Kinetics of digitoxin during antirheumatic therapy with azapropazone (author's transl)

The effect of chronic therapy with 5-dimethylamino-9-methylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4] benzotriazine-1,3-(2H)-dione-dihydrate (azapropazone-dihydrate; Prolixan 300) on the elimination of a single i.v. dose of digitoxin was studied in 8 patients with rheumatoid arthritis and osteoarthritis using a crossover design. 0.5 mg digitoxin were injected i.v. alone and together with a chronic oral therapy of azapropazone starting 3 weeks before digitoxin was given. Digitoxin plasma levels were determined by radioimmunoassay over a period of 19 days. The half-life for plasma digitoxin was 6.4 +/- 0.5 days after digitoxin alone and 7.0 +/- 0.6 days during azapropazone treatment. In two patients the half-life of digitoxin was increased by about one-third during azapropazone therapy. The areas under the plasma digitoxin curve were 2592 +/- 262 ng/ml X h and 2615 +/- 273 ng/ml X h, respectively. None of the differences were statistically significant. It was concluded that there was no clinically significant interaction between azapropazone and a single dose of digitoxin.     

Interactions between digitoxin and some antiarrhythmic drugs.

In the present study the pharmacokinetic interactions between digitoxin and the antiarrhythmic drugs amiodarone, mexiletine and propafenone have been examined. Experiments were performed on rabbits in which serum digitoxin concentration was used as indicator to detect drug interactions. The radioimmunoassay "Coat-A-Count" procedure of DPC was used for the quantitative measurement of digitoxin. It was determined that in order to achieve a considerable level of serum digitoxin, it was necessary to administer a multiple dose rather than the one tolerated by humans. It was also observed that serum contained digitalis like immunoreactive factor(s) (DLIF) measured as digitoxin. The mean (+/- SE) digitoxin equivalent value of the DLIF, measured by the "Coat-A-Count" radioimmunoassay in the serum of rabbits (n = 34) was 4.15 +/- 0.059 ng/ml. Each of the three antiarrhythmic drugs increased serum digitoxin levels; its values were almost double in relation to the control group where only digitoxin was administered. This increased digitoxin value was detected one hour after administration of the first dose of the antiarrhythmic drug and remained at a higher level than that of the control group for 6-8 hours. Rabbits given a single high dose of digitoxin and some of the antiarrhythmic drugs and those given a small dose of digitoxin for only four days, presented a retrogressive increase of digitoxin level in serum 5-6 days later. This mechanism needs to be further investigated.     

Digitoxin accumulation.

1 Nine healthy volunteers received single 1 mg intravenous doses of digitoxin, following which serum digitoxin concentrations were measured at multiple points in time over the next 14 days. 2 Mean kinetic variables for digitoxin were: volume of distribution, 0.76 l/kg; elimination half-life, 8 days; total clearance, 0.049 ml min-1 kg-1. 3 After a drug-free interval of at least 4 months, subjects took 0.07 mg of oral digitoxin daily for 28 consecutive days. Serum digitoxin concentrations were measured during the period of dosage and in the 21 day post-dosage washout. 4 Digitoxin accumulation was slow, proceeding with a mean half-life (7.9 days) that was nearly identical to the single-dose half-life. However, the two were not significantly correlated. 5 Mean observed steady-state serum concentrations (15.4 ng/ml) also were nearly identical to those predicted from the single-dose study (15.3 ng/ml), but again the two were not significantly correlated. 6 Steady state is very slowly attained after initiation of maintenance therapy with digitoxin. The kinetic data suggest that a loading dose on the average should be 12 times the maintenance dose.     

Steady-state serum pharmacokinetics and bioequivalence of 500 mg oral versus 200 mg intravenous ciprofloxacin

The pharmacokinetics of ciprofloxacin were examined after five days of treatment with 500 mg orally and 200 mg intravenously twice a day, in six healthy volunteers in an open, randomized crossover study. The ciprofloxacin concentrations were determined in serum by high performance liquid chromatography. The mean serum peak concentrations were obtained in 1 to 1.5 h by the oral route and the values reached were similar after the oral and intravenous dose (2.56 +/- 0.62 micrograms/ml and 2.6 +/- 0.67 micrograms/ml respectively). The terminal elimination half-life was about 4.5 h for oral form and 5 h for intravenous form. The absolute bioavailability of the oral ciprofloxacin was about 83%.     

