Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5·0 mg h^?1 for 150 min and after single equal oral doses of 12·5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml^?1 and 514 ng ml^?1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9–10 min. After oral doses, peak plasma levels of 26·6 ng ml^?1 and 12·7 ng ml^?1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0·32 1 min^?1 and 0·161 min^?1 were unexpectedly low for a drug of reported high liver extraction ratio.     

Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers

1. The objective of this study was to investigate the effects of continuous St. John’s wort administration on single-dose pharmacokinetics of bupropion, a substrate of cytochrome P450 (CYP) 2B6, in healthy Chinese volunteers.

2. Eighteen unrelated healthy male subjects participated in this study. The single-dose pharmacokinetics of bupropion and hydroxybupropion were determined before (control) and after a long-term period of St. John’s wort intake (325?mg, three times a day for 14 days). Plasma concentrations of bupropion and hydroxybupropion were determined before and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60 and 72?h after dosing.

3. St. John’s wort treatment decreased the area under the concentration versus time curve extrapolated to infinity of bupropion in healthy volunteers from 1.4 μg·h ml^?1 (95% confidence interval [CI]?=?1.2–1.6 μg·h ml^?1) after bupropion alone to 1.2 μg·h ml^?1 (95% CI?=?1.1–1.3 μg·h ml^?1) during St. John’s wort treatment. St. John’s wort treatment increased the oral clearance of bupropion from 108.3 l h^?1 (95% CI?=?95.4–123.0 l h^?1) to 130.0 l h^?1 (95% CI?=?118.4–142.7 l h^?1). No change in the time to peak concentration (t_max) and the blood elimination half-life (t_1/2) of bupropion was observed between the control and St. John’s wort-treated phases. However, the half-life of hydroxybupropion between two phases had a significant difference by a Student’s t test after logarithmic transformation. St. John’s wort treatment decreased the half-life of hydroxybupropion from 26.7?h (95% CI?=?23.8–29.9?h) to 24.4?h (95% CI?=?21.9–27.3?h).

4. St. John’s wort decreased, to a statistically significant extent, the plasma concentrations of bupropion, probably mainly by increasing the clearance of bupropion.

     

Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses

Summary Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the¹⁴C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and³H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg·ml^–1 and 3 ng·ml^–1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design.After i.v. administration the kinetic parameters were: V_c 38.4 l; t_1/2 5.3 min; t_1/2 142 min; AUC 8.9 h·ng·ml^–1; renal excretion 50.2%, k₁₀ 3.5 l·h^–1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.     

Antihypertensive effect of atenolol alone or combined with chlorthalidone in patients with essential hypertension

1 The effect of atenolol, a cardioselective β-adrenoceptor acting drug, was studied alone or combined with chlorthalidone on blood pressure, heart rate, systolic time intervals, limb blood flow and limb vascular resistance. Plasma renin activity and plasma atenolol levels were also measured in the study.

2 Supine blood pressure was reduced in group A (11 patients) from 169.4 ± 5.06/111.2 ± 2.63 mmHg to 136.9 ± 2.55/90.9 ± 1.19 mmHg (P < 0.001) during the administration of atenolol alone. Concomitantly supine heart rate was decreased from 83.9 ± 4.10 beats/min to 59.7 ± 1.67 beats/min (P < 0.01) — 4th week. After the administration of atenolol over 8 weeks, supine blood pressure was 138.6 ± 1.21/94.4 ± 2.12 mmHg and supine heart rate was 59.5 ± 2.05 beats/min.

3 Supine blood pressure was reduced in group B (27 patients) from 183.6 ± 4.58/118.7 ± 2.01 mmHg (mean ± s.e. mean of systolic and diastolic blood pressure) to 171.3 ± 4.08/108.9 ± 2.26 mmHg (P < 0.01) during the administration of atenolol alone. Concomitantly supine heart rate was decreased from 84.0 ± 1.89 to 68.7 ± 1.94 (P < 0.001) beats/min. When atenolol was combined with chlorthalidone, supine blood pressure was reduced from 171.3 ± 4.08/108.9 ± 2.26 mmHg to 143.5 ± 3.68/94.8 ± 2.63 mmHg (P < 0.001). Heart rate did not alter significantly with the addition of chlorthalidone.

4 After the administration of atenolol alone in 12 patients of group B, there was a decrease of mean blood pressure from 131.8 ± 2.88 (mean ± s.e. mean) mmHg to 119.0 ± 4.05 mmHg (P < 0.001); of heart rate from 76.4 ± 3.58 beats/min to 57.0 ± 2.55 beats/min (P < 0.001); of calf blood flow from 9.23 ± 1.39 ml 100 g^-1 min^-1 to 5.05 ± 0.89 ml 100 g^-1 min^-1 (P < 0.001); and an increase of calf vascular resistance from 16.54 ± 1.90 (mmHg min^-1 100 g^-1)/ml to 28.53 ± 3.40 (mmHg min^-1 100 g^-1)/ml (P < 0.005). Atenolol did not alter significantly pre-ejection period index (P < 0.1). In atenolol-treated patients upon addition of chlorthalidone, there was a further decrease of mean blood pressure from 119.0 ± 4.05 mmHg to 105.9 ± 4.12 mmHg (P < 0.001). There were no further significant alterations of heart rate, pre-ejection period index, calf blood flow, and calf vascular resistance (P> 0.01).

