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1.
T. Callréus J. Lundahl A. Broeders P. Höglund 《European journal of clinical pharmacology》1999,55(4):293-298
Objective: The aim of the present study was to study the pharmacokinetics, the antidiuretic effects and the safety of [D-Phe2, Thi3, α-Me-Abu4, Hyp7, D-Arg8]-dC1-vasopressin, a new antidiuretic peptide (F992, Ferring, Sweden), administered as intravenous infusion to orally overhydrated
male volunteers.
Methods: Eight healthy male volunteers participated in this open study consisting of two parts: a dose titration study and a safety
study. In the dose titration study ascending doses of F992 were administered to volunteers in pairs in order to find a dose
that within 1 h after the infusion, in both subjects, caused a reduction of the urine flow rate to below 5 ml · min−1 (target dose). Subsequently, this target dose was administered to all volunteers. In the safety study the target dose was
doubled and given to all volunteers. On each study occasion, in both study parts, the subjects were orally overhydrated with
water. F992 was administered as i.v. infusion approximately 1.5 h after the start of the hydration procedure. Throughout the
study days, blood was sampled for determination of plasma concentrations of F992 and for safety evaluation. Urine was collected
at intervals in order to estimate flow rate and osmolality.
Results: The target dose was found to be 4.0 μg as this dose fulfilled the criteria regarding antidiuretic effect, consequently 8.0 μg
was administered to all subjects in the safety study. After infusion of 4.0 and 8.0 μg, the median half-lives of elimination
were 4.72 (range 3.99–6.53) h and 3.85 (range 3.04–11.08) h, respectively. The plasma clearance and the volume of distribution
at steady state were estimated to be 0.88 (SD 0.24) ml · min−1 · kg−1 and 326 (SD 68) ml · kg−1 after infusion of 4 μg. After the highest dose (8 μg), the corresponding estimates were 0.86 (SD 0.32) ml · min−1 · kg−1 and 299 (SD 81) ml · kg−1, respectively. Significantly (P = 0.033) different maximum mean urine osmolalities were produced after infusion of 4.0 and 8.0 μg of F992 (534 (SD 318) vs
732 (SD 189) mOsmol · kg−1). The median times to reach these values showed some tendency to be longer for the highest dose, however statistical significance
was not reached. No serious adverse events were observed during the study.
Conclusion: We found it safe to administer F992 as infusion to overhydrated male volunteers. The results suggest that F992 has a longer
half-life and a lower potency than the widely used peptide desmopressin.
Received: 10 August 1998 / Accepted in revised form: 30 December 1998 相似文献
2.
E. Jacqz-Aigrain S. Nafa Y. Médard E. Bessa B. Lescoeur E. Vilmer 《European journal of clinical pharmacology》1997,53(1):71-74
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 相似文献
3.
Ericsson H Fakt C Höglund L Jolin-Mellgård A Nordlander M Sunzel M Regårdh CG 《European journal of clinical pharmacology》1999,55(1):61-67
Objective: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy
male volunteers following a constant rate infusion.
Methods: Eight healthy male volunteers received 1030 nmol · min−1 of clevidipine together with a tracer dose of 3[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing
infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed
for 7 days.
Results: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance
of 0.14 (0.03) l · min−1 · kg−1 and a mean volume of distribution at steady state of 0.6 (0.1) l · kg−1. The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite
H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary
metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h
infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min.
Conclusion: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The tmax value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination
from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination
rather than distribution. The duration of action of clevidipine is short.
Received: 23 September 1998 / Accepted in revised form: 20 November 1998 相似文献
4.
M. Borenstein R. Shupak R. Barnette G. Cooney W. Johnson T.- B. Tzeng 《European journal of clinical pharmacology》1997,51(5):359-366
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 Cmax 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 相似文献
5.
M. Grossmann J. Braune Ulrike Ebert W. Kirch 《European journal of clinical pharmacology》1998,54(1):35-39
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 相似文献
6.
E. Snoeck V. Piotrovskij P. Jacqmin R. L. Lins A. Van Peer M. Danhof R. Woestenborghs R. Van Gool A. G. Dupont J. Heykants 《European journal of clinical pharmacology》1997,53(1):57-63
Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated
in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed
by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h).
Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on
erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy)
was evaluated as a pharmacodynamic endpoint.
Results: The population typical value for the dissociation constant K
d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding
capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K
d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of
only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity
in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and
steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1.
Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might
be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed
by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen
could be justified in patients.
Received: 6 February 1997 / Accepted in revised form: 12 May 1997 相似文献
7.
Vinge E. Nergelius G. Nilsson L. G. Lidgren L. 《European journal of clinical pharmacology》1997,52(5):407-411
Objective: The pharmacokinetics of cloxacillin was investigated in 14 men and 24 women undergoing cemented hip (n = 19; age range 56–90) or knee replacement surgery (n = 19; age range 51–84) for osteoarthritis. Cloxacillin 1 g was given intravenously as a bolus dose at the induction of anesthesia,
and plasma samples and urine were collected for 6 h. Drug levels were determined using HPLC.
Results: Preoperative serum creatinine levels were 84 μmol · l−1 in hip patients and 72 μmol · l−1 in knee patients. The calculated values for creatinine clearance were 63 and 85 ml · min−1 · 1.73 m−2, respectively. Total clearance of cloxacillin was 134 ml · min−1 · 1.73 m−2 in eighteen evaluated patients undergoing hip replacement, and 162 ml · min−1 · 1.73 m−2 in eighteen patients undergoing knee surgery. Renal clearance was 72 and 79 ml · min−1 · 1.73 m−2, respectively. Non-renal clearance was 57 ml · min−1 · 1.73 m−2 in hip patients and 77 ml · min−1 · 1.73 m−2 in knee patients. Renal clearance of cloxacillin correlated with the estimated creatinine clearance (r = 0.652). Although women received higher doses than men (median 2.02 vs 2.32 mmol · 1.73 m−2), there were no sex differences in clearance corrected for body surface area.
Conclusion: Total clearance of cloxacillin was lower in patients undergoing hip replacement than in patients undergoing replacement
of the knee, but there was no difference between men and women.
Received: 7 May 1996 / Accepted in revised form: 15 October 1996 相似文献
8.
Summary The plasma levels and excretion of tritium-labeled iloprost in healthy elderly male and female volunteers have been measured
after i.v. infusion of 2 ng·kg−1·min−1 for 4 h and oral administration of 0.1 and 0.48 μg/kg.
During infusion, a steady-state of labeled compounds in the plasma was not achieved. Total radioactivity declined from a mean
of 408 pg equiv/ml in three phases, with half-lives of 24 min, 1.7 h and 5.0 h, respectively. A steady-state of unchanged
iloprost was reached rapidly with a peak of 81 pg/ml. Plasma levels declined biphasically with half-lives of 6 min and 31
min. Total clearance was 24 ml· min−1·kg−1.
Maximum concentrations of labeled substances after oral administration were 307 and 1,051 pg equiv/ml after 29 and 39 min
respectively. The peak of unchanged iloprost (116 pg/ml) was observed 7.5 min after an oral dose of 0.48 μg/kg.
Bioavailability was 16%. Iloprost was totally metabolized and the metabolities were mainly excreted in urine. The main biotransformation
products in plasma and urine were tentatively identified by cochromatography as dinor-and tetranoriloprost and their glucuronides.
ADP-induced platelet aggregation was reduce by 60% during the i.v. infusion and 15 min after oral administration of 0.48 μg/kg.
Heart rate and blood pressure were virtually unaffected. Common side-effects were facial flush, headache and nausea. 相似文献
9.
K. Malminiemi H. Laine M. J. Knuuti U. Ruotsalainen V. Oikonen M. Haaparanta P. Nuutila 《European journal of clinical pharmacology》1997,52(1):19-26
Objective: Recently the role of peripheral vasoconstriction in the aetiology of insulin resistance has been proposed. Celiprolol is
a β1-selective adrenoceptor antagonist with partial agonist activity at the β2-receptor as well as vasodilator properties. The acute effects of celiprolol on skeletal muscle blood flow and insulin sensitivity
were measured in this study.
Methods: Celiprolol (2 times 0.5 mg · kg−1) or saline was given intravenously to five healthy males in random order. Muscle blood flow was measured in femoral regions
using [15O]-labelled water and positron emission tomography (PET) during euglycaemic hyperinsulinaemia (serum insulin ˜65 mU · l−1) after an overnight fast. Thereafter, skeletal and heart muscle glucose uptake were determined using [18F]-2-deoxy-d-glucose.
