The effect of ion pair formation on the pharmacokinetics of drugs. 2. The effect of hexylsalicylic acid on the pharmacokinetics of quinine

The influence of the hexylsalicylic acid (2) on the pharmacokinetic of the quinine (1), was studied using rabbits. It could be observed that after i.v. application the mean resistance time (MRT) of 1 was increased by means of ion-pair-formation with 2. But the AUC of 1 was not influenced. After rectal application of the combination 1/2 an acceleration of the 1 absorption could be pointed out. The kinetic parameters of 2 were not increased significantly if 1 was applicated simultaneously.     

The effect of renal disease on the pharmacokinetics of diethylcarbamazine in man.

1 The pharmacokinetics of diethylcarbamazine (DEC) were studied in twelve patients with chronic renal function impairment. 2 Selected pharmacokinetic parameters, plasma half-life (T1/2), area under the plasma concentration-time curve (AUC), elimination rate constant (Kel) and 24 h urinary excretion were regressed versus parameters indicative of renal function. 3 Significant negative correlations were observed between creatinine clearance and both plasma T1/2 and log10 T1/2. 4 Significant positive correlations were obtained between (a) creatinine clearance and elimination rate constant of DEC and (b) reciprocal serum creatinine and l/T1/2. Creatinine clearance was significantly and positively correlated with 24 h urinary excretion of DEC. 5 No significant correlations were observed between age, sex or weight and renal function but DEC excretion did appear to decrease with increasing urinary pH. 6 Plasma half-life, and area under the plasma concentration-time curve were increased and 24 h urinary excretion of DEC was significantly reduced in patients with chronic renal function impairment, compared with normal volunteer subjects receiving an identical dosage of DEC at acidic urinary pH.     

The effect of respiratory manoeuvres and pharmacological agents on the pharmacokinetics of nedocromil sodium after inhalation.

1. Eight healthy subjects inhaled nedocromil sodium from a metered-dose inhaler using a standardised inspiratory technique. Blood samples were taken for up to 270 min after inhalation for radioimmunoassay of plasma nedocromil sodium concentrations. 2. To investigate the possibility that respiratory manoeuvres can alter the absorption of the drug from the lungs, on the first (control) study day at 70 min after dosing, subjects performed nine forced expiratory manoeuvres over a 3 min period. At 110 min after dosing, subjects took a slow, full inspiration with a 30 s breath-hold, and at 150 min after dosing the subjects performed one single forced expiration. 3. On the second study day, subjects inhaled methoxamine, 0.15 mg kg-1 of a 20 mg ml-1 solution at 60 min after dosing, and the study continued as above. On the third day, subjects repeated the sequence of respiratory manoeuvres, after having taken phenoxymethyl penicillin and probenecid by mouth for 48 h. 4. Both multiple forced expirations and the deep inspiration with breath-hold produced significant increases in the absorption of nedocromil sodium. Inhaled methoxamine did not alter airway calibre or the response to the respiratory manoeuvres. Probenecid, but not penicillin, was detected in the subjects' plasma, and had the effect of increasing the rise in plasma nedocromil sodium concentrations after the multiple forced expirations when compared with the control day. 5. These data suggest that disruption of epithelial tight junctions induced by the respiratory manoeuvres leads to enhanced paracellular transport of nedocromil sodium into the draining circulation of the airways and alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of anticholinergic bronchodilator therapy on cough during upper respiratory tract infections.

1. Oxitropium bromide (Oxivent), an anticholinergic bronchodilator, inhibits coughing induced by hypotonic aerosols in both asthmatic and non-asthmatic individuals. We have now extended this work to investigate whether this antitussive activity is reproducible in cough associated with viral infection. 2. The effect of oxitropium bromide (200 micrograms three times daily) on cough and pulmonary function has been studied in 56 non-asthmatic volunteers with upper respiratory tract infections (URTI) in a double-blind, randomised, parallel group, placebo controlled study over 10 days. 3. Lung function, symptom questionnaire and cough response to ultrasonically nebulised distilled water (UNDW) inhalation were initially recorded within 72 h of development of cough and again after the 10 day treatment period. By use of a diary card at home, frequency and severity of cough, nocturnal symptoms and general malaise were assessed daily throughout the treatment period using 5 cm visual analogue scales (VAS). Peak expiratory flow rate (PEFR) was recorded thrice daily before treatment over this 10 day period. 4. VAS scores of symptoms and UNDW-induced cough frequency all decreased over the 10 days of observation whether oxitropium bromide or placebo was administered. The mean PEFR showed a statistically significant fall in morning values during the early stages of infection which lessened with recovery but no effect of treatment with oxitropium bromide was observed (P > 0.05). 5. Oxitropium bromide, which inhibits the cough response to UNDW, does not offer an effective therapy for cough associated with an upper respiratory tract viral infection.     