The effect of colestipol on digitoxin plasma levels.

The effect of colestipol (colestipol hydrochloride; U-26 597 A), a copolymer of tetraethylenepentamine and epichlorhydrine, on plasma digitoxin levels has been investigated. Recently, it has been stated that colestipol decreases the enterohepatic circulation and the plasma half-life of digitoxin. Colestipol was administered to 11 patients having a digitoxin plasma level which is generally accepted to be above the therapeutic range (greater than 40 ng/ml). The elimination rate of digitoxin measured by serial radioimmunoassay in these colestipol treated patients was compared with the elimination rate of digitoxin in 11 patients not treated with colestipol. The results of this study did not demonstrate a significant difference in the mean (+/- S.D.) digitoxin plasma half-life between the colestipol treated (6.3 +/- 1.3 days) and the non-colestipol treated patients (6.8 +/- 1.0 days).     

Effects of some antibiotics on paraoxonase from human serum in vitro and from mouse serum and liver in vivo

Paraoxonase (PON1, EC 3.1.8.1) is an esterase protein which plays multifunctional role in metabolism. Therefore, in this study the effects of commonly used antibiotics, namely sodium ampicillin, ciprofloxacin, rifamycin SV and clindamycin phosphate, on human PON1 were investigated in vitro and in vivo. Human serum paraoxonase (PON1) was separately purified by ammonium sulfate precipitation and hydrophobic interaction chromatography. The in vitro effects of the antibiotics in purifying human serum paraoxonase was determined using paraoxon as a substrate, and the IC50 values of these drugs exhibiting inhibition effects were found from graphs of hydratase activity % by plotting the concentration of the drugs. It was determined that sodium ampicillin, ciprofloxacin, and clindamycin phosphate were effective inhibitors on human serum PON1, and the inhibition kinetics of interaction of sodium ampicillin, ciprofloxacin, and clindamycin phosphate with the human serum PON1 was also determined, with the Ki of sodium ampicillin, ciprofloxacin, and clindamycin phosphate being 0.00714+/-0.00068, 6.5x10(-6)+/-4.59x10(-7), 0.0291+/-0.0077 mM, respectively. The in vivo effects of the antibiotics on paraoxonase enzyme activity in mouse serum and liver PON1 were also investigated. Mouse liver PON1 activity showed a statistically significant change at 2, 4 and 6 h of drug application in vivo. Sodium ampicillin and clindamycin phosphate exhibited about 80% mouse liver PON1 at 2 or 4 h (p: 0.034, 0.003 and 0.021, respectively). In addition, ciprofloxacin and rifamycin SV only showed inhibition at 4 h incubation. Sodium ampicillin (17.12 mg/kg) lead to a significant decrease in mouse serum PON1 after 4 h drug administration. Ciprofloxacin (3.2 mg/kg), rifamycin SV (3.56 mg/kg) and clindamycin phosphate (2.143 mg/kg) did not exhibit any inhibition effect for the mouse serum PON1, in vivo.     

Nadolol in human serum and breast milk

1 Simultaneous serum and milk samples were collected over a 10-day period from twelve normotensive, lactating subjects who ingested 80 mg nadolol once daily for a period of 5 days. For comparative purposes, serum samples were also collected from seven patients with a history of mild essential hypertension who ingested the same dose of nadolol for a period of 13 days. 2 In lactating subjects, steady-state serum concentrations of nadolol were attained in 3 days. Milk concentrations of nadolol were much higher than serum concentrations starting on Day 3 and throughout the remainder of the study. The mean (+/- s.e. mean) steady-state levels of nadolol in milk (356.9 +/- 40.4 ng/ml) were 4.6 times higher than the mean steady-state levels in serum (77.3 +/- 6.9 ng/ml). 3 In hypertensive patients, the mean serum concentration of nadolol 24 h after the twelfth dose was 40.3 +/- 8.2 ng/ml as compared to a mean serum concentration in lactating subjects of 40.7 +/- 3.4 ng/ml, 24 h after the fifth dose. Mean serum concentrations in hypertensive patients at 1 and 4 h after the final daily dose were not significantly different from those in lactating subjects. 4 It can be estimated that a 5 kg nursing infant would consume about 2-7% of the daily adult therapeutic dose of nadolol. The data suggest that caution should be exercised in the use of nadolol in lactating patients.     

