共查询到20条相似文献,搜索用时 31 毫秒
1.
C. P. Chijioke R. E. Umeh A. U. Mbah P. Nwonu L. L. Fleckenstein P. O. Okonkwo 《European journal of clinical pharmacology》1998,54(3):249-251
Objective: Ten male patients with onchocerciasis received six weekly infusions of suramin according to the WHO-recommended regimen.
Results: In no case did the plasma concentration of suramin exceed 300 mg · l−1, and serious toxicity was not observed. The apparent volume of distribution (median 20.6 l) was comparable to that reported
for patients with prostatic carcinoma. Elimination from patients with onchocerciasis was relatively slow (median plasma clearance
6.2 ml · h−1, median terminal elimination half-life 91.8 days).
Conclusion: Microfilariae were eliminated in eight out of ten patients. Spontaneous nodule regression was noted in four patients.
Received: 8 September 1997 / Accepted in revised form: 27 January 1998 相似文献
2.
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
3.
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
4.
Objective: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone
also known as L1 or, using meta-analysis of the literature.
Methods: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic.
Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration
or urinary iron excretion (UIE). Efficacy data had to have been reported after ≥3 months of treatment. Data were combined
using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence
interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average
(mg · l−1) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize
efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg · kg−1 · day−1, which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg
per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges
of deferiprone dosage: ≤50 mg · kg−1 · day−1 and ≥75 mg · kg−1 · day−1.
Results: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients.
After a mean of 16 months of therapy (range 6.4–36 months) with 66.4 mg · kg−1 · day−1 (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average
drop in serum ferritin of 0.8 mg · l−1 was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving ≥75 mg · kg−1 · day−1 over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When
studies with patients receiving lower dosage (≤50 mg · kg−1 · day−1) were included, the success rate was 45.1%.
Conclusion: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron
overloaded patients. After an average of 16 months of deferiprone in doses ≥75 mg · kg−1 · day−1, most patients had a decrease in ferritine concentration.
Received: 1 July 1998 / Accepted in revised form: 17 November 1998 相似文献
5.
The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice 总被引:2,自引:0,他引:2
C. P. Clifford D. A. Adams S. Murray G. W. Taylor M. R. Wilkins A. R. Boobis D. S. Davies 《European journal of clinical pharmacology》1997,52(4):311-315
Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant
administration of grapefruit juice.
Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min
after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on
the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC),
maximum terfenadine concentration (Cmax) and the time to maximum concentration (tmax) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram.
Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine
was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml−1 · h), as was the Cmax (median values 7.2 vs 2.1 ng · ml−1). The tmax was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine
levels. The 95% confidence interval for the difference in the change in QTc interval at Cmax was −13 to +38 ms.
Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability,
but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does
not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of
time.
Received: 14 October 1996 / Accepted in revised form: 10 December 1996 相似文献
6.
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
7.
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
8.
Lee CT Kuo BI Chen CY Chang FY Lee SD 《European journal of clinical pharmacology》1999,54(11):817-820
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 相似文献
9.
Masche UP Rentsch KM von Felten A Meier PJ Fattinger KE 《European journal of clinical pharmacology》1999,54(11):865-868
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 相似文献
10.
Korhonen T Hannuksela ML Seppänen S Kervinen K Kesäniemi YA Savolainen MJ 《European journal of clinical pharmacology》1999,54(12):903-910
Background: Apolipoprotein E (apo E) allele E 4 is associated with high atherogenic lipid levels and coronary heart disease. Cholesteryl
ester transfer protein (CETP) transfers cholesteryl esters from (high density lipoprotein) HDL to other lipoproteins. CETP
gene expression is enhanced in hypercholesterolaemia and correlates with plasma apo E concentration.
Objective: The effect of the apo E phenotype on plasma CETP activity and the hypolipidaemic efficacy of colestipol and lovastatin was
studied in patients with type II a or II b hypercholesterolaemia.
Results: The baseline mean plasma total, low density lipoprotein (LDL) and HDL cholesterol, triglyceride, apolipoprotein A I (apo
A I) concentrations and CETP activity were 8.89 mmol · l−1, 6.78 mmol · l−1, 1.39 mmol · l−1, 1.59 mmol · l−1, 1.49 g · l−1 and 114 nmol · h−1 · ml−1, respectively. The colestipol-induced changes were −26%, −36%, +5%, +12%, −1% and −17%, and the lovastatin-induced changes
−34%, −44%, +6%, −18%, +1% and −19%. The lipid and apo A I concentrations or the CETP activity did not differ statistically
significantly according to the apo E phenotype, although the HDL cholesterol and apo A I levels were lowered in patients with
apo E 4/4 but elevated in patients with the other phenotypes. The CETP activity correlated with the LDL cholesterol concentration
(r = 0.52, P = 0.01) and the change in the LDL cholesterol during colestipol (r = 0.51, P = 0.02) and lovastatin (r = 0.65, P = 0.001) treatment, but only in patients without the apo E 4 allele.