The effect of ion pair formation on the pharmacokinetic properties of drugs. 1. The effect of alpha-methylpalmitic acid on the pharmacokinetics of quinine in rabbits

The transport of quinine through artificial lipid membranes is significantly increased by use of alpha-methylpalmitinic acid (alpha-MPS). Using rabbits it could be shown that the alpha-MPS causes a significant increase of the mean resistance time (MRT) of quinine. Besides the alpha-MPS causes an increases Cmax and a shorter tmax of the quinine blood levels.     

The effect of thyroid hormones on the action of some centrally acting drugs

1. The effect of administration of thyroxine or thyroidectomy on the pharmacological action of (+)-amphetamine, caffeine, hexobarbitone and morphine was determined in rats or mice.2. Locomotor activity induced by (+)-amphetamine or caffeine was increased by hyperthyroidism and decreased by hypothyroidism.3. The LD50s of (+)-amphetamine and caffeine in hyperthyroid rats were 1/30 and 2/5 that of control rats. With each drug, the LD50 regression lines in hyperthyroid and control rats were not parallel, suggesting that hyperthyroidism modifies the mechanism of the toxic effects. Hypothyroidism reduced toxicity to (+)-amphetamine.4. Hexobarbitone sleeping time was prolonged in hyperthyroid male rats, but was shortened in hyperthyroid female rats. In control rats, sleeping time was approximately four times as long in females as it was in males. Ethinyloestradiol treatment and castration also prolonged sleeping time in male rats. No further prolongation was produced by combined administration of thyroxine and ethinyloestradiol, but thyroxine further prolonged the sleeping time of castrated rats indicating that its mode of action in producing these changes is not mediated via sex hormones.5. In contrast to rats, a sex difference in the duration of action of hexobarbitone was not found in mice. Thyroxine prolonged sleeping time equally in each sex.6. Analgesia induced by morphine in mice was unaffected by hyperthyroidism. No increase in sedative or ;Straub tail' activity could be detected, but toxicity was increased when higher doses of morphine were used.7. The mechanism by which thyroid hormones produce these changes in sensitivity to centrally acting drugs is discussed. It is suggested that the effects of thyroxine vary according to whether the mode of action of the drug or its metabolism is modified.     

The effect of meloxicam on the pharmacokinetics of beta-acetyl-digoxin.

The influence of multiple-dose administration of meloxicam on the pharmacokinetics of oral beta-acetyl-digoxin was studied in 12 healthy male volunteers in a randomized double-blind two-way crossover study. The primary endpoint, Cminss, was within the accepted range for bioequivalence, as were Cmaxss and AUCss. The 90% confidence interval and the point estimator of 98.7 for Cminss were within the equivalence range of 0.8-1.25. MRT and tmax were also unchanged, while the elimination rate constant was decreased slightly by 12%, which is of no therapeutic relevance. It is concluded that co-treatment with meloxicam has no effect on the pharmacokinetics of oral digoxin.     

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.     

The effect of age on the pharmacokinetics of pentisomide.

The effects of age on the pharmacokinetics of pentisomide (CM7857), an orally effective antiarrhythmic agent, were studied in two groups of volunteers. Sixteen young volunteers (mean age 26.4 years) and 10 elderly volunteers (mean age 67.8 years) received a single 200 mg oral dose of pentisomide. Mean AUC was larger and terminal elimination half-life longer in the elderly subjects, due to a decrease in total plasma clearance of pentisomide in the elderly. This decrease was due to a reduction in renal clearance of the drug which was paralleled by a significantly lower creatinine clearance in the elderly subjects. Dosage reduction, or a reduced frequency of dosing of pentisomide would be necessary in the elderly or those with impaired renal function.     

