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1.
Kolade YT Babalola CP Olaniyi AA Scriba GK 《European journal of clinical pharmacology》2008,64(1):77-81
Objective To study the effect of the concomitant consumption of kolanut, a caffeine-containing nut, on the pharmacokinetics of halofantrine.
Methods A single dose of 500 mg halofantrine hydrochloride was orally administered either alone or concomitant with 12.5 g kolanut
to 15 healthy male volunteers in a Latin-square randomized crossover design with a wash-out period of 6 weeks between treatments.
Blood samples were collected and analyzed by HPLC for halofantrine and the active metabolite N-desbutylhalofantrine.
Results Concomitant intake of kolanut with halofantrine significantly decreased Cmax and AUC of both halofantrine and the metabolite desbutylhalofantrine, while no significant effect was observed for t
max and t
1/2 of the compounds. In the case of halofantrine, Cmax decreased from 179 ± 119 to 98 ± 32 ng/ml, and the AUC was reduced from 17,450 ± 4,611 to 11,821 ± 4,069 ng·h/ml. Cmax of desbutylhalofantrine decreased from 124 ± 41 to 62 ± 23 ng/ml and the AUC from 13,341 ± 4,749 to 7,359 ± 3,018 ng·h/ml
when kolanut was co-administered.
Conclusions Co-administration of halofantrine and kolanut caused a significant decrease in the plasma concentrations of halofantrine and
the active metabolite desbutylhalofantrine probably during adsorption of the drug due to complex formation. This indicates
that caution should be exerted when the drug is taken together with caffeine-containing nutrients. 相似文献
2.
Grapefruit juice increases the bioavailability of artemether 总被引:3,自引:0,他引:3
M. A. van Agtmael V. Gupta T. H. van der Wösten J.-P. B. Rutten C. J. van Boxtel 《European journal of clinical pharmacology》1999,55(5):405-410
Objective: To evaluate the effect of grapefruit juice on the pharmacokinetics of artemether in plasma and saliva after a single oral
dose and to detect concentration-dependent electrocardiographic changes (bradycardia and QTc prolongation).
Methods: Six healthy male subjects were given a standard breakfast followed by two tablets of 50-mg artemether administered with
water; 1 week later, the tablets were administered with 350 ml double-strength fresh frozen grapefruit juice. For 8 h, 17
blood- and saliva samples were collected, and 17 electrocardiograms were recorded. Drug and metabolite concentrations were
measured by means of high-performance liquid chromatography with electrochemical detection. The pharmacokinetic parameters
were determined using a one-compartment model.
Results: Grapefruit juice significantly (P = 0.001) increased the mean peak concentration (Cmax) of artemether more then twofold from 42 (SD 17) ng/ml to 107 (28) ng/ml. The time to reach Cmax (tmax) with grapefruit juice was 2.1 (0.6) h compared with 3.6 (17) h with water (P = 0.02). The area under the concentration–time curve (AUC) almost doubled with grapefruit juice from 177 ng · h/ml to 336 ng.h/ml
(P = 0.003). The elimination half-life remained unchanged (1.0 h vs 1.3 h). No major changes in the kinetics of the metabolite
dihydroartemisinin were detected. Low artemether levels and zero dihydroartemisinin levels were found in saliva. No influences
of artemether were observed on 17 electrocardiograms during the 8 h after drug intake – in particular there were no signs
of bradycardia or QTc prolongation.
Conclusion: Grapefruit juice significantly increases the oral bioavailability of artemether without an effect on the elimination half-life.
It suggests a role for intestinal CYP3A4 in the presystemic metabolism of artemether.
Received: 21 December 1998 / Accepted in revised form: 15 March 1999 相似文献
3.
Almeida L Falcão A Vaz-da-Silva M Nunes T Santos AT Rocha JF Neta C Macedo T Fontes-Ribeiro C Soares-da-Silva P 《European journal of clinical pharmacology》2008,64(10):961-966
Objective Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9,
which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone
on warfarin pharmacokinetics and pharmacodynamics in healthy subjects.