Conclusion: Colestipol and lovastatin reduced CETP activity to the same amount, regardless of the apo E phenotype. The apo E phenotype
seems to modify the interaction between CETP activity and LDL cholesterol in hypercholesterolaemia and during pharmacological
lowering of cholesterol.
Received: 13 May 1998 / Accepted in revised form: 3 October 1998 相似文献
11.
Objective: Published pharmacokinetic data on ketotifen are sparse, although it is a commonly used prophylactic agent in various allergic
disorders in adults and children. The aim of this study was to assess the steady-state pharmacokinetics of ketotifen in children
with atopic perennial asthma who were participating in a clinical trial. Method: The NONMEM population approach with sparse sampling was utilized. The data set consisted of 239 samples from 48 children
who were randomized to receive either 1 mg or 2 mg oral ketotifen daily. Patients underwent a clinical examination and had
a blood sample taken at 2-week intervals for 12 weeks. The ketotifen concentrations were measured by RIA. Results: A one-compartment model with first-order absorption was fit to the data. Volume was estimated at 394 l and clearance (CL)
at 97.4 l · h−1 (3.6 l · h−1 · kg−1). Weight or body surface area were the most influential covariates for explaining interindividual variability in CL. The
2-mg dose appeared to have a relative bioavailability of 85% of the 1-mg dose. Conclusion: Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight
to give comparable steady-state levels.
Received: 15 September 1996 / Accepted in revised form: 31 January 1997 相似文献
12.
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
13.
A. Vermeire J. P. Remon M. T. Rosseel F. Belpaire J. Devulder M. G. Bogaert 《European journal of clinical pharmacology》1998,53(5):325-330
Objective: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability
of the disposition of morphine administered by subcutaneous infusion in cancer patients.
Methods: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60–3000 mg
per day) via chronic (8–160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible,
on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine
and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography
assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and
its degradation products in the solutions.
Results: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations
of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual
variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng · ml−1 · mg−1 to 0.8 ng · ml−1 · mg−1 for morphine, from 1.0 ng · ml−1 · mg−1 to 3.1 ng · ml−1 · mg−1 for morphine-6-glucuronide and from 6.8 ng · ml−1 · mg−1 to 24.3 ng · ml−1 · mg−1 for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised
plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide
and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did
not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found.
Conclusion: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition
which could be of clinical relevance.
Received: 5 August 1997 / Accepted in revised form: 8 October 1997 相似文献
14.
A. Lesne-Hulin P. Bourget F. Ravat C. Goudin J. Latarjet 《European journal of clinical pharmacology》1999,55(7):515-519
Objective: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum
and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects.
Methods: Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree
burns was 31.8 ± 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during
the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental
method was used for kinetic and graphic analysis of concentration–time pairs.
Results: No adverse effects were noted. Trough concentrations measured on day 3 (mean ± SD) were above the minimum inhibitory concentration
(MIC) for the organism responsible for infection; i.e., 2.0 ± 1.2 μg · ml−1, and maximum concentrations were high 9.9 ± 3.4 μg · ml−1. An area under the concentration–time curve (AUC)/MIC ratio above 125 SIT−1 (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial
eradication, was achieved in 11 patients with a MIC of 0.5 μg · ml−1. There was a statistically significant difference between Cmin and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased.
Conclusion: The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF,
i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy.
Received: 13 October 1998 / Accepted in revised form: 8 June 1999 相似文献
15.
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
16.
Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart 总被引:10,自引:0,他引:10
Objective: With the aim to obtain a premixed rapid-acting insulin with a serum insulin profile more closely resembling the endogenous
meal-stimulated serum insulin profiles, a 30/70 (rapid/intermediate-acting) premixed suspension of the rapid-acting insulin
analogue insulin aspart (BIAsp30) was compared with a similar premixed suspension of biphasic human insulin 30/70 (BHI30)
after a single subcutaneous injection.
Methods: The study had a randomised, double-blind, two-period crossover design. Twenty-four healthy male subjects received a single
subcutaneous dose of either 0.2 U · kg−1 bodyweight of BIAsp30 or BHI30 on two study days.
Results: BIAsp30 was absorbed faster than BHI30, as reflected in the area under the insulin concentration-time curve from 0 to 90 min
after dosing [AUC(0–90 min)]. This was significantly larger for BIAsp30 than for BHI30 (1403 ± 372 versus 752 ± 191 mU · l−1 · min−1 [mean ± SD]; P < 0.0001). Furthermore, the time to maximum serum insulin concentration (tmax) of BIAsp30 was approximately half the tmax of BHI30 (60 [45–70] versus 110 [90–180] min [median, interquartile range]; P=0.0001) and the maximum insulin concentration (Cmax) was significantly higher for BIAsp30 than for BHI30 (23.4 ± 5.3 versus 15.5 ± 3.7 mU · l−1 [mean ± SD]; P < 0.0001). The serum glucose profiles showed a significantly earlier onset of the glucose-lowering effect following BIAsp30
than following BHI30.
Conclusions: The improved absorption properties of soluble insulin aspart in its premixed formulation provide a basis for a more efficient
meal-related glucose control and immediate pre-meal delivery when compared with a similar human premixed insulin in the treatment
of diabetes mellitus.
