Single and multiple dose pharmacokinetics of felbamate in the elderly

Aims The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers.
Methods The single and multiple dose pharmacokinetics of felbamate were examined in an open-label two-dose level parallel group study in 24 elderly (66 to 78-year-old) and 11 young (18 to 45-year-old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120  h after administration of single 600  mg or 1200  mg doses, and after multiple doses of 600  mg or 1200  mg administered every 12  h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events.
Results Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1  ml  min⁻¹; 90% CI −11.4 to −0.9; P =0.02) and a trend towards a greater half-life (18.6 vs 21.0  h; 90% CI −0.6 to 5.4; P =0.11). Mean AUC and C _max values were also higher in elderly subjects. No gender differences were noted for weight-adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age-related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate's pharmacodynamic effects.
Conclusions These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non-elderly subjects.     

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

1 To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500  mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine.
2 Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3  h, means±s.d., P< 0.001) and higher apparent oral clearance (CL/ F) values (15.3±3.8 vs 9.2±1.9  ml  kg⁻¹  h⁻¹, P< 0.001). The apparent volume of distribution ( V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1  l  kg⁻¹, P< 0.05).
3 These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity.
4 The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.     

Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

Thirty-three healthy male and female volunteers aged 21 to 87 years received a single 0.5 mg oral dose of triazolam. Plasma triazolam concentrations were measured in multiple samples drawn during 24 h after the dose. Mean triazolam elimination half-life was not significantly different between young and elderly men (3.0 vs 4.6 h), nor between young and elderly women (2.7 vs 3.2 h). However, apparent oral clearance of triazolam was significantly reduced in elderly as compared to young groups of both sexes, leading to higher peak plasma concentrations and increased total area under the curve. Values of half-life and clearance of antipyrine, a low-extraction hepatically oxidized compound, were poorly correlated with those of triazolam (r = 0.34 and 0.44, respectively), suggesting different mechanisms controlling age-related changes in clearance of these two hepatically oxidized drugs.     

Concentrations and effects of buspirone are considerably reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated.
Methods In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600  mg rifampicin or matched placebo once daily for 5 days. On day 6, 30  mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10  h.
Results The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3–14.5%) of that after placebo (1.64±0.35  ng  ml⁻¹ h vs 22.0±15.1  ng  ml⁻¹ h (mean±s.d.); P <0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6±3.7  ng  ml⁻¹ to 0.84±0.23  ng  ml⁻¹ ( P <0.01) and the half-life from 2.8±0.7  h to 1.3±0.5  h ( P <0.01). A significant ( P <0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment.
Conclusions The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.     

The bioavailability and disposition of 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil (882C87), a potent, new anti-varicella zoster virus agent.

1. The bioavailability and disposition of 882C87, an anti-varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. 2. The mean bioavailability of a 200 mg tablet was 21.1% in the young (range 13.3-33.0%, n = 10) and 24.6% in the elderly (range 14.4-38.4%, n = 8), which is sufficient to achieve plasma concentrations well above the IC50 for anti-VZV activity. 3. Plasma concentrations of 882C87 after 50 mg i.v. were higher in the elderly than in the young, associated with a significantly longer half-life (13.7 vs 11.8 h) and decreased renal clearance (0.11 vs 0.14 ml min-1 kg-1) and total clearance (0.15 vs 0.17 ml min-1 kg-1). 4. After intravenous administration, the main route of elimination of 882C87 was renal with 81.6% recovered unchanged in urine in the young and 71.2% in the elderly. The pyrimidine base, 5-propynyluracil (5-PU) was unquantifiable in plasma and only present in trace amounts in urine. 5. After oral administration to four healthy volunteers, only 17% of a dose of [14C]-882C87 was recovered unchanged in urine and 58% as 5-PU, with total recovery in urine accounting for 86% of the dose. There was a lag of 4-12 h before the appearance of 5-PU in plasma, peak concentrations were one-third to a half those of 882C87. The data suggest that 5-PU is formed from unabsorbed 882C87 in the gut lumen and then absorbed and excreted in urine. 6. 882C87 is a potential once daily treatment for shingles.     

