digoxin clearance was unaltered in the presence of quinine (181.5 +/- 24.2 vs. 174.1 +/- 26.5 ml/min). An increase in quinine dose (to 750 mg/day) caused further increments in plasma digoxin levels, whereas renal digoxin clearance remained unchanged. Quinine elevates plasma digoxin concentrations in a stepwise fashion probably due to an impairment of extrarenal digoxin clearance.     

The inhibition of drug metabolism by cimetidine in patients with liver cirrhosis

Summary The effect of cimetidine treatment, 1 g daily over 6 days, on the disposition of theophylline was studied in nine patients with liver cirrhosis and in nine patients without liver disease. Plasma elimination half-life tended to increase from 14.6±8.2 h to 24.3±14.1 h in the cirrhotic patients (P>0.05) and from 8.3±4.2 h to 10.3±4.1 h in the control patients (P<0.05). Total plasma clearance decreased from 0.50±0.23 ml/kg/min to 0.41±0.21 ml/kg/min (P<0.05) in the cirrhotics and from 0.77±0.34 ml/kg/min to 0.58±0.18 ml/kg/min (P<0.05) in the controls. Pretreatment clearance values were also significantly reduced in the cirrhosis group. No change was observed in the volume of distribution of theophylline. The degree of inhibition of theophylline metabolism did not depend on whether the patients were smokers, or whether they had low pretreatment clearance values. In liver cirrhosis, inhibition of drug metabolism by cimetidine varies widely and is unpredictable in the individual patient.Supported by the Deutsche Forschungsgemeinschaft (Gu 86/8-3)     

Toxicokinetics of formate during hemodialysis

During hemodialysis in a methanol poisoned patient, formate elimination followed first order kinetics with a plasma half-life of formate of 165 min. The mean dialysator (1.6 m2) clearance of formate was 148 ml/min (n = 8, SD +/- 11, range 128-161) at a blood flow of 215 ml/min. By applying first order kinetics, a volume of distribution of 0.5 l/kg was found, assuming that the dialysator clearance equals the total body clearance of formate. Formate, the main toxic agent in methanol poisoning, is thus probably more effectively removed by hemodialysis than methanol. This fact, and the very slow endogenous methanol elimination during appropriate ethanol treatment, should be considered when deciding on the treatment of a methanol poisoned patient presenting with metabolic acidosis.     

A case of divergent digitoxin values under treatment of a patient with acute digitoxin overdose with digitalis antibody fragments

Summary A 36 year old male was admitted to the intensive care unit with acute digitalis intoxication after ingestion of 350 digitoxin tablets (=35 mg digitoxin).He was treated with Fab fragments of a digitalis antiserum raised in sheep, the concentrations of digitoxin in serum, urine and dialysates being measured with two automated digitoxin immunoassays based on fluorescence labelling techniques. Whereas one assay reflected the total digitoxin concentrations, including that bound to the antidote, the other measured only the bioactive free form of the drug.This article examines the use and limitations of both assay systems in assessing and monitoring cases of digitalis poisoning.     

Renal function and digoxin clearance during quinidine therapy

To investigate further the handling of digoxin by the kidneys during quinidine therapy, clearances of digoxin, 51Cr-EDTA, PAH and endogenous creatinine were measured together with beta 2-microglobulin in the urine before and during quinidine therapy in 10 patients on maintenance digoxin therapy. Renal clearance of digoxin (corrected for 30% plasma binding) decreased on the average by 55% (137 +/- 73 to 73 +/- 25 ml/min, mean +/- SD). The steady state plasma concentration of digoxin increased more than twofold (1 . 0 +/- 0 . 34 to 2 . 5 +/- 0 . 79 nmol/L, mean +/- SD). The clearances of 51Cr-EDTA and PAH were not altered during quinidine therapy, indicating that neither glomerular filtration nor total renal blood flow changed when quinidine was added. The ratio of the renal clearance of unbound digoxin to that of the glomerular filtration rate was above one for all 10 patients before quinidine, indicating the involvement of tubular secretion in the renal elimination of digoxin. After the administration of quinidine this ratio decreased in all patients (from 1 . 51 +/- 0 . 30 to 0 . 83 +/- 0 . 38, mean +/- SD). Some patients had ratios well below one suggesting re-absorption of digoxin. Beta 2-microglobulin excretion was unchanged during treatment with quinidine. It is concluded that a significant portion of the renal elimination of digoxin in man results from tubular secretion and that this excretory mechanism is inhibited by quinidine.     