5 Atenolol decreased plasma renin activity from 4.69 ± 0.87 to 2.85 ± 0.68 ng ml^-1 h^-1 (P < 0.05), and chlorthalidone increased it from 2.85 ± 0.68 to 3.81 ± 0.98 ng ml^-1 h^-1 (P < 0.05). Plasma renin activity on atenolol plus chlorthalidone was not significantly different from that on placebo (P> 0.1).

6 There was a 7.8 fold-interindividual variability in the relationship between plasma atenolol concentrations and the atenolol dose upon administration of a single oral dose of 100 mg.

     

抗孕唑(DL-111-IT)在恒河猴体内药代动力学

恒河猴分别iv抗孕唑20%cremophorEL生理盐水液25,12.5及6.3mg·kg^-1后,用柱切换HPI(法测定给药后24h内各时间点的血药浓度,根据各猴血药浓度-时间数据拟合曲线,均呈二房室动力学模型.其Y1/2a分别为0.38h,0.20h及0.36h;Y_1/2β分别为6.60h,10.2h及10.1h;V(C)分别为5.30,1.26和1.48L·kg^-1.分别im抗孕唑茶油液50,25和12.5mg·kg-13种剂量后,同上测定血药浓度,各猴血药浓度一时间数据拟合曲线,均呈-房室动力学模型。其Ka分别为0.98h,1.03h及1.45h;Ke为0.42h,0.37h及0.59h;T1/2Ke为1.66h,1.90h及1.16h;T(peak)为1.52h,1.57h及1.09h。     

Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam

1 The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age 67-76 years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years).

2 The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively.

3 The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) l/kg and 1.89 (1.44-2.23) l/kg in the elderly and young groups respectively (P < 0.05).

4 The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4)% and 13.0 (11.0-15.9)% in elderly and young respectively.

5 Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively.

6 There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59 (26-85) ml/min and 2.17 (1.57-3.22) l/kg respectively in patients and 31 (19-64) h, 63 (47-91) ml/min and 2.38 (1.44-5.33) l/kg in healthy subjects.

7 The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3)% as compared to 13.8 (11.0-15.9)% in the healthy subjects (P < 0.001).

8 Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320 (163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min (P < 0.001).

9 The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.

     

Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration

1 Plasma cyclophosphamide levels were estimated by gas-chromatography in seven patients following intravenous and oral cyclophosphamide administration. Plasma alkylating activity was determined by the nitrobenzyl pyridine (NBP) reaction.

2 The plasma T_½ after intravenous administration ranged from 5.97 to 12.37 h but after oral administration was shorter, 1.32-6.8 h. The mean total body clearance was 66.6 ml kg^-1 h^-1 after intravenous dosing and 93.1 ml kg^-1 h^-1 following oral dosing. V_dβ was 0.71 (0.10 s.d.) 1 kg^-1 suggesting that cyclophosphamide is distributed largely in body water.

3 The mean hepatic extraction ratio was 0.25, indicating a modest first pass metabolism. The metabolic clearance was 3.72 1 kg^-1 and the intrinsic hepatic clearance 5.17 1 kg^-1.

4 The mean renal clearance was 4.8 ml kg^-1 h^-1 with 6.5% of the administered dose excreted unchanged in the urine suggesting tubular reabsorption of cyclophosphamide.

5 The mean T_½ of plasma alkylating activity was 8.82 h, there being no significant difference following oral and intravenous administration. On average, 3.5 times the alkylating activity was produced by an oral dose of cyclophosphamide as compared to an intravenous dose. It is possible that this may reflect production of a different pattern of alkylating metabolites following cyclophosphamide administration by different routes. The clinical significance of these observations is unknown.

     

Renal clearance of pyridostigmine in myasthenic patients and volunteers under the influence of ranitidine and pirenzepine

1. To assess the contribution of tubular secretion to the renal excretion of pyridostigmine, and its modification by other cationic drugs, six volunteers were given single oral doses of 60-mg pyridostigmine bromide with and without co-administration of ranitidine or pirenzepine. Renal clearances were determined by?h.p.l.c. analysis of pyridostigmine and enzymic measurement of endogenous creatinine in plasma and urine.

2. In patients with myasthenia receiving continuous pyridostigmine therapy, renal clearance values were obtained in the same manner with and without ranitidine (10 patients) or pirenzepine (nine patients) co-medication.