Methods Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received
nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning
dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment
periods were separated by a washout of 14 days.
Results For R-warfarin, mean ± SD Cmax was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC0-t
was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean
ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for Cmax and 1.247 (1.170–1.327) for AUC0-t
. For S-warfarin, mean ± SD Cmax was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC0-t
was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI
were 0.932 (0.845–1.028) for Cmax and 0.914 (0.875–0.954) for AUC0-t
. No differences were found for the pharmacodynamic parameter (INR).
Conclusion Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition
of the R-warfarin metabolism was found but is unlikely to be of clinical relevance. 相似文献
4.
Lunell E Molander L Ekberg K Wahren J 《European journal of clinical pharmacology》2000,55(10):737-741
Objective: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared
with that after cigarette smoking.
Methods: Using a catheterisation technique, the nicotine plasma concentration–time profiles in arterial and jugular venous blood
after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers.
Results: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5.9 ± 1.5 ng/ml at a mean time
to reach peak concentration (t
max) of 9.0 ± 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 ± 5.4 ng/ml at 6.7 ± 0.3 min. The concentration–time
curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal
absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to
a maximum level of 49.2 ± 9.7 ng/ml after 4.0 ± 0.6 min, while the maximum concentration of nicotine in the jugular vein was
22.4 ± 3.9 ng/ml after 6.4 ± 0.4 min, indicating primarily pulmonary absorption of nicotine.
Conclusion: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs
slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse
of the nicotine inhaler is probably small.
Received: 7 June 1999 / Accepted in revised form: 6 October 1999 相似文献
5.
Kan Usuda Koichi Kono Yukio Orita Tomotaro Dote Kozo Iguchi Hiroyuki Nishiura Mika Tominaga Teruaki Tagawa Eita Goto Yumi Shirai 《Archives of toxicology》1998,72(8):468-474
The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several
groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were
collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6 ± 7.9. The relationship
between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete.
Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The
serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open
model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t
1/2a=0.608±0.432 h; elimination half-life, t
1/2=4.64±1.19 h; volume of distribution, Vd=142.0±30.2 ml/100 g body wt.; total clearance, C
tot=0.359 ± 0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (C
max) was 2.13 ± 0.270 mg/l, and the time needed to reach this maximum concentration (T
max) was 1.76 ± 0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the
gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum
proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding
in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is
partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of
environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.
Received: 1 December 1997 / Accepted: 24 March 1998 相似文献
6.
7.
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
8.
Mazzu AL Lettieri JT Kelly E Vargas R Marbury T Liu MC Sundaresan P 《European journal of clinical pharmacology》2000,56(1):69-74
Objective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated
in this non-randomized, non-blinded, 7-day, multiple-dose study.
Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CLCR >90 ml/min/1.73 m2, n=9), or patients with either mild (CLCR 61 ml/min/1.73 m2 to ≤90 ml/min/1.73 m2, n=9), moderate (CLCR 30 ml/min/1.73 m2 to ≤60 ml/min/1.73 m2, n=8), or severe (CLCR <30 ml/min/1.73 m2, but not on dialysis, n=9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin,
including the area under the concentration–time curve (AUC)0–24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance
(ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events,
and laboratory safety indices.
Results: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 μg/h/l vs
19.2 μg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40–60%
higher (30.8 μg/h/l and 29.0 μg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 μg/l, respectively.
This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved
in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation.
This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient
groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction
to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function.
Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved
without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were
no clinically significant laboratory changes other than those consistent with renal disease.
Conclusion: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal
impairment is likely unnecessary.
Received: 2 August 1999 / Accepted in revised form: 12 January 2000 相似文献
9.
P. C. Ho S. C. Chalcroft P. F. Coville S. Wanwimolruk 《European journal of clinical pharmacology》1999,55(5):393-398
Objective: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice
on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated.
Methods: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three
occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control),
full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given
a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of
quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance
liquid chromatography method.