Renal handling of norepinephrine and epinephrine in the pig

To investigate the renal handling of catecholamines in the pig, intravenous infusions of⁵¹Cr-EDTA and PAH were performed in 7 animals, and samples for simultaneous measurement of norepinephrine (NE), epinephrine (E),⁵¹Cr-EDTA and PAH were obtained through catheters placed into the aorta, left renal vein and both urethers. For both kidneys together,⁵¹Cr-EDTA clearance [GFR] averaged 48±14 (±SD) ml/min (2.23±0.66 ml/kg/min). In the left kidney, GFR averaged 22±9 ml/min, arteriovenous PAH extraction 0.87±0.09, and calculated total renal plasma flow 91±30 ml/min. Plasma NE and E were lower in renal venous than arterial blood (P<0.005), extraction ratios averaging 0.36 and 0.77, respectively. NE excretion rate in final urine (8.9±4.3 ng/min) exceeded transrenal NE extraction rate (5.2±3.9 ng/min) by 3.7±4.4 ng/min. In contrast, urinary E excretion rate (2.9±2.0 ng/min) was slightly lower than transrenal E extraction rate (3.6±3.8 ng/min). These observations suggest that in pig kidneys, plasma PAH extraction rate and GFR related to body weight are quite similar to values in man. Three quarters of circulating E are extracted for the most part by tubular secretion, and the slightly smaller amount appearing in urine is consistent with some intrarenal metabolism. NE, presumably originating from intrarenal neuronal release and/or de novo production, is secreted into the urine.This study was supported by the Swiss National Science Foundation     

Kinetics of the redistribution phenomenon after extracorporeal elimination

Evaluation of the efficiency of extracorporeal elimination is rendered difficult by the rebound phenomenon which may occur in plasma concentrations after hemodialysis, hemoperfusion, or plasma exchange. The term clearance, derived from the extraction rate, has the drawback that it is often based on the incompatible terms plasma concentration and blood flow. To avoid these difficulties, clearance may be calculated from kinetics of plasma concentrations. But this approach will lead to an overestimation of the eliminative efficiency, because plasma concentrations may decline faster than tissue levels, which will be indicated by the rebound phenomenon. The rebound is due to a redistribution from tissue into plasma and follows 2-compartment kinetics. However, the amount removed by extracorporeal elimination reflects the redistribution phenomenon and, simultaneously, can be used to evaluate the absolute efficiency. The amount removed can be derived from 1-compartment kinetics if redistribution can be neglected, and from 2-compartment kinetics if a redistribution takes place. The amount removed can also be evaluated using model- independent approaches, which may be applied even if sustained absorption or proliferation must be assumed. According to these approaches, the removed amount is given by graphic extrapolation, and it can be calculated from extracorporeal clearance and from concentrations in the removed fluid, or it can be eluted from the extracorporeal device.     

Severe suicidal digoxin and propranolol toxicity with insulin overdose

We present a case of a 32-year-old male doctor, with type I diabetes mellitus on daily insulin therapy, who allegedly consumed large doses of digoxin and propranolol along with simultaneous administration of large dose of insulin with suicidal intent. Initial investigations revealed serum digoxin levels of 7.5 ng/ml, serum insulin 500 μIU/ml, and serum C-peptide 0.43 ng/ml. He was managed with charcoal-based hemoperfusion for digoxin overdose along with injection glucagon for propranolol overdose. His blood sugar levels were maintained with continuous infusion of 20% dextrose till the patient was allowed to take oral diet. Significant clinical improvement was noticed with this therapy which was evident by progressively declining serum digoxin levels, normalization of pulse rate, and adequate blood glucose levels. Finally, with a good hemodynamic profile and a serum digoxin level well within normal limits, he was discharged following consultation with a psychiatrist.     