Received: 22 November 1999 / Accepted in revised form: 7 April 2000 相似文献
17.
Absorption, metabolism and excretion of a single oral dose of 14C-repaglinide during repaglinide multiple dosing 总被引:2,自引:0,他引:2
P. N. M. van Heiningen V. Hatorp K. Kramer Nielsen K. T. Hansen J. J. van Lier N. C. De Merbel B. Oosterhuis J. H. G. Jonkman 《European journal of clinical pharmacology》1999,55(7):521-525
Objective: The present study was designed to assess the disposition of 14C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine
and faeces after a single 2-mg oral dose of 14C-repaglinide during multiple dosing.
Methods: In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator,
repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose
was given as an oral solution containing 2 mg of 14C-repaglinide.
Results: After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng · ml−1 (range: 16.84–36.65 ng · ml−1) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites
were distributed into red blood cells. No measurable 14C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with 14C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major
compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine
(M1) (24%), and the dicarboxylic acid (M2) (22%). In the faeces, the major metabolite was M2 (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite
of repaglinide in humans was M2. During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost
always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well
tolerated, and there were no episodes of hypoglycaemia.
Conclusion: After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations
decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin
secretagogue for all patients with type-2 diabetes who retain sufficient β-cell function.
Received: 13 January 1999 / Accepted in revised form: 15 June 1999 相似文献
18.
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
19.
Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults 总被引:1,自引:0,他引:1
A. M. Wilson D. J. Clark M. M. Devlin L. C. McFarlane B. J. Lipworth 《European journal of clinical pharmacology》1998,53(5):317-320
Objective: The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate (FP) and budesonide
(BUD) on adrenocortical activity in asthmatic patients.
Methods: Ten asthmatic patients with a mean age of 31.2 years, a mean forced expiratory volume in 1 s (FEV1) of 91% predicted and a forced mid-expiratory flow (FEF25–75) of 62.3% predicted were studied in a single-blind randomised crossover design comparing placebo (PL), FP (375 μg per day
and 750 μg per day) and BUD (400 μg per day and 800 μg per day) all given once daily for 4 days at each dose via a pressurised
metered dose inhaler (pMDI) at 0800 hours. After 4 days of treatment, plasma cortisol was measured at 0800 hours (24 h after
the last dose) and a 10-h overnight urine collection was taken, 14 h after the last dose (2200–0800 hours) for analysis of
cortisol and creatinine excretion.
Results: Plasma cortisol levels (nmol · l−1, as geometric mean) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD (424.1 vs
510.3 nmol · l−1, respectively) but not between the low doses (506.8 vs 514.9 nmol · l−1; PL 532.2 nmol · l−1). For the highest dose FP (750 μg) this equated to 20% suppression of 0800 hours plasma cortisol. Likewise, for overnight
urinary cortisol output (nmol · 10 h−1, as geometric mean), there was a significant difference at the high doses of FP and BUD (25.5 vs 38.2 nmol · 10 h−1), but not at the low doses 31.3 vs 34.8 nmol · 10 h−1; PL 32.0 nmol · 10 h−1. For the overnight urinary cortisol/creatinine ratio (nmol · mmol−1, as geometric mean) there was a similar trend; 4.5 vs 6.1 nmol · mmol−1 for high dose and 5.6 vs 6.3 nmol · mmol−1 for low dose; PL 5.9 nmol · mmol−1.
Conclusion: Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily, when comparing effects
on plasma cortisol levels at 0800 hours, 24 h after the last dose, as well as effects on overnight urinary cortisol output.
Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression.
Received: 29 April 1997 / Accepted in revised form: 5 July 1997 相似文献
20.
C. Crevoisier J. Handschin J. Barré D. Roumenov C. Kleinbloesem 《European journal of clinical pharmacology》1997,53(2):135-139
Objectives: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy
volunteers.
Methods: In an open, two-way cross-over study, 20 healthy male volunteers who had fasted overnight were randomised to receive a single
oral dose of 750 mg mefloquine in the absence or presence of a standardised, high-fat breakfast, administered 30 min before
drug administration. Blood samples were taken at specific times over an 8-week period. Plasma concentrations of mefloquine
and its carboxylic acid metabolite were determined by high-performance liquid chromatography for pharmacokinetic evaluation.
Results: The parameters Cmax and AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher under post-prandial conditions than under fasting conditions (mefloquine: mean Cmax 1500 vs 868 μg · l−1, mean AUC 645 vs 461 mg l−1 · h; metabolite: Cmax 1662 vs 1231 μg · l−1, AUC 1740 vs 1310 mg l−1 · h). The intersubject variability in Cmax and AUC of mefloquine was less than 30% (coefficient of variation). The time to peak plasma concentration of mefloquine was
significantly shorter after food intake (17 vs 36 h). Compared with absorption in volunteers who had fasted, food did not
alter t1/2 (mefloquine and its metabolite) and tmax (metabolite).
Conclusion: Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to
recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving
curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly
after meals should be attempted as soon as feasible.
Received: 10 February 1997 / Accepted in revised form: 16 June 1997 相似文献