Results: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant
differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma
drug concentration (Cmax), the time to reach Cmax (tmax), the terminal elimination half-life (t1/2), the area under the concentration–time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine
metabolite were slightly changed when volunteers received grapefruit juice. The mean Cmax of the metabolite (0.25 ± 0.09 mg l−1, mean ± SD) while subjects received full-strength grapefruit juice was significantly less than during the control period
(0.31 ± 0.06 mg l−1, P < 0.05) and during the intake of half-strength grapefruit juice (0.31 ± 0.07 mg l−1, P < 0.05).
Conclusion: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice,
so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since
quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4,
the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit
juice is mainly in the gut.
Received: 2 November 1998 / Accepted in revised form: 18 February 1999 相似文献
10.
Juan H Terhaag B Cong Z Bi-Kui Z Rong-Hua Z Feng W Fen-Li S Juan S Jing T Wen-Xing P 《European journal of clinical pharmacology》2007,63(7):663-668
Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol.
Methods The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy
volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant
administration of curcumin (300 mg day−1 for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma
by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to
characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered
to be significant at p < 0.05 (two-sided test).
Results The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity () of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL−1, the highest observed concentration values (Cmax) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL−1, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h−1 (p < 0.05). There was no significant difference in sampling time for Cmax (tmax) and elimination half-life (t1/2) values between the two periods (p > 0.05). The interindividual variability in AUC0–60 and Cmax of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC0–60 and Cmax was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively.
Conclusion We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration,
or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues. 相似文献
11.
Objective: To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations
are affected by administration of grapefruit juice.
Methods: In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength grapefruit juice
or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml grapefruit juice or
water. Additionally, 200 ml grapefruit juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration.
Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS)
over a 47-h period.
Results: Grapefruit juice increased the total area under the plasma methylprednisolone concentration–time curve (AUC0–∞) by 75% (P < 0.001) and the elimination half-life (t
1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (Cmax) was increased by 27% (P < 0.01). Grapefruit juice delayed the time to the Cmax from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration,
between the water and grapefruit juice phases. However, grapefruit juice slightly decreased the morning plasma cortisol concentrations
before methylprednisolone administration (P < 0.05).
Conclusions: Grapefruit juice given in high amounts moderately increases the AUC0–∞ and t
1/2 of oral methylprednisolone. The increase in t
1/2 suggests that grapefruit juice can affect the systemic methylprednisolone metabolism. The clinical significance of the grapefruit
juice–methylprednisolone interaction is small, but in some sensitive subjects high doses of grapefruit juice might enhance
the effects of oral methylprednisolone.
Received: 17 February 2000 / Accepted in revised form: 9 May 2000 相似文献
12.
Akinyinka OO Sowunmi A Honeywell R Renwick AG 《European journal of clinical pharmacology》2000,56(2):153-158
Objectives: Caffeine-containing beverages are generally consumed by Nigerians suffering from malaria and kwashiorkor in the belief that
caffeine aids early recovery from these illnesses, which are common in the tropics. However, there are no studies on the influence
of these diseases on the absorption and pharmacokinetics of caffeine in Africans.
Materials and methods: A single oral dose of caffeine was given to five healthy children and to five and seven children suffering from malaria
and kwashiorkor, respectively. Caffeine and its dimethylxanthine metabolites were measured in plasma using high-performance
liquid chromatography.
Results: The maximum plasma concentration (Cmax) of caffeine and the time of Cmax were similar (P > 0.05) in the three groups. However, the elimination half-life of caffeine was significantly longer in children with malaria
(9.2 ± 3.5 h) (P < 0.01) and kwashiorkor (13.1 ± 7.9 h) (P < 0.05) than in the healthy controls (3.7 ± 1.8 h). The total plasma oral clearance of caffeine of 4.4 ± 1.9 ml/min/kg in
healthy children was significantly higher (P < 0.01) than in those with kwashiorkor (2.0 ± 0.9 ml/min/kg) and malaria (1.6 ± 1.0 ml/min/kg) (P < 0.05). Paraxanthine was the principal metabolite in all the three groups with Cmax significantly higher in healthy children (1.3 ± 0.3 μg/ml) than in children with malaria (0.8 ± 0.4 μg/ml) (P < 0.05) and kwashiorkor (0.3 ± 0.1 μg/ml) (P < 0.0001). CYP1A2 activity, measured by the plasma ratios of paraxanthine: caffeine, was significantly lower in kwashiorkor
and malaria.
