Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humour of patients by different topical application modes

Objectives: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humour. Methods: Two hundred and twenty-four patients undergoing cataract extraction received 0.3% ciprofloxacin, norfloxacin or ofloxacin eye drops by two different administration modes with different frequencies and intervals of application. At the beginning of cataract extraction (0.5–3 h after the last drop), 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using high-performance liquid chromatography. Results: Generally, topical ofloxacin and ciprofloxacin yielded aqueous humour levels higher than topical norfloxacin. The highest concentrations of all tested fluoroquinolones were measured after using an application mode, in which one drop was given every 15 min between 0600 hours and 0800 hours, prior to operation. When applied by this mode, ciprofloxacin achieved a mean aqueous level of 0.380 (±0.328) μg · ml⁻¹ (range 0.033–1.388 μg · ml⁻¹), norfloxacin 0.182 (0.118) μg · ml⁻¹ (range 0.038–0.480 μg · ml⁻¹) and ofloxacin 0.564 (0.372) μg · ml⁻¹ (range 0.064–1.455 μg · ml⁻¹). These mean concentrations were above the minimum inhibitory concentration (MIC₉₀), concentrations required for inhibition of 90% of pathogen strains in vitro of gram-negative bacteria, such as Proteus mirabilis and Escherichia coli. Therapeutic values above the MIC₉₀ of Staphylococcus epidermidis, the pathogen causing eye infections most frequently, were reached by 67.5% of patients after ofloxacin and by 41% after ciprofloxacin, but never after norfloxacin treatment. Conclusion: Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humour concentration. This fluoroquinolone may be an useful ophthalmic agent for topical antibacterial management, but it does not seem to be prophylactically effective against Streptococcus pneumoniae or Pseudomonas aeruginosa. Received: 22 April 1997 / Accepted: 8 June 1997     

Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease

Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.) dose of theophylline, both in patients with idiopathic Parkinson's disease (PD). Methods: Pharmacokinetic parameters (AUC and C_max) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in 12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at doses of up to 300 mg b.i.d. The parameters AUC, C_max and t_max for ropinirole were compared before, during and after oral theophylline co-treatment. Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and without ropinirole: 68.6 μg · h⁻¹ · ml⁻¹ and 70.0 μ· h⁻¹ · ml⁻¹, respectively; mean C_max with and without ropinirole: 11.07 μ g · ml⁻¹ and 11.83 μg · ml⁻¹, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h⁻¹ · ml⁻¹ and 22.09 ng · h⁻¹ · ml⁻¹, respectively; mean C_max for ropinirole with and without theophylline: 5.65 ng · ml⁻¹ and 5.54 ng · ml⁻¹, respectively; median t_max for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively). Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses. Received: 10 August 1998 / Accepted in revised form: 27 January 1999     

Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses

Objectives: In order to improve the penetration of topically applied drugs in ophthalmology, the suitability of hydrophilic contact lenses (Acuvue, Vistacon, power −1.0 D) as a drug delivery system for antibiotics was tested. A prospective study was undertaken to determine the transcorneal penetration of five topically applied aminoglycosides and fluoroquinolones into the aqueous humour of patients. Methods: Two hundred and sixty-five patients undergoing cataract extraction received 0.3% gentamicin, kanamycin, tobramycin, ciprofloxacin or ofloxacin solution by two different modes of administration: either as eye drops (nine drops every 15 min, starting 2 h prior to surgery) or by means of a drug delivery system (Acuvue contact lenses soaked for 1 h in eye drop solution without preservatives, 1–5 h prior to surgery). At the beginning of cataract extraction, 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using fluorescence polarisation immuno-assays (aminoglycosides) or high-performance liquid chromatography (fluoroquinolones). Results: After soaking for 1 h in 0.3% eye drop solutions, Acuvue contact lenses released about 190–250 μg aminoglycoside and ofloxacin and 1000 μg ciprofloxacin. These amounts are considerably lower or in the same order of magnitude than obtained with application of eye drops (1350 μg). From the aminoglycosides tested, only gentamicin and tobramycin, but not kanamycin, were able to penetrate into the aqueous humour of patients. After the wearing of antibiotic-soaked lenses, mean aqueous humour concentrations were higher than after the use of eye drops. This difference reached significance in tobramycin (1.09 (1.30) μg · ml⁻¹ vs 0.49 (0.79) μg · ml⁻¹), ciprofloxacin (1.23 (0.60) μg · ml⁻¹ vs 0.38 (0.33) μg · ml⁻¹) and ofloxacin (5.55 (2.53) μg · ml⁻¹ vs 0.56 (0.37) μg · ml⁻¹). The percentage of patients with aqueous humour concentration above the MIC₉₀ of Staphylococcus epidermidis, the most common cause of postoperative endophthalmitis, was 92% and 100% after wearing ciprofloxacin- or ofloxacin-soaked lenses, respectively. Conclusion: Gentamicin and tobramycin penetrated into the aqueous humour of patients, whereas kanamycin was not able to overcome the corneal barrier. Acuvue contact lenses soaked in 0.3% eye drop solutions can release sufficient amounts of gentamicin, ciprofloxacin and ofloxacin to produce bacteriostatic concentrations in the humor aquosus. Acuvue contact lenses can be recommended as a drug delivery system for fluoroquinolones. Received: 15 October 1998 / Accepted in revised form: 16 December 1998     