Enhanced effect of triazolam with diltiazem

Aims Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans.
Methods We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25  mg dose of triazolam, a 0.25  mg dose of triazolam after a 3-day treatment of diltiazem (180  mg day⁻¹), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24  h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8  h.
Results Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0±2.4 to 18.2±3.1  ng  ml⁻¹  h; P <0.001; mean±s.d.). Peak triazolam concentration was increased (2.1±0.7 to 3.6±1.0  ng  ml⁻¹, P <0.05) and the elimination half-life prolonged (4.1±2.1 to 7.6±1.9  h; P <0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group.
Conclusions Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.     

Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man

Aims Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.
Methods After an overnight fast, eight healthy volunteers were treated with either 400  ml grapefruit juice or water before intravenous (12  mg) or oral saquinavir (600  mg) was administered. Serial blood samples were obtained over the following 24  h and standardized meals were served 5 and 10  h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.
Results The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76±96 (water, mean (s.d.) to 114±70 (μg  l⁻¹  h (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.
Conclusions The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.     

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250  mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/ F was 6.5±1.8 l  h⁻¹, V _ss/ F 815±165  l, and k 0.0081± 0.0023  h⁻¹. The kinetics of (−)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h⁻¹, 95% CI for the difference 0.86–1.60 l h⁻¹ ) and a longer half-life (345 vs 185  h, 95% CI for the difference 47–291  h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (−)SR-MQ was significantly correlated within subjects ( r =0.69, P <0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (−)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.     

Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects

Aims The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.
Methods The effect of oral ketoconazole (200  mg day⁻¹ for 14 days) on the kinetics of a single oral dose of imipramine (100  mg) and desipramine (100  mg) was evaluated in two groups of six healthy male subjects.
Results Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16±0.21 to 0.96±0.20  l h⁻¹  kg⁻¹, mean±s.d.; ' of2\P<0.02), a prolongation in imipramine half-life (from 16.7±3.3 to 19.2±5.4  h, ' of2\P<0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507±1707 to 3180±1505  nmol  l⁻¹  h, P <0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.
Conclusions These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N -demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.     

Pharmacokinetics of digoxin-specific Fab: effects of decreased renal function and age

Aims To study the influence of age and renal function on digoxin-specific Fab (DS-Fab) pharmacokinetics.
Methods Sixteen patients (35–91 years) with creatinine clearance ranging from 10.6 to 122.1  ml  min⁻¹ who had been admitted to hospital with severe digoxin or digitoxin self-poisoning were treated with DS-Fab (80 to 800  mg). Plasma DS-Fab concentrations were determined by radioimmunoassay.
Results The mean (±s.d.) distribution and elimination half-lives, apparent volume of distribution and total body clearance were 1.1±0.4  h, 20.2±7.3  h, 13.1±5.8  l, and 17.6±10.8  ml  min⁻¹ , respectively. Interindividual variability of DS-Fab total body clearance was linked linearly with the decrease in creatinine clearance or with the increase in age and DS-Fab distribution volume was not dependent on creatinine clearance or age.
Conclusions The data suggest that DS-Fab should be given to elderly and renal-impaired patients at doses similar to those given to younger or normal renal function patients.     

Concentrations and effects of zopiclone are greatly reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied.
Methods In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600  mg rifampicin or placebo once daily for 5 days. On the 6th day, 10  mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10  h.
Results The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5–22.5%) of that after placebo (86.1±34.5  ng  ml⁻¹ h vs 473±114  ng  ml⁻¹  h (mean±s.d.); P <0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9±27.2  ng  ml⁻¹ to 22.5±6.0  ng  ml⁻¹ ( P <0.001) and the half-life from 3.8±0.6  h to 2.3±0.9  h ( P <0.005). A significant ( P <0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment.
Conclusions The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

Effect of age and gender on the pharmacokinetics of eprosartan

Aims To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods Twenty-four subjects (eight subjects/group) received a single 200  mg eprosartan oral dose followed by serial blood sampling over 24  h.
Results Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and C _max values were ≈2-fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; C _max 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and C _max values were, on average, ≈2-fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound C _max 95% CI: 1.02, 4.12]. t _max was delayed in the elderly men compared with young men, with a median difference of 2.5  h (95% CI: 1.00, 3.01  h).
Conclusions No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈  two fold higher AUC and C _max values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200  mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.     

Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen

Aims The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13  M, 12  F) suffering from recurrent high-grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120  mg/m² twice daily).
Methods Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7  h post dose. Tamoxifen and metabolites were analysed by h.p.l.c.
Results Steady-state plasma concentrations (mean  μm±s.d.) were determined for tamoxifen (2.94±3.44), N -desmethyltamoxifen (4.37±2.13), N -desdimethyltamoxifen (1.49±0.54), 4-hydroxytamoxifen (0.13±0.05) and tamoxifen primary alcohol (1.07±0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone-treated patients than untreated patients: 3.94±4.35  μm (95% C.I.: 1.43–6.46) vs 1.67±0.84  μm (95% C.I.: 1.11–2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85±0.87  μm (95% C.I.: 1.37–2.34) vs 4.58±5.05  μm (95% C.I.: 0.97–8.19), with vs without. The differences approached but did not reach statistical significance ( P =0.065 and 0.078 respectively).
Conclusions There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.     

The effects of age and gender on the pharmacokinetics of irbesartan

Aims Single dose pharmacokinetics and safety of irbesartan, an angiotensin II receptor antagonist, were evaluated in healthy young and elderly male and female subjects.
Methods Irbesartan was administered as two 25  mg capsules after a 10  h fast to 12 young men, 12 young women, 12 elderly men and 12 elderly women. Serial blood and urine sample were collected up to 96  h after the dose. Plasma and urine samples were analysed for irbesartan by h.p.l.c./fluorescence methods.
Results No statistically significant gender effects were observed in peak plasma concentration ( C _max ), area under the curve (AUC), and terminal elimination half-life ( t _1/2 ) of irbesartan. The geometric mean AUC and C _max increased by about 43% and 49%, respectively, in the elderly subjects. Also the time to peak was significantly shorter in the elderly subjects compared with that observed in the young subjects. Renal clearance of irbesartan was significantly reduced in the elderly females but this reduction is not likely to be of any clinical relevance since less than 3% of the administered dose of irbesartan is excreted unchanged in the urine.
Conclusions Although there was an effect of age on the pharmacokinetics of irbesartan, based on the safety and efficacy profile, no adjustment in irbesartan dosage is necessary with respect to age or gender.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control

1 The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50  u  kg⁻¹). Twenty subjects then received repeated subcutaneous administrations of high dose (200  u  kg⁻¹) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine.
2 Serum Epo concentration-time profiles were best described by a one-compartment open model with zero-order input. The mean elimination half-life (±s.d.) was 42.0±34.2  h. Clearance, uncorrected for bioavailability, was 0.05±0.01  l  h⁻¹  kg^{& minus;1}. Erythropoietin concentrations returned to normal values in serum and urine, 7 and 4 days after the last administration, respectively.
3 The recombinant hormone was well tolerated. Significant changes in reticulocytes and red blood cells, haemoglobin concentrations and haematocrit were observed after administration of rHuEpo. In the control group, these parameters remained unchanged.
4 The change in reticulocytes was used as an index of the therapeutic effect of rHuEpo. The concentration-effect relationship was best described by an exponential model.
5 These data show the limitations of the measurement of Epo concentrations in blood and urine samples, collected in athletes during competition, for antidoping control. Epo doping can be detected only during or within 4 to 7 days of ending, a course of rHuEpo.     

Pharmacokinetics and metabolism of diltiazem in rats: comparing single vs repeated subcutaneous injections in vivo

The objective of the study was to determine the effect of repeated administration on the pharmacokinetics and metabolism of diltiazem (DTZ) using an in vivo rat model. Male SD rats (n = 6-10 per group) weighing 350-450 g were used. Each rat received either a single 20 mg/kg dose of DTZ by subcutaneous (s.c.) injection or 5 mg/kg s.c. twice daily for five doses. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8 h. Compared with the single dose, repeated administration resulted in higher dose normalized plasma concentrations of DTZ (AUC 26.4+/-14.2 vs 13.9+/-11.5 microg-h/ml), longer apparent half-life (t(1/2) = 12.5+/-14.6 vs 3.7+/-1.4 h) and lower systemic clearance (CL = 1.1+/-1.0 vs 2.9+/-2.7 l/h/kg). Higher dose normalized plasma concentrations, longer t(max), but shorter apparent t(1/2) of the major metabolites were observed following the repeated administration. The results also suggest that possible binding of DTZ may occur at the site of injection when administered subcutaneously in the higher dose.     