Results: Celiprolol increased muscle blood flow by 74%, from 3.4 to 5.9 ml · min−1 · 100 g−1 muscle in the basal state. It decreased peripheral resistance by 40%, from␣32.0 to 19.2 mmHg · ml−1 · min−1 · 100 g−1. Celiprolol significantly decreased diastolic blood pressure from 82 to 73 mmHg and increased heart rate from 61 to 68 beats · min−1, which suggests sympathetic activation. Insulin-stimulated glucose uptake was reduced by 46% in the whole body, from 39 to
21 μmol · kg−1 · min−1 and by 59% in the femoral muscles, from 99 to 41 μmol · kg−1 · min−1, with celiprolol as compared to saline. The effect on heart glucose uptake did not statistically differ between the treatments.
Conclusion: Celiprolol given intravenously increased muscle blood flow and decreased peripheral resistance at rest. It also acutely
increased heart rate probably via sympathetic activation, and decreased insulin sensitivity in the muscles of healthy male
volunteers. The enhanced muscle perfusion when celiprolol is given intravenously does not explain the improved insulin sensitivity
seen in the long-term oral use in dyslipidaemic hypertensive patients.
Received: 19 September 1996 / Accepted in revised form: 13 November 1996 相似文献
10.
Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease 总被引:1,自引:0,他引:1
C. Thalamas A. Taylor C. Brefel-Courbon S. Eagle K. Fitzpatrick O. Rascol 《European journal of clinical pharmacology》1999,55(4):299-303
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 Cmax) 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, Cmax and tmax 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 Cmax 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 Cmax for ropinirole with and without theophylline: 5.65 ng · ml−1 and 5.54 ng · ml−1, respectively; median tmax 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 相似文献
11.
Vancomycin dosing in morbidly obese patients 总被引:4,自引:0,他引:4
Objectives and methods: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine
the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal
weight population.
Results: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg · kg−1 · d−1 TBW or 81.9 mg · kg−1 · d−1 IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg · kg−1 · d−1 to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2=3.3 h,
V=52 l, CL =197 ml · min−1; normal: t1/2=7.2 h, V=46 l, CL=77 ml · min−1, 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients
in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW
and CL, but only fair correlation between TBW and V.
Conclusion: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when
TBW is used as a dosing weight for the obese (approximately 30 mg · kg−1 · d−1). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain
above 5 μg · ml−1 in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be
obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly
obese patients with renal dysfunction require further study.
Received: 9 March 1998 / Accepted in revised form: 30 June 1998 相似文献
12.
Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and polysulfone dialysers
L. Gabutti L. Taminelli-Beltraminelli C. Marone 《European journal of clinical pharmacology》1997,53(2):123-126
Objective: The purpose of the present study was to investigate whether the clearance of ceftriaxone during haemodialysis is influenced
by the type of membrane used (cuprophane, haemophane or polysulphone).
Methods: After administration of a single 2-g dose of ceftriaxone, the half-life of the drug during haemodialysis and the clearance
of the dialyser were measured.
Results: The mean dialysis clearance normalised for square metre of membrane surface was significantly different for the three dialysers
(haemophane 24 ml · min−1 · m−2; cuprophane 32 ml · min−1 · m−2; polysul phone 42 ml · min−1· m−2).
Conclusions: Polysulphone membranes are more permeable and increase the extraction of ceftriaxone more than the other dialysers studied
(haemophane and cuprophane membranes). These results, taken together with previous data, show that an increase of the dose
in dialysis patients treated with large surface (>0.8 m2) and high permeability membranes might be necessary.
Received: 18 November 1996 / Accepted in revised form: 12 May 1997 相似文献
13.
F. Castelli L. Tomasoni C. Zeroli F. Suter G. Trespi G. Carosi A. Hedman 《European journal of clinical pharmacology》1997,52(5):397-401
Objective: To compare the pharmacokinetics of foscarnet administered as an infusion twice daily (BID) or thrice daily (TID), and to
compare the effects on the electrolyte balance, cardiac and renal functions over a 3-week induction treatment of Cytomegalovirus (CMV) retinitis.
Methods: Pharmacokinetics/dynamics of foscarnet were investigated on treatment days 1, 14 and 21. Twelve AIDS patients with CMV retinitis
completed the investigation period. Concentrations of foscarnet and electrolytes were assayed by high-performance liquid chromatography
(HPLC) and by an ion-selective analyser, respectively.