Conclusions: This study showed that the plasma kinetics of caffeine are significantly altered in malaria and kwashiorkor, and CYP1A2
activity was lower in these two disease groups.
Received: 12 April 1999 / Accepted in revised form: 30 November 1999 相似文献
13.
Baris N Kalkan S Güneri S Bozdemir V Guven H 《European journal of clinical pharmacology》2006,62(7):535-538
Objective The activity of the human cytochrome P450 and P-glycoprotein (P-gp) changes according to gender. The present study evaluated the effect of gender on the influence of carvedilol on serum digoxin levels in patients with heart failure.Methods Twenty-four patients (12 female and 12 male) with New York Heart Association class II-III heart failure were included in the study. Patients were taking oral digoxin (0.0625–0.25 mg, once a day) and were administered oral carvedilol (6.25 mg, two times daily) for 7 days.Results In the male group, carvedilol led to statistically significant increases in the area under the concentration time curve to 16 h (AUC0–16h) and the peak concentration (Cmax) for digoxin, with no change in time to peak (tmax)(AUC0–16h= 24.1±9.2 ng.h/ml vs. 15.4±5.8 ng.h/ml, p<0.001, Cmax=2.2±1.0 ng/ml vs. 1.6±0.6 ng/ml, p<0.01, tmax=2.4±2.2 h vs. 2.1±1.0 h, p>0.05). In the female group, carvedilol administration did not cause statistically significant change in the AUC0–16h, Cmax, or tmax for digoxin (p>0.05). In the male group, carvedilol resulted in a significant increase in the AUC0–16h and Cmax for digoxin compared with the female group (AUC0–16h=24.1± 9.2ng.h/ml vs. 17.0±6.8 ng.h/ml, Cmax=2.2±1.0 ng/ml vs. 1.5±0.6 ng/ml, p<0.05, respectively).Conclusion Men seem to have a higher activity relative to women for the drug efflux transporter P-gp. Our results suggest that carvedilol will cause drug interaction with digoxin following the inhibition of P-gp-mediated transcellular transport of digoxin in males.The first two authors contributed equally. 相似文献
14.
J. Rouru A. Gordin R. Huupponen S. Huhtala E. Savontaus K. Korpela K. Reinikainen M. Scheinin 《European journal of clinical pharmacology》1999,55(6):461-467
Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the
treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of
levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to
evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during
the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was
studied after a single dose of levodopa/carbidopa during the same conditions.
Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals
from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to
0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours.
Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice
daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared
with each other.
Results: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant.
No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after
the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT
inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa.
Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.
Received: 28 December 1998 / Accepted in revised form: 29 March 1999 相似文献
15.
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
16.
O. A. Aswania S. A. Corlett H. Chrystyn 《European journal of clinical pharmacology》1998,54(6):475-478
Objective: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethylglutaryl
coenzyme A (HMG-CoA) reductase inhibitor.
Methods: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every
morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by
a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses
were compared.
Results: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin
with cimetidine. Mean values for Cmax (the maximum concentration) were 5.11 ng · eq · ml−1 and 4.54 ng eq · ml−1, for tmax (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0–24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq · h · ml−1 and 58.5 ng eq · h · ml−1, and for t1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with
cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change
from baseline for total cholesterol were −29.5% and −29.9%, for low-density lipoprotein (LDL) cholesterol −41.0% and −42.6%,
for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides −33.8% and −25.8%, respectively.
Conclusions: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced
by coadministration of cimetidine.
Received: 17 February 1997 / Accepted in revised form: 3 November 1997 相似文献
17.
