Effect of 6-hourly intermittent intravenous boluses of oxmetidine and ranitidine on gastric acidity and serum prolactin

Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function.The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml^–1 vs 0.181 µg·ml^–1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml^–1 vs 0.924 µg·ml^–1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis.This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.     

The penetration of ciprofloxacin into bronchial mucosa,lung parenchyma,and pleural tissue after intravenous administration

Summary We have studied the concentrations of ciprofloxacin in serum, bronchial mucosa, lung parenchyma, and pleural tissue after a single intravenous dose of 200 mg in 20 patients subjected to lung surgery.The concentrations of ciprofloxacin in the tissues exceeded that in the serum by 3-fold to 7-fold: serum 0.6 g·ml^–1, bronchial mucosa 1.9 g·g^–1 lung parenchyma 3.4 g·g^–, and pleural tissue 1.7 g·g^–1.The achievable concentrations of ciprofloxacin in the tissues of the lower respiratory tract are above the MICs for most lung pathogens.     

Pharmacokinetic and pharmacodynamic modelling with pancuronium

Summary The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (C_p) of the neuromuscular blocking agent (NMBA) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79±0.28 ml·min^–1·kg^–1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The steady-state C_p necessary to produce 50% paralysis (EC_pss(50)) was estimated to be 0.21±0.08 µg·ml^–1 (mechanical response) and 0.18±0.05 µg·ml^–1 (EMG response). An analysis using the Hill equation of the C_p-response relationship, during and after the constantrate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis (EC_p50) of 0.35±0.06 µg·ml^–1 and 0.20±0.09 µg·ml^–1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32±0.06 µg·ml^–1 and 0.17±0.06 µg·ml^–1. Using this latter approach, the EC_p50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p<0.05); no such difference was apparent between this latter parameter and the EC_pss(50) of the integrated effect model (p>0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p>0.05).     

Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment

Summary Flutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease.After oral administration flutamide is absorbed from the gastrointestinal tract with a t_max of about 2 h.Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline.After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 µg·ml^–1 respectively were observed. Maximum plasma concentrations of 2-hydroxylfutamide for the same flutamide doses were 1.3 and 2.4 µg·ml^–1 (mean ofn=2 orn=3).Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94±0.23 µg·ml^–1, mean±SD,n=5) were found at 2–4 days after the administration of 250 mg every 8 h.The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5–29.4,n=3) µg·ml^–1·h for 250 mg and 500 mg flutamide orally.2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3–21.9 and 4.3–17.2 h (n=5) respectively.     

The pharmacokinetics of ceftriaxone and cefotaxime in cirrhotic patients with ascites

Summary We have compared in two separate studies the kinetics of ceftriaxone and cefotaxime in 8 cirrhotic patients with ascites and 8 control subjects after a single 20 min intravenous infusion of 1 g of each drug.The apparent volumes of distribution (V_z) were found to be significantly higher in cirrhotics than in control subjects (0.87, versus 0.49, l·kg^–1, for cefotaxime and 0.23 versus 0.13 for ceftriaxone).The elimination kinetics of ceftriaxone were similar in the two groups. In contrast, the total and non-renal clearances of cefotaxime were reduced in cirrhotic patients.The two drugs rapidly entered the ascitic fluid. Peritoneal concentrations of ceftriaxone were higher than 7 µg·ml^–1 from the second hour after the infusion and were 8.9 µg·ml^–1 at 24 h. Peritoneal concentrations of cefotaxime were higher than 4 µg·ml^–1 from 0.5 to 8 h after the infusion.     

A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers

Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg^–1 for 60 min and increasing to a maximum of 2.0 µg·kg^–1·min^–1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg^–1·min^–1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN.Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations >0.8 µg·ml^–1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations.The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min^–1 and a half-life of 2.0±0.4 h.     

Plasma concentrations and haemodynamic effects of nimodipine in patients resuscitated after cardiac arrest

Summary As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest.In 7 patients nimodipine was infused at increasing rates up to 30 µg·kg^–1·h^–1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng·ml^–1 was obtained, and the mean plasma clearance was 1.4 l·kg^–1·h^–1. There were no marked changes in mean arterial blood pressure or heart rate.In 9 other patients nimodipine was given as a bolus infusion of 10 µg·kg^–1 over 3 min, followed by a continuous infusion of 30 µg·kg^–1·h^–1. A mean steady-state plasma concentration of 17.6 ng·ml^–1 was obtained and the mean plasma clearance was 1.9 l·kg^–1·h^–1. Heart rate did not change significantly, but the mean arterial blood pressure fell.The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.     