Results: The pharmacokinetics of the two regimens were essentially similar. Foscarnet plasma and creatinine clearances were 2.0 and
1.6 ml · min−1 · kg−1, respectively, in the BID group at steady state (day 21). In the TID group the corresponding values were 1.8 and 1.7 ml · min−1 · kg−1, respectively. In both regimens the elimination half-life of foscarnet was 2–3 h. Ionized calcium concentrations were transiently
decreased and strongly inversely correlated to foscarnet plasma concentrations in both regimens with no significant differences
between groups. A trend towards prolongation of the QTc interval was seen when data from both treatments were analysed together.
Conclusion: Our data suggest comparable pharmacokinetics of foscarnet after intermittent administration BID or TID during a 3-week induction
period.
Received: 22 January 1996 / Accepted in revised form: 6 November 1996 相似文献
14.
Thürmann PA Lissner R Struff WG Harder S 《European journal of clinical pharmacology》1999,55(1):49-51
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 (AUC0∞) 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 (Cltot) 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 相似文献
15.
K. Harada M. Ohmori K. Sugimoto A. Fujimura 《European journal of clinical pharmacology》1998,54(1):31-34
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 相似文献
16.
J. F. W. Hoogkamer C. H. Kleinbloesem A. Nokhodian M. J. A. Ouwerkerk G. Lankhaar W. Ungethüm W. Kirch 《European journal of clinical pharmacology》1998,54(1):59-61
Objective: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting
enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal
failure [mean creatinine clearance (CLCR) 64 ml · min−1; range 42–77 ml · min−1], eight patients with severe chronic renal failure (mean CLCR, 18 ml · min−1; range 11–29 ml · min−1) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day
for 7 days.
Results: No statistical differences of either maximum concentration (Cmax) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However,
Cmax and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy
volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion
of both imidapril and imidaprilat.
Conclusion: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency.
Received : 11 July 1997 / Accepted in revised form : 6 October 1997 相似文献
17.
K. M. Koch M. Liu I. M. Davis S. Shaw Y. Yin 《European journal of clinical pharmacology》1997,52(3):229-234
Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function
to determine the effect of this condition on acid-antisecretory activity.
Methods: Subjects with creatinine clearances (CCr) ranging from 0 to 213 ml · min−1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine
concentrations, and continuous gastric pH monitoring for 24 h.
Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min−1, correlated with CPAH (r
2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal
impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the
pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects.
Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when CCr<50 ml · min−1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when
CCr<10 ml · min−1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.
Received: 10 September 1996 / Accepted in revised form: 7 December 1996 相似文献
18.
K. Harada M. Ohmori Y. Kito A. Fujimura 《European journal of clinical pharmacology》1998,54(3):227-230
Objective: To compare the venoconstricting effect of dopamine with that of noradrenaline and to investigate the influence of age on
the responsiveness to dopamine in human subjects.
Methods: In eight young and eight elderly male subjects, increasing doses of dopamine or noradrenaline were infused into a dorsal
hand vein and its diameter was measured using a linear variable differential transformer.
Results: There was no significant difference between the maximum venoconstriction (Emax) for dopamine and that for noradrenaline. The infusion rate to induce 50% of Emax (ED50) for dopamine in the young and elderly subjects was 363 ng · min−1 and 352 ng · min−1, and the ED50 for noradrenaline was 40.7 ng · min−1 and 43.8 ng · min−1, respectively. Neither in the Emax nor in the ED50 for these drugs were there significant differences between the young and elderly subjects.
Conclusion: The venoconstricting effect of dopamine is 5–20 times less than that of noradrenaline, and aging does not influence the
responsiveness to dopamine and noradrenaline in human subjects.
Received: 29 August 1997 / Accepted in revised form: 5 February 1998 相似文献
19.
M. T. V. Chan P. J. Anderson J. C. N. Chan G. S. N. Lau J. A. J. H. Critchley 《European journal of clinical pharmacology》1997,52(4):285-288
Objective: A single oral dose of paracetamol (20 mg · kg−1) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function
or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min−1 · 1.73 m−2. The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid
chromatography (HPLC).
Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration
time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency.
Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence
of altered metabolic activation with renal impairment.
Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation
of conjugates may occur.
Received: 2 September 1996 / Accepted in revised form: 11 December 1996 相似文献
20.
J. A. M. Avontuur S. L. C. E. Buijk H. A. Bruining 《European journal of clinical pharmacology》1998,54(8):627-631
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 (Cmax 6.2 μg · ml−1 at 12 h) whereas l-NAME concentrations reached a plateau within 1.5 h (Cmax 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 相似文献