T. Callréus J. Lundahl P. Höglund P. Bengtsson 《European journal of clinical pharmacology》1999,55(4):305-309
Objective: The antidiuretic effect of desmopressin is widely utilized in the treatment of neurogenic diabetes insipidus and nocturnal
enuresis in children. The objective of the present study was to assess how changes in gastrointestinal motility, induced by
erythromycin and loperamide, influence the pharmacokinetics of orally administered desmopressin.
Methods: This study was conducted using an open randomized, three-period, three-treatment design in 18 healthy subjects. On each
study day a single oral dose of 400 μg desmopressin was administered in the morning. The desmopressin dose was either given
alone (reference) or after pretreatment with either loperamide tablets (4 mg at −24, −12 h and −1 h) or erythromycin capsules
(250 mg q.i.d, with the first dose in the morning 3 days before the study day and the last dose at −1 h). On each study day,
blood was sampled up to 8 h after dosing for assessment of desmopressin concentration.
Results: Compared with administration of 400 μg of desmopressin alone, pretreatment with loperamide produced significantly (P < 0.05) altered pharmacokinetics of desmopressin as the endpoints; area under the curve up to infinity (AUC), area up to
the last determinable plasma concentration (AUCt) and maximum plasma concentration (Cmax) increased 3.1-fold (95% CI 2.3–4.2), 3.2 (2.3–4.4) and 2.3 (1.6–3.2), respectively. Although the estimates were lower, pretreatment
with erythromycin did not result in any significant changes in these endpoints. There were no significant changes observed
between the three treatments regarding the terminal elimination half-life (t1/2). However, significant (P < 0.05) changes in the time to reach Cmax (tmax) values (median and range) were observed as, compared with administration of desmopressin alone (1.3 h and 0.5–4.0), it was
longer after pretreatment with loperamide (2.0 h and 0.5–3.0) and shorter following pretreatment with erythromycin (0.9 h
and 0.5–1.3).
Conclusion: Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal
absorption of desmopressin. Except for a shortening of tmax, pretreatment with erythromycin did not significantly influence absorption of the drug.
Received: 1 September 1998 / Accepted in revised form: 29 December 1998 相似文献
18.
Yasui-Furukori N Saito M Inoue Y Niioka T Sato Y Tsuchimine S Kaneko S 《European journal of clinical pharmacology》2007,63(1):51-56
Objective Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between
paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of
CYP2D6, on pharmacokinetics of paroxetine.
Methods Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted.
Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine
were monitored up to 48 h after dosing.
Results Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (Cmax) of paroxetine, by 1.9-fold (6.4 ± 2.4 versus 12.1 ± 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0–48)] of paroxetine by 2.5-fold
(127 ± 67 vs 318 ± 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 ± 2.4 vs 22.7 ± 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than Cmax or AUC.
Conclusion The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting
that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required
to confirm this phenomenon at steady state. 相似文献
19.
Simon NM Connor KM LeBeau RT Hoge EA Worthington JJ Zhang W Davidson JR Pollack MH 《Psychopharmacology》2008,197(4):675-681
Rationale More data are needed to guide “next step” strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic
despite initial pharmacotherapy.
Objective This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD
remaining symptomatic with initial paroxetine CR pharmacotherapy.
Materials and methods Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label
paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] ≥ 7)
at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day.
Results For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean ± SD = 22.4 ± 4.2 to endpoint mean ± SD = 11.2 ± 6.9;
paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of
continued paroxetine CR (HAM-A reduction mean ± SD = 2.6 ± 5.8 points quetiapine, 0.3 ± 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2.
Conclusions Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition
of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant
pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed. 相似文献
20.
The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated.
Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole
12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean Tmax value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t1/2value (12.5 ± 3.2 versus 14.3 ± 3.4 h, P < 0.05) of alprazolam. The mean Cmax (18.5 ± 4.9 versus 18.5 ± 4.8 ng/ml) and AUC (266 ± 68 versus 275 ± 57 ng⋅h/ml) values of alprazolam did not change statistically
significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole
and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an
inhibitor of the metabolism of alprazolam.
Received: 5 March 1997/Final version: 28 July 1997 相似文献