Tolerability and steady-state pharmacokinetics of terodiline and its main metabolites in elderly patients with urinary incontinence

Summary The elderly form an important target group for the treatment of urinary urge incontinence with drugs such as terodiline (Mictrol, Terolin). In order to evaluate its steady-state pharmacokinetics and tolerability in geriatric patients terodiline 12.5 mg b.d. was given to 28 hospitalized patients with urinary incontinence (mean age 85 years) for six weeks. The patients were monitored during the study and for 6 weeks afterwards, blood samples being taken at regular intervals. In addition to these multi-diseased and polymedicated patients, a small, homogenous group of healthy volunteers (mean age 40 years) was studied as a reference group, being given terodiline 12.5 mg b.d. for 2 weeks.Terodiline was generally well tolerated by the patients and no significant change in blood pressure or heart rate were found. One patient was withdrawn due to adverse effects. The mean terminal half-life of terodiline was 131 h and the clearance after oral administration (clearance/systemic availability) was 39 ml·min^–1. The corresponding figures for the healthy volunteers were 57 h and 75 ml·min^–1.The average steady-state serum concentration was 518 µg·l^–1 in the geriatric patients and 238 µg·l^–1 in the healthy volunteers. Steady-state was reached within 3 weeks in 20 of the 28 patients and within 5 weeks in 7 patients.In the geriatric patients the steady-state serum concentration of the main metabolite p-hydroxyterodiline, during the last three weeks on terodiline was 45 µg·l^–1, 57 µg·l^–1, and 45 µg·l^–1, respectively, and a similar value was found in the healthy volunteers, 47 µg·l^–1. The serum concentration of p-hydroxy-m-methoxyterodiline was <15 µg·l^–1 both in the geriatric patients and in the healthy volunteers.Thus, terodiline 25 mg/day given to fragile elderly patients was well tolerated. It produced serum concentrations similar to those found after the standard dose of 37.5–50 mg given to younger, healthier patients.     

Evaluation of a proposed method for phenytoin maintenance dose prediction following an intravenous loading dose

Summary A large clinical study, designed to investigate the induction of theophylline metabolism by phenytoin, provided the opportunity to test a previously proposed method for estimating dose requirements of phenytoin. This method involves prediction of the oral maintenance dosage from data obtained following the administration of an intravenous loading dose.In 30 subjects, trough plasma concentration at steady-state were 12.0±4.9 µg·ml^–1 (mean ±SD) and differed by –2.7±39.3% from a mean target plasma concentration of 12.5±1.5µg·ml^–1.A Bayesian regression programme was used to forecast an estimate of each subject's individual pharmacokinetics. These were then used to predict the steady-state plasma concentrations which would be expected from a standard dosing regimen (4 mg per kg per day). When compared to the results expected from the use of this standard dosage, the proposed method gave acceptable steady-state plasma phenytoin concentrations with significant reductions in deviations from target concentrations.This method for the rapid individualization of phenytoin dosage requirements provides an improvement over more traditional methods of choosing an arbitrary dose adjusted for body weight followed by dosage adjustments based on achieved plasma concentration.     

In vitro protein binding of propafenone in normal and uraemic human sera

Summary The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory.The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure.In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 µg · ml^–1, 0.041 within the therapeutic concentration range (0.5–2 µg · ml^–1), 0.138 at a propafenone concentration of 25 µg · ml^–1, and 0.187 when the propafenone concentration was increased to 100 µg · ml^–1.There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5–1.5 µg · ml^–1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 µg · ml^–1.A high-affinity, low-capacity binding site (K₁=6.53×10⁵ l · mol^–1; n₁P₁=1.73×10^–4 mol · l^–1) and a low-affinity, high-capacity binding site (K₂=8.77×10³ l · mol^–1; n₂P₂=8.57×10^–3 mol · ×l^–1) were identified.In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1–5 µg · ml^–1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha₁-acid glycoprotein concentrations, and there was a correlation (r=0.8302) between alpha₁-acid glycoprotein concentration and the propafenone binding ratio.     