Studies on sultamicillin in the field of pediatrics

Pharmacokinetic and clinical studies on sultamicillin (SBTPC) were carried out in the field of pediatrics. 1. Absorption and excretion. A crossover study with a single oral administration of 10 mg/kg of SBTPC in fasting and after meal, and that with 10 mg/kg and 20 mg/kg of SBTPC after meal were carried out in 11 children (5-15 years) and in 6 children (8-15 years), respectively. Serum levels and urinary excretion of sulbactam (SBT) and ampicillin (ABPC) were determined. Mean serum concentrations of ABPC after oral administration of 10 mg/kg of SBTPC with in fasting or after meal, in the former study, peaked at 4.75 +/- 1.97 micrograms/ml in 1 hour and declined with a mean half-life of 0.81 +/- 0.18 hour and the mean serum concentration of ABPC at 6 hours after administration was 0.06 +/- 0.07 micrograms/ml. Mean serum concentration of ABPC study in the latter peaked at 2.95 +/- 0.79 micrograms/ml in 1 hour, and declined with a mean half-life of 1.35 +/- 0.43 hours, and the mean serum concentration of ABPC at 6 hours was 0.22 +/- 0.13 microgram/ml. Mean urinary recovery rates of ABPC in 6 hours after administration were 54.5 +/- 17.6% in the former study, and 63.2 +/- 14.3% in the latter. These results suggested a delay of absorption with meal. Mean serum concentrations of ABPC after oral administration of 10 mg/kg or 20 mg/kg of SBTPC after meal, in the former study, were 3.10 +/- 0.72 micrograms/ml at 1 hour and declined with a half-life of 1.22 +/- 0.32 hours, and those of ABPC were 0.22 +/- 0.12 microgram/ml at 6 hours, and they were 6.46 +/- 1.57 micrograms/ml, 1.48 +/- 0.51 hours and 0.55 +/- 0.40 microgram/ml, respectively in the latter study. Mean urinary recovery rates of ABPC in 6 hours, were 50.4 +/- 10.2% in the former study and 57.7 +/- 11.4%, in the latter. A dose response was observed with time course of mean serum concentrations. Mean serum concentrations of SBT were lower than those of ABPC, and they declined in a similar manner. The mean urinary recovery rate of SBT was similar or lower than that of ABPC. 2. Clinical study SBTPC was used for the treatment of a total of 38 pediatric patients with ages 6 months to 11 years and it's clinical effectiveness, bacteriological efficacy and adverse effects were evaluated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Aspects of chronic oral treatment with thyrotropin-releasing hormone: the hypothalamic-pituitary-thyroid axis in rats. A study with a pharmacological dose of thyrotropin-releasing hormone.