The effect of age and cardiac failure on xamoterol pharmacokinetics.

1. Xamoterol is a cardioselective beta-adrenoceptor partial agonist which may have a role in the management of cardiac failure. Excretion is mainly by the renal route. 2. The kinetics of a single 200 mg oral dose of xamoterol were studied in eight elderly (age 67-82 years) volunteers, eight young (age 21-43 years) volunteers; eight patients with mild to moderate cardiac failure and eight age and sex matched controls. 3. Elderly volunteers had a significantly longer time to reach peak concentration (mean +/- s.e. mean 2.1 +/- 0.2 vs 1.1 +/- 0.1 h) and elimination half-life time (27.0 +/- 2.8 vs 16.4 +/- 3.1 h) compared with young volunteers. The renal clearance of xamoterol was lower in the elderly (115 +/- 12 vs 185 +/- 19 ml min-1) and showed a significant correlation with creatinine clearance (r = 0.85, P less than 0.001). 4. There was no significant difference in any of the pharmacokinetic parameters measured in patients with cardiac failure compared with healthy age and sex matched controls. 5. These results suggest that the maintenance dose of xamoterol could be reduced in elderly patients in relation to impairment of renal function.     

盐酸纳美芬在颈髓损伤治疗中的疗效评价

目的 探讨盐酸纳美芬在治疗颈髓损伤中的疗效.方法 将64例颈髓损伤患者完全随机平均分为治疗组与对照组,其中治疗组患者给予纳美芬0.3mg,静脉滴注,2次/d,连用14d;对照组给予盐酸纳洛酮2mg,静脉滴注,3次/d,连用14d.结果 治疗组于治疗后3、6、9个月JOA评分增加值分别较对照组治疗后3、6、9个月后的JOA评分增加值高,2组比较差异有统计学意义[治疗后3个月:(6.1±0.5)分比(3.4±0.6)分;治疗后6个月:(7.3±0.8)分比(4.1±0.6)分;治疗后9个月:(9.0±0.6)分比(4.6±0.7)分;P＜0.05].结论 和纳洛酮相比,作为新一代阿片受体拮抗剂的纳美芬具有更强的阿片受体亲和性、更长的半衰期、更好的生物利用度和更高的安全性,可更好地用于治疗脊髓损伤患者.     

Pharmacokinetic profile of controlled release ketoprofen in elderly patients.

The pharmacokinetics of ketoprofen following the administration of the first and final dose of a controlled release formulation (200 mg ketoprofen) once daily for 10 days to nine elderly patients have been studied. Plasma ketoprofen concentrations were measured by h.p.l.c. The data were compared to previously reported studies in young male volunteers. Mean +/- s.d. peak plasma concentrations (5.6 +/- 1.75 micrograms ml-1 and 6.3 +/- 2.7 micrograms ml-1 on day 1 and day 10, respectively) were higher than those reported in young volunteers given similar treatment, but similar to those reported in young volunteers following 50 mg four times daily of conventionally formulated ketoprofen, and markedly lower than reported following a single 100 mg dose of ketoprofen. The half-life for drug release (mean +/- s.d.) from the controlled release formulation (8.5 +/- 7.4 h) and accumulation upon repeated dosing (28%) were essentially the same as reported for young volunteers. The area under the plasma concentration-time curve was about 65% greater than reported in young volunteers following administration of controlled release ketoprofen. This increase in exposure to ketoprofen is probably partly due to the lower volume of distribution in the elderly and partly due to a reduced renal excretion of the glucuronide metabolite of ketoprofen. It was concluded that controlled release ketoprofen may be administered in standard doses (200 mg once daily) to elderly patients whose elimination processes are not severely impaired (i.e. severe renal failure or hepatic disease).(ABSTRACT TRUNCATED AT 250 WORDS)