The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects

Summary We have studied the absolute systemic availability (f) of an oral formulation (Hydergin spezial = Hydergine FAS^R 4 mg per tablet) of codergocrine by three different methods.Twelve healthy volunteers received single doses of 0.9 mg co-dergocrine intravenously and 8.0 mg orally in a randomized crossover design. The pharmacological effect of co-dergocrine was monitored as a reduction in plasma prolactin.Maximal plasma concentrations of co-dergocrine after oral dosing ranged between 0.181 and 1.307 ng·ml^–1. Maximal urinary excretion ranged between 4.7 and 9.9 µg·h^–1 and between 0.3 and 2.3 µg·h^–1 after intravenous and oral doses respectively. Clearance was measured as 90±22 l·h^–1 and the absolute systemic availability (f) as 2.25±0.65% by using the areas under the plasma concentration-time curves extrapolated to infinity. Calculation of f by comparing areas up to 32 h or the fractions of the dose excreted in urine led to identical results.The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f.     

Hepatic enzyme induction and vitamin K1 elimination in man

Summary We have studied the single dose and steady-state pharmacokinetic of tiaprofenic acid in ten elderly arthritic patients living in the community (5 men and 5 women) taking 200 mg tid for 8 days.The mean area under the plasma concentration-time curves to 8 h (AUC (0–8)) did not alter significantly from day 1 to day 8 (77.25 to 79.61 µg·ml^–1. h). The mean terminal phase half-life (t_1/2) was 2.05 h and 2.25 h on Days 1 and 8 respectively in patients in whom the calculations were possible (7 patients on Day 1 and 6 patients on Day 8). The median observed time of maximum concentration (t_max) and the mean observed maximum plasma concentration (C_max) of 100 min and 21.3 µg·ml^–1 respectively on Day 1 were not significantly different from the values obtained on Day 8 (t_max 120 min; C_max 20.7 µg·ml^–1). The kinetic data suggest that there should be no significant accumulation of tiaprofenic acid in elderly ambulant people suffering from arthritis.     

Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children

Summary We have studied the mechanisms of the increased dosage requirements of the H₂-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study.Cimetidine (10–15 mg·kg^–1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis.The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml^–1.The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg^–1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg^–1 and 2.21 h respectively.Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min^–1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r ²=0.85).The plasma concentration of cimetidine needed to increase gastric pH to 4.0 was 1.0 µg·ml^–1, which contrasts with the value of >0.5 µg·ml^–1 required for adult burned patients.These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.     

The effect of atrial natriuretic peptide on plasma renin activity,plasma aldosterone,and urinary dopamine in man

Summary The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect.We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol·kg^–1·min^–1 for 30 min followed by 15 pmol·kg^–1·min^–1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion.On the placebo day, plasma renin activity (PRA) rose from 1.26±0.08 to 1.57±0.14 ng A1·ml^–1·h^–1, while on the ANP study day PRA fell from 1.45±0.15 to 1.28±0.05 ng A1·ml^–1·h^–1 (p<0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion.These results provide evidence that ANP suppresses renin release in man.     

Penetration of pefloxacin and its desmethyl metabolite into the uroepithelium after a 800-MG single oral dose in human patients

Penetration of pefloxacin into the uroepithelium was studied in 20 patients (10 men and 10 women) receiving a single oral dose of 800 mg. Samples of serum, urine, and uroepithelium were taken 1.8 h (mean) after the dose. Pefloxacin and its active metabolite, norfloxacin, were assayed by liquid chromatography, and the microbiologically active compounds were quantified by a microbiological assay. Both procedures were correlated (r>0.7); nevertheless, slight differences detected in concentrations depended on the levels of norfloxacin achieved in the biological samples. The serum and tissue concentrations were higher than the concentration of bactericide (4 g·ml^–1), except in one case. The uroepithelium concentration of pefloxacin was proportional to the serum concentration (r=0.79). The urinary concentrations ranged from 1.2 g·ml^–1 to 82.4 g·ml^–1. The mean norfloxacin/pefloxacin ratios were 3% in serum, 8% in uroepithelium, and 44% in urine. The mean uroepithelium/serum concentration ratios were 1 for pefloxacin and 2.3 for norfloxacin. This result shows that, at a time close to that of the maximum concentration, there is good penetration of pefloxacin and norfloxacin into the uroepithelium.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Biliary elimination of indomethacin in man