The effects of 16 days of oral treatment with thyrotropin-releasing hormone (TRH, 1 mg/24 h) on serum levels of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) and the kinetics of TRH in the blood were studied in normal rats. A second group of animals served as controls. TRH was dissolved by sonification (10 mg/l) and was stable in tap water. TRH was measured by a radioimmunoassay procedure (normal range: 20-80 pmol/l, antiserum K2B9 1:120,000 final dilution). An increase in basal TSH (7,200 +/- 440 ng/l, mean +/- SD) was found after 2 days of treatment (11,420 +/- 810 ng/l), but a significant increase was observed after 5 days of treatment (12,530 +/- 640 ng/l, p less than 0.001). T4 serum concentrations remained in the normal range during the entire period of study, whereas T3 serum concentrations (0.76 +/- 0.1 micrograms/l) were increased to 1.22 +/- 0.2 micrograms/l on day 5 (p less than 0.001). A subsequent decline of TSH, T4 and T3 up to the end of the study was observed. TRHmax concentrations were registered on day 5 (790 +/- 24 pmol/l). The mean value of TRHmax was 723 +/- 34 pmol/l. To improve the stability of TRH in tap water, 1-ml samples of drinking water with dissolved TRH were measured. The mean TRH concentration in drinking water was 73 +/- 1.5% (SD). No significant correlations were found between the area under the curve of TSH (184,340 ng.l-1.24 h) and that of TRH (14,954 pmol.l-1.24 h).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered. The mean pharmacokinetic parameters for the first dose were: maximum serum concentration (C(max)) 12.5+/-4.7 mg/L (range 5.6-16.0mg/L) (fC(max) 8.8+/-3.3, where f indicates the levofloxacin free or non-protein-bound fraction), area under the serum concentration-time curve (AUC) 85.4+/-14.1 mgh/L (range 66.2-96.8 mgh/L) (fAUC 59.8+/-9.9) and serum half-life (t(1/2)) 6.7+/-0.5h. Mean urine concentrations were 88.0+/-100mg/L at the 0-3 h collection, 307+/-143 mg/L at 3-6 h, 170+/-107 mg/L at 6-12 h and 85+/-8 mg/L at 12-24 h. Mean levofloxacin serum pharmacodynamics for infecting Escherichia coli were: C(max)/minimum inhibitory concentration (MIC) 323+/-185(fC(max)/MIC 226+/-129); and AUC/MIC 2339+/-830(fAUC/MIC 1647+/-579). Mean urine levofloxacin concentration/MIC ratios were: 900+/-1389 for 0-3 h, 12100+/-4950 for 3-6 h, 5922+/-3912 for 6-12 h and 2233+/-1037 for 12-24 h. Levofloxacin eradicated E. coli from the urine by 3-6 h after the first dose. Levofloxacin 750 mg once daily for 5 days has pharmacodynamics that support further evaluation of this regimen for treatment of women with acute uncomplicated pyelonephritis.     

Concentrations of ampicillin and cefadroxil in human serum and mixed saliva following a single oral administration of talampicillin and cefadroxil, and relationships between serum and mixed saliva concentrations

The concentrations of ampicillin (ABPC) from talampicillin (TAPC) and cefadroxil (CDX) in serum and mixed saliva were assayed by the thin layer disc plate method. Talampicillin and cefadroxil (500 mg) were given by a single oral administration. The relationships between serum and mixed saliva ampicillin and cefadroxil concentrations were evaluated in the paired specimens collected from 10 different persons, respectively. The means of concentration ratios of mixed saliva to serum ampicillin and cefadroxil were 0.006 +/- 0.003 and 0.025 +/- 0.010 (mean +/- SD), respectively. Significant correlation coefficients between mixed saliva and serum concentrations were found for both ampicillin and cefadroxil, which were r = 0.78, P less than 0.001, and r = 0.67, P less than 0.001, respectively.     

Steady-state pharmacokinetics of rufloxacin in elderly patients with lower respiratory tract infections.

The pharmacokinetics of rufloxacin, after repeated doses, was evaluated in 12 elderly patients with lower respiratory tract infections. Patients were given a single loading dose of 400 mg on the first day of treatment and single daily maintenance doses of 200 mg for the next 6-9 days. Serum concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at regular intervals during treatment and fitted to a one-compartment open model for repeated doses. The maximum serum concentration after the first dose was 6.46 +/- 1.06 (mean +/- SEM) micrograms/ml and was reached in 4.3 +/- 0.8 h after the first administration. The elimination half-life was 28.7 +/- 4.1 h. The area under the serum levels-time curve from 0 to 24 h was 103 +/- 14 micrograms/h/ml after the first dose. On the last day of observation it increased to 155 +/- 28 micrograms/h/ml, with a mean extent of accumulation of 2.3 +/- 0.3 times. The elimination half-life was comparable to those in other studies in healthy young subjects, while plasma levels were about 80% higher. These results suggest that in elderly patients elevated drug concentrations may be reached in the serum. Although no untoward reactions related either to the drug concentration in serum or the dose have been noted with rufloxacin, this patient population should nevertheless be monitored carefully for adverse effects.     

Pharmacokinetics of the gonadotropin-releasing hormone agonist buserelin after injection of a slow-release preparation in normal men.