Pharmacokinetics of oxypolygelatine in healthy volunteers

Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg⁻¹ body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml⁻¹, the area under the plasma concentration/time curve (AUC_0∞) was calculated to 70.135 (15.861) μg · h · ml⁻¹. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cl_tot) of 24.6 (6.8) ml · min⁻¹. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites. Received: 9 June 1998 / Accepted in revised form: 23 November 1998     

Multidrug resistance modulation in vivo: The effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia

Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h⁻¹ · m⁻² vs 139.65 (69.45) l · h⁻¹ · m⁻²; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l⁻¹ vs 2896.60 (736.38) μg · h · l⁻¹; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vd_ss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg⁻¹ daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered. Received: 2 June 1998 / Accepted in revised form: 3 December 1998     

Lack of a pharmacokinetic interaction between atovaquone and proguanil

Objective: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers. Methods: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given. Results: The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the last dose (AUC_0→24h) was 180 μg · ml⁻¹ · h following administration of atovaquone alone and 193 μg · ml⁻¹ · h following atovaquone with proguanil. The geometric mean AUC_0→24h for proguanil was 6296 ng · ml⁻¹ · h after proguanil alone and 5819 ng · ml⁻¹ · h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng · ml⁻¹ · h and 1187 ng · ml⁻¹ · h, respectively. The geometric mean elimination half-life (t_1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric mean values of t_1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics of atovaquone, proguanil, or cycloguanil. Conclusion: The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and proguanil were given alone or in combination. Received: 14 October 1998 / Accepted in revised form: 8 February 1999     

Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia

Objective: The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n°58881. Results: After 1 month of oral treatment at a dose of 50 mg · m⁻² · day⁻¹, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g · m⁻² (bolus dose of 0.2 g · m⁻² followed by an 8-h infusion of 0.8 g · m⁻²) in 11 patients: systemic clearance was 23.02 l · h⁻¹, volume of distribution was 0.75 l · kg⁻¹, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol × 10⁸ packed RBC) or within 24 h of infusion (223 pmol × 10⁸ packed RBC). The CSF concentration was 3.78 μmol · l⁻¹, 1–6 h after the beginning of infusion (n=28) and the CSF to plasma ratio was 0.15 (n=16). In patients receiving the oral dose of 50–165 mg · m⁻² · day⁻¹ of 6-mercaptopurine, CSF concentrations were below 0.18 μmol · l⁻¹, 1–24 h after drug intake (n=67), and the CSF to plasma ratio was not calculated. Conclusion: Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n°5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses. Received: 15 August 1996 / Accepted in revised form: 8 April 1997     

Myocardial amiodarone concentrations after short- and long-term treatment in patients with end-stage heart failure