The Clinical Randomized Controlled Trial on the Safety and Efficacy of Polyethersulfone Membrane Dialyzer in the Maintenance of Hemodialysis Patients

Objective:To observe the safety and efficacy of polyethersulfone membrane dialyzer used by chronic renal failure patients in clinical maintenance hemodialysis(MHD).Methods:From January to February 2009,36 patients were recruited from Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.The experiment was approved by the ethnical committee of Xinhua Hospital and under permissions from patients.All the patients were randomized into polyethersulfone group(PES,n=18) and polysulfone group(PS,n=18).Hemodialysis was given by using Fresenius 4008S capacity-controlled dialyser and ultra-purified bicarbonate dialysate,more than 3.5 h each time,three times per-week,followed by heparin anticoagulation for a week,three times totally.Changes in blood urea nitrogen(BUN),serum creatinine(Scr),phosphate(P2+),hemoglobin and albumin levels were determined for the efficacy and safety evaluation.Results:The serum BUN,Scr and P2+ concentrations significantly reduced after hemodialysis with different dialyzers,and the decrease amplitude of two groups was equivalent(P0.05).The clearance rate of the serum BUN and Scr had no significant difference among two groups(P0.05).The clearance rate(ml/min) of the serum P2+ was 144.57±27.83 v.s.117.15±22.77 in two groups.The clearance rate of the serum P2+ in PES group was more than that in PS group,and the difference was significant between two groups(P=0.0001).It was indicated that PES and PS membrane could efficiently eliminate serum micromolecule solute in MHD patients,so PES membrane excelled PS membrane in eliminating serum P2+.The hemodialysis safety index,for example serum hemoglobin,albumin and blood pressure,had no significant difference between the two groups before and after hemodialysis(P0.05).Conclusion:The efficacy and safety of the PES hollow fiber membrane dialyzer is equivalent to that of the imported PS membrane dialyzer in hemodialysis for MHD patients.The PES membrane excels PS membrane in eliminating serum P2+.     

Digitalis pharmacokinetics and therapy with respect to impaired renal function

Summary The various cardiac glycosides differ significantly in their retention as a result of renal failure. In the case of digoxin, digitoxin, and strophanthin the retention is directly related to the normal renal clearance of these cardiac glycosides: Strophanthin has the highest clearance and the most marked prolongation of pharmacological action in renal failure, whereas digitoxin shows the lowest renal clearance and even in uremic patients a total elimination comparable to normal subjects as a result of increased hepatic clearance; digoxin takes an intermediate position.The quantity of a cardiac glycoside and its metabolites excreted by the kidneys depends, besides the renal clearance, on the plasma concentration which increases considerably during the first days after onset of treatment. From the daily dose approximately 90% of strophanthin, 70% of digoxin, 50% of digitoxin plus metabolites are excreted by normal kidneys under steady-state conditions.The efficiency of hemodialysis in the elimination of cardiac glycosides is low (3–5%) if estimated in relation to a single dose injected before dialysis and high (30–50%) if estimated in relation to the excretory capacity of normal kidneys during a period corresponding to the duration of a dialysis. During hemodialysis the plasma concentration of digoxin decreases as rapidly as in patients with normal renal function. Beside the efficiency of dialysis this finding may be explained by the decrease in the apparent volume of distribution of cardiac glycosides in patients with advanced renal failure; a reduced tissue protein binding seems likely to be the main reason for these changes in chronic renal insufficiency.A reduced volume of distribution and a reduced myocardial sensitivity are the main reasons for a very low predictability of the necessary individual maintenance dose of cardiac glycosides from the creatinine clearance. In patients with advanced renal insufficiency the tolerance to cardiac glycosides is reduced with respect to the daily dose, but it is rather increased in relation to the plasma concentration required to maintain the positive inotropic effect. The combination of hyperkalemia, hypermagnesemia, hypocalcemia and acidosis which is found almost exclusively with chronic renal failure, may explain the reduced myocardial sensitivity. Dosage regimens based on the measurement of creatinine-clearance are of little help in effective digitalisation. Serial measurements of steady-state plasma concentration of cardiac glycosides may be the only way to reduce the risk of under-and overtreatment in patients with impaired renal function.Our own studies were supported by the Deutsche Forschungsgemeinschaft, SFB 89 Kardiologie Göttingen     

The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.

BACKGROUND. Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific-antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication. METHODS. Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes. RESULTS. In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to greater than 100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab. CONCLUSIONS. We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested greater than or equal to 0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of greater than or equal to 6.4 nmol per liter (greater than or equal to 5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses.     