The pharmacokinetics of the gonadotropin-releasing hormone (GnRH) agonist buserelin (D-Ser(BUt)6-GnRH-(1-9) nonapeptide-ethylamide, Hoe 766, CAS 57982-77-1) after injection of a slow-release preparation was investigated in 16 healthy young male volunteers. Eight volunteers received a buserelin implant of 3.3 mg and 8 volunteers one of 6.6 mg by subcutaneous injection. In order to prevent androgen deficiency symptoms caused by the GnRH agonist all volunteers were injected with an initial loading dose of 400 mg of the androgen 19-nortestosterone hexyloxyphenylpropionate one week prior to the buserelin administration, followed by injections of 200 mg once every three weeks up to week 23. Maximal buserelin serum levels were measured two days after injection of the implant. Following a slow decrease in serum concentrations up to week 8, serum buserelin had disappeared by week 14 in the 3.3 mg group and by week 17 in the 6.6 mg group. The areas-under-the-serum-concentration-versus-time-curves (AUCs) for the 3.3 and 6.6 mg implants were 691 +/- 60 ng x h/ml and 1050 +/- 102 ng x h/ml, respectively (p less than 0.01). The mean residence times (MRTs) of buserelin after administration of 3.3 mg and 6.6 mg buserelin implant were 4.7 +/- 0.4 and 4.1 +/- 0.3 weeks, respectively (p greater than 0.05). Urinary excretion of buserelin showed a similar pharmacokinetic profile. However, urinary buserelin was still detectable at very low concentrations by the end of the study, i.e. 29 weeks after implant injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical use of a bio-assay of serum digitoxin activity

Summary In 73 patients on digitoxin maintenance medication a progressive increase of mean serum digitoxin activity was found with increasing dose. However, there were considerable variations within each group. Change of dose was followed by a new steady state level close to that predicted by zero order absorption-first order elimination kinetics of the drug. In atrial fibrillation the expected fall in ventricular rate was always observed with increasing serum concentration. No significant difference in serum level was found 24 h after identical peroral and intravenous doses had been given to different groups of patients. However, significantly higher serum values were found in normal subjects than in patients with heart disease after identical peroral treatment. This probably indicates poorer absorption by the patients. In 13 subjects, the estimated serum digitoxin half-lives were 3.7 to 11.3 days. These large differences may explain much of the variation in serum values found during steady state therapy. The elimination curves were in accordance with a first order drug kinetics. Only three patients with definite digitalis intoxication were seen, all of whom had high serum values which did not overlap patients without features of intoxication. The results showed that several patients on maintenance therapy were under-digitalized. It is hoped that this or similar methods may make it possible to adjust individual treatment to compensate for differences in absorption, distribution and elimination, and thereby to increase the benefits and decrease the risks of toxicity of digitoxin therapy.     

Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine

AIM AND METHOD: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. RESULTS: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (+/- SEM) elimination half-life of CBZ was 33.0+/-1.8 h after pretreatment with placebo and 30.1+/-2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638+/-45 micromol/l after placebo and 624+/-53 micromol/l after LTG (NS). Changes in the peak serum concentration, from 9.0+/-0.3 micromol/l to 9.2+/-0.4 micromol/l (LTG), and in the time to peak serum concentration, from 9.3+/-1.1 h to 9.1+/-1.2 h (LTG), were also not significant. CONCLUSION: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.     

Dose-related pharmacokinetics after oral administration of a new formulation of erythromycin base.

1 Erythromycin concentrations in serum and urine were determined in 24 healthy male, fasting subjects after oral administration of 250, 500, or 1000 mg of erythromycin base (250 mg capsules containing enteric-coated pellets). The subjects also received a film-coated erythromycin stearate tablet (equivalent to 500 mg base). 2 The mean +/- s.d. maximal serum erythromycin concentrations were 1.9 +/- 0.8, 3.8 +/- 1.4, 6.5 +/- 2.9 and 2.9 +/- 1.7 mg/l for 250, 500, or 1000 mg base and 500 mg stearate, respectively. The serum peaks usually occurred after 2 h irrespective of dosage form given. 3 The mean +/- s.d. areas under the serum concentration v time curves (AUC0-infinity) were 4.5 +/- 1.7, 11.2 +/- 4.3, 27.2 +/- 10.6 and 7.5 +/- 3.4 mg l -1 . h after 250, 500, or 1000 mg base, and 500 mg stearate, respectively. 4 The urinary recoveries were 5.0, 6.7, 8.6% of the base doses given and 4.4% of the stearate dose given. 5 Dose-dependent excretion of erythromycin occurred. The increase in AUC was larger than multiples of the lowest base dose.     