Background: Pharmacokinetics and tissue concentrations of amiodarone may vary considerably in end-stage heart failure, but may be crucial for treatment efficiency and antiarrhythmic drug therapy. Objective: This study was undertaken to determine plasma amiodarone and desethylamiodarone concentrations and to determine whether they correlate with myocardial concentrations in explanted hearts from patients with end-stage heart failure. Patients and methods: Eight patients with idiopathic dilated cardiomyopathy and normal coronary arteries were included in the present study. Myocardial tissue samples (seven sites) and epicardial fat were taken from each explanted heart, and drug concentrations of amiodarone and desethylamiodarone were determined. In addition, plasma drug levels were measured and compared with the myocardial amiodarone/desethylamiodarone concentrations. Results: The mean cumulative amiodarone dose was 91 g and the mean plasma concentrations of amiodarone and desethylamiodarone were 0.68 and 0.84 μg · ml⁻¹, respectively. The tissue concentrations of amiodarone amounted to 13.2 and 28.3 μg · g⁻¹, respectively, in the atria and to 13.0 and 40.8 μg · g⁻¹, respectively, in the ventricles. The distribution of the drug and its metabolite were similar in the right and left ventricles. There was a good correlation between myocardial concentration of amiodarone and desethylamiodarone and the cumulative ingested dose of amiodarone. Tissue drug concentrations correlated only poorly with plasma amiodarone or desethylamiodarone levels. The highest drug levels were measured in the epicardial fat tissue, where the ratio of amiodarone 105 μg · g⁻¹ to desethylamiodarone 32 μg · g⁻¹ was reversed (3.3 compared with 0.29 in the ventricles). Thus, amiodarone concentrations in epicardial fat were approximately 10 times higher than myocardial and 150 times higher than plasma levels. Conclusions: Our data confirm the slow equilibrium of amiodarone and desethylamiodarone concentrations between plasma and myocardium. Myocardial tissue concentrations of desethylamiodarone and, to a lesser degree, amiodarone correlate with the cumulative ingested dose of amiodarone. Monitoring of the total cumulative dose may be more relevant clinically than monitoring plasma levels. These results support the clinical practice of reducing the maintenance dose of amiodarone in patients who are on long-term treatment. Received: 12 July 1997 / Accepted in revised form: 25 September 1997     

Dilatory effects of phosphodiesterase inhibitors on human hand veins in vivo

Objective: To compare the venodilator potencies of the phosphodiesterase (PDE) III inhibitors amrinone and enoximone with the unspecific PDE inhibitors theophylline and pentoxifylline in human hand veins in vivo. Methods: Eighteen healthy nonsmokers (16 men and two women) were studied using the dorsal hand vein technique. After preconstriction with the selective α₁-adrenergic-receptor agonist phenylephrine dose–response curves were constructed for amrinone (1–270 μg · min⁻¹), enoximone (1–270 μg · min⁻¹), theophylline (5–1500 μg · min⁻¹) and pentoxifylline (2–877 μg · min⁻¹) in a random order on separate occasions. Due to limitation in the maximum dose infused in order to avoid systemic effects, full dose–response curves could not be constructed for pentoxifylline. In this case, the individual dose of pentoxifylline and theophylline producing 50% venodilation were compared. Results: All PDE inhibitors induced dose-dependent venodilation. The value of maximum venodilation was the same for amrinone, enoximone and theophylline. The infusion rate needed to induce 50% of maximum venodilation (ED₅₀) was not significantly different for amrinone (geometric mean, 8.8 μg · min⁻¹) and enoximone (14.2 μg · min⁻¹), whereas the ED₅₀ of theophylline (84.0 μg · min⁻¹) was significantly higher than either amrinone or enoximone. The dose necessary to dilate the vein to 50% the maximum dilation (as determined during sodium chloride infusion) was significantly higher for pentoxifylline than for theophylline (409 vs 71 μg · min⁻¹). Conclusions: These findings demonstrate that enoximone and amrinone have similar venodilatory potency which is six times higher than that of theophylline. The least potent vasodilator in this study was pentoxifylline. Received: 16 September 1997 / Accepted in revised form: 4 December 1997     

Pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure elevation

Objective: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug. Methods: We studied 17 patients with transient IOP elevation, who were given 62.5–500 mg acetazolamide orally as single or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. Results: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation, as follows: 0.0468 · CCR l · h⁻¹. The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 l · kg⁻¹, 0.821 · h⁻¹, and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an E_max model. The maximal effect in lowering the IOP (E_max) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC₅₀) was 1.64 μg · ml⁻¹. As 70% of E_max was achieved at a plasma concentration of 4 μg · ml⁻¹, this concentration was considered satisfactory for lowering IOP. The recommended dosage was calculated so that the minimum plasma concentration at steady state exceeded this target concentration; 250 mg t.i.d., 125 mg t.i.d., 125 mg b.i.d., and 125 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml · min⁻¹, respectively. Conclusion: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient rises in IOP following intraocular surgery. Received: 10 April 1997 / Accepted in revised form: 21 October 1997     

Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole

Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml⁻¹, the mean C_max was 0.14 vs 0.31 μg · ml⁻¹and the mean t_max was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola. Received: 4 November 1996 / Accepted in revised form: 21 January 1997     

Comparison of venodilatory effect of nicardipine, diltiazem, and verapamil in human subjects

Objective: Venodilatory effects of calcium antagonists have not been fully investigated, especially in human subjects. The present study was undertaken to compare the direct venodilatory effects of nicardipine, diltiazem and verapamil using the dorsal hand-vein technique. Methods: In eight healthy male subjects, increasing doses (0.001, 0.01, 0.1, 1 and 10 μg · min⁻¹) of these drugs and saline alone were infused, on four separate occasions, into the dorsal hand vein preconstricted with noradrenaline, and its diameter was measured by a linear-variable differential transformer. Result and conclusions: Diltiazem caused significant venodilation at a dose of 0.01 μg · min⁻¹ or more, while verapamil and nicardipine only caused this effect at 1 μg · min⁻¹ or more. The potency of the effect was diltiazem > verapamil > nicardipine. The venodilation at a dose of 1 μg · min⁻¹ was 41.7%, 16.2% and 8.5%, respectively, for each drug. These findings indicate that the venodilatory effect of diltiazem is larger than that of verapamil and nicardipine in human subjects. Received: 15 July 1997 / Accepted in revised form: 27 October 1997     

Distribution and metabolism of N G-nitro-l-arginine methyl ester in patients with septic shock

Objective: The pharmacokinetics of N ^G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. Methods: Blood was sampled at intervals before, during and after 12-h infusion of l-NAME 1 mg · kg⁻¹ · h⁻¹ in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined. Results: Incubation of l-NAME with plasma and blood in vitro revealed hydrolysis to N ^G-nitro-l-arginine (l-NOARG), the active inhibitor of NO synthesis. l-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg · kg⁻¹ · h⁻¹ of l-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of l-NOARG (C_max 6.2 μg · ml⁻¹ at 12 h) whereas l-NAME concentrations reached a plateau within 1.5 h (C_max 1.0 μg · ml⁻¹). After the infusion was stopped l-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas l-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for l-NAME was 0.45 l · kg⁻¹ body weight and 1.96 l · kg⁻¹ for l-NOARG. The renal clearance for l-NOARG was 3.5% of total body clearance for l-NOARG, whereas l-NAME could not be detected in urine. Conclusion: We conclude that vasoconstriction with l-NAME in septic patients may result from hydrolysis to l-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for l-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite l-NOARG follows other pathways. Received: 13 March 1998 / Accepted in revised form: 30 June 1998     

Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

   Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg⁻¹ sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg⁻¹ · min⁻¹, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min⁻¹ · kg⁻¹), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg⁻¹) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean C_max values of 421 (group I), 125 (group II), and 53 (group III) ng · ml⁻¹ and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg⁻¹ tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate. Received: 23 August 1995 / Accepted in revised form: 19 August 1996     

Plasma esterases in cystic fibrosis: the impact of a respiratory exacerbation and its treatment