Subacute effects of thiazide administration on renal hemodynamics and calcium metabolism

Summary To elucidate the renal effects of thiazides as a function of sodium intake, 8 healthy volunteers without renal disease were studied at baseline and 1 day as well as 4 days after the administration of 100 mg hydrochlorothiazide/day. The subjects were compared on two different dietary sodium intakes (120 mmol/day and 220 mmol/day). Measurements comprised inulin clearance (Cin) and paraaminohippurate clearance (Cpah) by infusion clearance technique, total and ionised calcium, immunoreactive parathyroid hormone (1,84 iPTH), 1.25 (OH)₂ vitamin D₃, and indices of hemoconcentration. Acute administration of hydrochlorothiazide (HCTZ) caused no change in Cin (before 111 ± 3 ml/min 1.73 m² ; 24 h after, 107 ± 2 ml/min 1.73 m²) or Cpah (before, 579 ± 9 ml/min 1.73 M²; after, 584 ± 12 ml/min 1.73 m²), while a significant (P < 0.01) decrease was noted on the 4th day after 100 mg HCTZ/day and normal sodium intake. No significant change of creatinine clearance (Ccr) was seen with either manouever. Renal hemodynamic changes after HCTZ administration were marginal when hemoconcentration was prevented by a high salt intake. Acute administration (1 h) of HCTZ caused suppression of 1,84 iPTH (before, 2.3 ±0.5 pmol/l; after, 1.9 ± 0.2 pmol/l; P < 0.01), but after 4 days a lower ionised calcium (baseline, 1.25 ± 0.01 mmol/l; day 5, 1.20 ± 0.02 mmol/l; P < 0.01) was noticed in parallel with hemoconcentration, metabolic alkalosis, and reduced 1,25 (OH)₂ vitamin D₃ concentrations. The level of 1,84 iPTH was elevated. We conclude that (i) hydrochlorothiazide does not affect the renal hemodynamics if hemoconcentration is avoided and (ii) hydrochlorothiazide acutely lowers PTH, while subacutely metabolic alkalosis and decreased ionised calcium may occur with concomitant increase in 1,84 iPTH and decrease in 1,25 (OH)₂ vitamin D₃ concentrations unless hemoconcentration is prevented.Abbreviations GFR glomerular filtration rate - PTH parathyroid hormone - iPTH immunoreactive PTH - PAH paraaminohippurate - HCTZ hydrochlorothiazide - FF filtration fraction - cAMP cyclic adenosine monophosphate - Cin inulin clearance - Cpah PAH clearance - Ccr creatinine clearance - CV coefficient of variation - HPLC high performance liquid chromatography - PRA plasma renia activity     

Hemodialysis machine with one-touch volume replacement and one-touch hemodialysis completion

In order to encourage the spread of home hemodialysis, we have developed a hemodialysis machine that enables “one-touch” voluem replacement and “one-touch” hemodialysis completion, by modifying a viscous pump-type hemodialysis machine. When emergency volume replacement is needed, pressing the volume replacement button will serve to transfer 200 ml of dialysate to the blood side as a replacement fluid, at 100 ml/min within the dialyzer. Pressing the completion procedure button when the hemodialysis is over causes 420 ml of the dialysate to be transferred to the blood side, at 100 ml/min within the dialyzer, so that the blood within the dialyzer and the blood tubing is replaced by the thus-transferred dialysate. The two puncture needles on the arterial and venous sides are then removed, and the hemodialysis completion procedure is finished. In a trial, the new hemodialysis machine, together with a cellulose triacetate membrane artificial kidney, was used a total of 144 times over a period of 4 months in three outpatients receiving maintenance hemodialysis. With the machine, 32 emergency volume replacements were performed. Both the hemodialysis completion and the emergency volume replacement procedure were performed uneventfully.     

Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications.

Administration of quinidine with digoxin increased serum digoxin concentrations in 79 patients and five volunteers. In 38 patients on a constant glycoside maintenance dose, the addition of quinidine to digoxin therapy resulted in a mean 2.5-fold increase (from 0.98 +/- 0.37 to 2.47 +/- 0.71 ng per milliliter, mean +/- 1 S.D.) (P less than 0.001). The addition of quinidine decreased renal glycoside clearance (from 91.6 +/- 27.8 to 40.6 +/- 15.8 ml per minute) (P less than 0.001). Unlike other investigations, our studies provided no evidence that quinidine displaced digoxin at specific cardiac binding sites. The elevated digoxin levels found during quinidine administration suggest a 30 to 50 per cent reduction of the digoxin dose. Adverse reactions to combined quinidine-digoxin therapy may be partly due to digitalis intoxication.