The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects

Thirty Japanese (J) and 32 American (A) healthy subjects received single doses of etanercept by subcutaneous injection, in 3 separate trials. Serum samples were collected for 480 hours after dosing. Concentrations were determined using enzyme-linked immunosorbent assay methods. Pharmacokinetic parameters were calculated using both non-compartmental and compartmental methods. Etanercept was slowly absorbed, with mean+/-SD time to maximum serum concentration of 47+/-15 hours (J), and 51+/-20 hours (A). The maximum serum concentration and area under the concentration time curve increased for doses 10 mg, 25 mg, and 50 mg, in a linear relationship. Etanercept was slowly eliminated, with observed mean+/-SD half-life of 80+/-25 hours (J) and 75+/-15 hours (A) and mean+/-SD apparent clearance of 144+/-65 mL/h (J) and 132+/-74 mL/h (A). Very low concentrations of etanercept were observed in the urine samples collected in the Japanese subjects. All adverse reactions observed resolved without issue, and none required discontinuation from the study.     

Clinical pharmacokinetics and tissue penetration of teicoplanin

The pharmacokinetic properties were investigated of teicoplanin, including its penetration into suction blister fluid (SBF), after a single intravenous bolus administration of 600 mg in seven pneumological patients with normal renal and hepatic function. Blood and SBF samples were collected during the 60-hour period drug administration. Teicoplanin was assayed microbiologically and the mean serum concentration at the end of the i.v. injection was 98.7 +/- 16 mg/l falling to 2.3 +/- 0.4 mg/l at 60 h. The antibiotic was rapidly distributed into a fast equilibrating peripheral compartment and, at a lower rate, into a slowly equilibrating peripheral compartment, while the mean elimination half-life (t1/2 beta) was 34.1 +/- 6.8 h. Penetration into the SBF, though slow, was good, reaching a mean peak level of 8.7 +/- 1.7 mg/l at a mean time of 2.1 h, with a penetration index (obtained by percentage ratio of the area under curve in the SBF to that of serum) of 42.9%.     

Pharmacokinetics and bioavailability of digitoxin by a specific assay

Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum. Supported by a Clinician-Scientist Award from the American Heart Association     

Plasma, bone, hip capsule and drain fluid concentrations of ampicillin and flucloxacillin during total hip replacement after intravenous bolus injection of magnapen

1. A rapid intravenous bolus injection of 4.0 g Magnapen (which contains 2.0 g of ampicillin and 2.0 g of flucloxacillin) was to seven patients undergoing total hip replacement immediatly before induction of general anesthesia. Postoperatively the patients patients received 2.0 g Magnapen by intramuscular injection every 6 h for up to 72 h until removal of the wound drains. 2. The plasma, bone, hip capsule and drain fluid concentrations of ampicillin and flucloxacillin were measured by a differential small plate microbiological assay method using Sarcina lutea and a penicillinase producing Staph. aureus Russell as the test organisms. 3. The mean +/- s.e. mean concentrations of ampicillin after this regimen were 4222.2 +/- 285.0 microgram/ml (plasma), 65.6 +/- 1.3 microgram (g (hip capsule), 19.1 +/- 3.8 microgram/g (cancellous bone), and 211.1 +/- 65.6 microgram/g (ground up bone) respectively. 4. The mean +/- s.e. mean flucloxacillin concentrations after this regime were 137.2 +/- 28.4 microgram/ml (plasma), 61.8 +/- 15.0 microgram/g (hip capsule), 47.1 +/- 9.5 microgram/g (cancellous bone) and 139.4 +/- 21.8 microgram/g (ground up bone) respectively. 5. An intravenous bolus injection of Magnepen (4.0 g), given immediately before induction of general anaesthesia, provides concentrations of ampicillin and flucloxacillin in plasma, hip capsule, cancellous and ground up bone, and drain fluid that exceed the MICs of these antibiotics against Staph. aureus and E. coli. 6. The plasma, hip capsule, cancellous and ground up bone concentrations of ampicillin after this dose of Magnapen do not, however, exceed the MICs of the Gram negative anaerobes that sometimes cause postoperative wound infections in these patients.