The effect of azithromycin on the pharmacokinetics of indinavir.

This study was performed to examine the effect of the coadministration of azithromycin on the pharmacokinetics of the protease inhibitor indinavir (Crixivan). In an open-label, parallel-design study, 32 healthy male and female volunteers were given indinavir (800 mg tid) for 5 days. One hour prior to the first dose of indinavir on day 5, 18 subjects received 1200 mg azithromycin (Zithromax), and 14 subjects received matching placebo. Serial samples of plasma were obtained for 8 hours following the morning dose of indinavir on days 4 and 5 and assayed for indinavir by HPLC/UV. Twenty-seven subjects completed the study. Following coadministration of azithromycin with indinavir, there was no significant change between day 5 and day 4 in AUC (20.7 mg.hr/ml and 23.1 mg.hr/ml; 90% CI on the ratio 81%-100%) or Cmax (9.88 mg/ml and 10.3 mg/ml; 90% CI 86%-108%). The day 5 to day 4 difference in indinavir concentrations following coadministration with azithromycin was not significantly different from the day 5 to day 4 difference with placebo (AUC p = 0.68; Cmax p = 0.074). Therefore, azithromycin does not significantly alter the kinetics of indinavir.     

The effect of allopurinol on the steady-state pharmacokinetics of indomethacin.

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).     

肠内或肠外营养支持对机械通气患者营养状况、呼吸功能及费用等的影响

目的观察肠内营养与肠外营养支持对机械通气患者营养状况、呼吸功能及费用等的影响。方法将60例机械通气患者随机分为肠内营养支持组(30例)和肠外营养支持组(30例),观察动脉血气、撤机的时间,同时在营养支持前1天及营养支持第8天观察血清白蛋白和血红蛋白、前白蛋白的变化以及ICU住院天数、费用。结果肠内营养支持组撤机时间明显早于肠外营养支持组(P<0.05),2周内的撤机成功率明显高于肠外营养支持组(P<0.01);患者的血清白蛋白、前白蛋白在营养支持后较前升高明显(P<0.05)。结论机械通气患者给予肠内营养支持符合生理状态,较肠外营养有更好的营养效果,能显著缩短机械通气时间,增加撤机成功率。同时可缩短患者在ICU的住院天数、减轻患者的住院费用。     

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.     

The effect of verapamil on the pharmacokinetics of paclitaxel in rats.

The purpose of this study was to investigate the effect of verapamil on the pharmacokinetic parameters of paclitaxel (50 mg/kg) when paclitaxel is co-administered with verapamil (1, 5, and 15 mg/kg) or pretreated with verapamil (5 mg/kg) for 0.5 h, 3 days, and 6 days orally in rats. When paclitaxel was either co-administered or pretreated with verapamil, the peak plasma concentrations (C(max)) of paclitaxel with verapamil were significantly higher (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) than that of the control. The areas under the plasma concentration-time curve (AUC) of paclitaxel with verapamil were significantly (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control. The AUCs of paclitaxel were increased with verapamil in the dose dependent manner. The half-life (t(1/2)) of paclitaxel with verapamil was significantly prolonged compared with that of the control, except for 1 mg/kg co-administration. The absolute bioavailability of paclitaxel with verapamil (3.9-5.4%) was significantly (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control (2.2%). The relative bioavailability of paclitaxel pretreated with verapamil was higher than that of co-administration in rats. Based on these results, it might be considered that the pharmacokinetic parameters of paclitaxel was significantly affected by verapamil which is an inhibitor of the metabolizing enzyme (CYP3A4) in the intestinal mucosa and liver, and the p-glycoprotein efflux pump in the intestinal mucosa. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with verapamil.     

The effect of haemodialysis on the pharmacokinetics of tenoxicam in patients with end-stage renal disease

Summary We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis.After a single dose, tenoxicam had a half-life (t_1/2) of 33 h, an apparent clearance (CL·f^–1) of 4.3 ml·min^–1, and an apparent volume of distribution (V_z·f^–1) of 11.8 l. The maximum tenoxicam concentration (C_max) was 4.3 mg·l^–1 at a median t_max of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples.Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate.Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.