Objectives: To determine the effect of an exacerbation of respiratory symptoms in cystic fibrosis (CF) on the activities of plasma benzoylcholinesterase and butyrylcholinesterase. Methods: Twenty-nine patients with CF in a respiratory exacerbation and 27 healthy volunteers matched for age and sex were recruited. Blood was obtained from the patients when commencing antibiotic treatment and 14 days later on completion of treatment. One blood sample was taken from the healthy volunteers. The activities of benzoylcholinesterase and butyrylcholinesterase were determined by spectrophotometric assay. The circulating inflammatory markers, C-reactive protein and neutrophil elastase-α₁antiproteinase complex were also measured. Results: Benzoylcholinesterase activity was significantly (P = 0.001) lower in patients at the start of a respiratory exacerbation, compared with healthy controls [mean (SD): 917 (274) versus 1191(298) nmol · ml⁻¹ · min⁻¹]. Benzoylcholinesterase activity increased significantly in patients to 1013 (237) nmol · ml⁻¹ · min⁻¹, following a course of antibiotic treatment (P = 0.006). Butyrylcholinesterase activity was also lower (P = 0.001) in patients at the start of a respiratory exacerbation, compared with healthy controls [5.54 (1.64) versus 7.01 (1.79) μmol · ml⁻¹ · min⁻¹], and increased significantly in the patients to 6.31 (1.58) μmol · ml⁻¹ · min⁻¹ following treatment (P = 0.006). Conclusion: We demonstrated significant suppression of plasma esterase activities during an exacerbation of respiratory symptoms in CF, which was only partially reversed after antibiotic treatment. Further studies are needed to examine other pathways of drug metabolism in this group of chronically infected patients. Received: 8 June 1998 / Accepted in revised form: 18 September 1998     

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery

Objective: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. Methods: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. Results: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 μg · kg⁻¹ · day⁻¹). The total plasma concentration (2.19 vs. 2.43 μg · ml⁻¹), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng · ml⁻¹) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/C_uss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml · kg⁻¹ · h⁻¹). Conclusions: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160␣years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery. Received: 23 August 1996 / Accepted November 11 1996     

Renal handling of drugs in the healthy elderly Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged

Objective: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions. Methods: We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (C_in) and para-aminohippurate [PAH (C_PAH)] clearance (infusion clearance technique), endogenous (C_Cr) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of β-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days. Results: C_in was significantly (P < 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml · min⁻² · 1.73 m⁻² in the young], but remained within the normal range (>90 ml · min⁻² · 1.73 m⁻²). In contrast, C_Cr was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml · min⁻¹ in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml · min⁻¹]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) μg · h⁻¹ · ml⁻¹ in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) μg · ml⁻¹], but the proportion of the drug excreted in urine was marginally (P < 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly. Conclusions: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly. Received: 2 April 1998 / Accepted in revised form: 19 October 1998     

No clinically relevant effect of Iornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics

Objective: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. Methods: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). Results: The median (range) areas under the concentration-time curve (AUC) for (R)-acenocoumarol were 3458 (3035–7312) μg · h l⁻¹ in the absence of and 3667 (2907–7741) μg · h l⁻¹ in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381–853) μg · h l⁻¹ and 612 (425–1241) μg · h l⁻¹. The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics. Received: 22 June 1998 / Accepted in revised form: 1 October 1998     

Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients

Objective: To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans. Methods: Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole concentration was 16 ng · ml^–1. Results: Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC_0–24 was 3.28 vs 0.39 μg · h · ml⁻¹ in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC_0–24 was 1.07 vs 0.38 μg · h · ml^–1 in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 64% compared with phase 1. Conclusion: Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered concomitantly. Received: 2 September 1997/Accepted in revised form: 16 December 1997     

Helicobacter pylori clearance and serum gastrin and pepsinogen I concentrations in omeprazole treatment of duodenal ulcer patients

Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients undergoing omeprazole treatment. Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females, aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels. Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml⁻¹, SD 32.0 pg · ml⁻¹ vs 133.9 pg · ml⁻¹, SD 71.6 pg · ml⁻¹, P < 0.01), and pepsinogen I (111.0 ng · ml⁻¹, SD 36.7 ng · ml⁻¹ vs 253.6 ng · ml⁻¹, SD 64.8 ng · ml⁻¹, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD 67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity to predict antral H. pylori clearance. Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia I probably provides a non-invasive alternative for predicting H. pylori clearance. Received: 22 August 1996 / Accepted in revised form: 1 October 1998