Summary The biliary elimination of indomethacin 100 mg p.o. has been investigated in patients with a T-tube drain after cholecystectomy, who had normal or abnormal liver function (Group In=5, and Group IIn=4, respectively). In plasma, the concentration maximum (Group I 9.5±1.4 µmol·1^–1; Group II 19.4±3.8 µmol·1^–1) and the total clearance (Group I 1.56±0.28 ml·min^–1·kg^–1, Group II 0.5±0.06 ml·min^–1·kg^–1) were significant different in the two groups. The bile:plasma ratio (bpr) in Group I was 1.3±0.33 and 10.1±3.2, respectively, for indomethacin (In) and conjugated In. The conjugated fraction of In was 87.5±1.9% of the total concentration. In Group II the bpr was lower (0.65±0.1). In is eliminated in bile by diffusion and conjugated In by active secretion. In Group I 0.99±0.1 mg In and 6.1±0.7 mg conjugated In and in Group II 2.1±0.3 mg In (p<0.05) were eliminated in bile. No influence of In on the biliary lipids was observed or on the bile acid-independent fraction of bile flow. It is concluded that the total plasma clearance of In was dependent of liver function. Conjugated In undergoes enterohepatic circulation.     

The effects of diltiazem on methotrexate-induced nephrotoxicity

Summary We have tested the effects of calcium channel blockade with diltiazem on methotrexate-induced nephrotoxicity in patients with biopsy-proven malignant disease. The patients were randomized in a cross-over fashion to receive MTX (4 g · m^–2 body surface area) with or without Diltiazem (360 mg per day orally) during two consecutive periods separated by a 3-week interval.Methotrexate caused reversible acute renal failure, with an increase in serum creatinine from 89 (7)µmol·1^–1 on day 0 to 150 (6)µmol.·1^–1 on Day 6. The patterns of ₂-microglobulin and N-acetyl glucosaminidase urinary excretion were similar, with a sharp increase from Day 0 to Day 3. Urinary ₂-microglobulin excretion increased from 161 (57) µg·1^–1 on Day 0 to 1160 (840) µg·l^–1 on Day 3 and fell to 918 (530) µg·l^–1 on Day 10. Urinary Nacetyl glucosaminidase excretion increased from 250 (100) mmol·h^–1 per mg of creatinine on Day 0 up to 655 (261) on Day 3 and fell to 285 (82) on Day 10.The evolution of renal function was not influenced by diltiazem. In patients receiving diltiazem, serum creatinine increased from 93 (0) µmol·l^–1 on Day 0 to 151 (68) µmol·l^–1 on Day 6 (p = NS when compared with control values). Urinary enzyme excretion also markedly increased from Day 0 to Day 3 to the same extent as in the group not receiving diltiazem.Our data indicate that acute deterioration in renal function caused by methotrexate is accompanied by tubular damage. Diltiazem was ineffective in preventing the acute renal failure induced by methotrexate. An inadequate dosage of diltiazem or multifactorial toxic effects of methotrexate may account for this negative result.     

The effect of cardiopulmonary bypass on plasma protein binding of alfentanil

Summary The effect of cardiopulmonary bypass (CPB) on plasma concentration and protein binding of alfentanil was studied during continuous infusions in five cardiac surgical patients. Patients were given a loading infusion of 10 µg·min^–1·kg^–1 lean body mass (LBM) over 30 s followed by a fixed rate maintenance infusion of 1 µg·min^–1·kg^–1 LBM for the duration of surgery.Prior to the commencement of CPB the total plasma alfentanil concentration was 177 µg·l^–1. This fell to 92 µg·l^–1 2 min after commencement of CPB and rose to 155 µg·l^–1 at the end of CPB 2.01 h later. During the same period the unbound fraction of alfentanil rose from 0.16 to 0.35 two min after the start of CPB and fell gradually to 0.22 at the end of CPB. The unbound concentration prior to CPB was 29 µg·l^–1 and was essentially unchanged by the onset of CPB, being 35 µg·l^–1 at two min and then 31 µg·l^–1 at the end of CPB. There was a good correlation between alfentanil bound/unbound concentration ratio and plasma albumin concentration (r=0.57) and plasma ₁-acid glycoprotein concentration (r=0.80), indicating that the decrease in binding during CPB was due primarily to haemodilution.In assessing the effects of CPB on plasma drug concentrations, it is therefore necessary to monitor unbound as well as total concentrations because the effects on these differ greatly.