3. Pyridostigmine was not bound to plasma proteins. Its renal clearance averaged 6.65 ml/min per kg (350% of the creatinine clearance) in all subjects, 74% being due to net tubular secretion.

4. Mean values for pyridostigmine renal clearance and for clearance by secretion were decreased in the presence of pirenzepine, but plasma concentrations were not affected significantly. Ranitidine caused a small non-significant decrease of the pyridostigmine clearance in patients.

5. Pyridostigmine had a higher elimination (2 h^?1) than the absorption rate constant (0.23 h^?1) when administered orally as a non-retarded preparation.

6. The renal clearance of creatinine was slightly increased by pyridostigmine in volunteers and slightly decreased by pirenzepine in the total group of subjects.     

Simplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma

A high-performance liquid chromatographic (HPLC) method was developed for the assay of verapamil in rat plasma. After deproteinization of the plasma sample with an acetonitrile-perchloric acid (8:2) mixture containing dextromethorphan, the internal standard, an aliquot of the supernatant was directly analyzed on a cyanopropylsilane column with methanol-acetonitrile-triethylamine acetate buffer (10:30:60) as the mobile phase and detection at 235 mm. At a flow rate of 1.5 ml min⁻¹, a complete analysis was completed in less than 6 min. The method was linear for verapamil concentrations in the range 0.5–10 μg ml⁻¹ (r=0.9999). Recoveries for the same drug concentrations from spiked rat plasma ranged from 85.6-93.0% (n=8). The mean RSD values for intraday and interday assay reproducibility (n=3) were, in both cases, less than 0.9%. The limit of detectability was about 0.1 μg ml⁻¹. The method was found useful to monitor the plasma levels of verapamil in rats that had received this drug by the nasal, oral and intravenous routes of administration.     

Atenolol ν placebo in mild hypertension: Renal, metabolic and stress antipressor effects

1 The effects of 8 week treatment periods of atenolol and placebo on effective renal plasma flow (ERPF), glomerular filtration rate (GFR), plasma renin activity (PRA), oral glucose, fasting lipids and Achilles tendon reflex were compared in a double-blind crossover trial in ten subjects with mild hypertension.

2 Atenolol reduced resting blood pressure and pulse rate but did not prevent the rise in blood pressure and pulse rate in response to three kinds of stress.

3 Mean glomerular filtration rate and effective renal plasma flow were below the normal range during placebo (1.31 ml/s and 7.40 ml/s respectively) but were not significantly different on atenolol (1.23 ml/s and 7.18 ml/s). Serum urea was significantly (P < 0.01) higher on atenolol (6.7 mmol/l) than on placebo (5.6 mmol/l) but serum creatinine did not change. PRA was lower on atenolol (0.42 nmol l^-1 h^-1) than on placebo (1.01 nmol l^-1 h^-1).

4 The mean values of fasting cholesterol, triglycerides, ankle jerk contraction time, spirometry, weight, serum potassium, sodium and chloride were similar on atenolol and placebo.

5 Fasting blood sugar was a little higher (P < 0.05) on atenolol and the 1 and 2 h post-glucose serum insulin levels were a little lower (P < 0.01).

6 The cardioselectivity of atenolol does not impair its anti-hypertensive effect and may be associated with less effect on renal function. The metabolic effects of atenolol seem to differ from those of metoprolol.

     

环氧司坦在大鼠的药代动力学

大鼠灌胃(ig)环氧司坦三种剂量50,100及200 mg·kg^-1后,测定12 h的血药浓度,根据各鼠血药浓度—时间数据拟合曲线,均呈一室动力学模型。其Ka分别为0.578 h^-1,0.553 h^-1,0.439 h^-1;K分别为0.308 h^-1,0.282 h^-1,0.224 h^-1;T_1/2分别为2.27 h,2.54 h,3.12 h;AUC分别为786.89,1644.43和3335.35 μg·h^-1·ml^-1。组织中以肾上腺、肝、胃肠、生殖器(子宫与卵巢)为高,其次是肾、心、脑、肺、脾,高峰浓度在3 h左右,与血药浓度分布情况一致。三种剂量的血浆蛋白结合率均在90%左右,结合率与给药剂量无关。原形药在胆汁、尿及粪便中排泄百分率甚少。提示大部分药物可能在体内进行转化。     

Renal,Biliary and Intestinal Clearance of a Quaternary Ammonium Compound,Emepronium in the Dog

Abstract Different routes of elimination of emepronium have been quantitated in conscious and anaesthetized dogs. Smoothed plasma concentration time curves and urinary excretion data obtained following intravenous bolus injection of 5 mg/kg indicate at least four different phases with the following half-lives: 5 min., I hour, 10 hours and 9 days. The initial dilution space, 0.2-0.6 l/kg, is rather similar to the extracellular volume (0.20-0.35 l/kg). From infusion experiments plasma clearance of emepronium have been found to be 33±2 ml. min^-1.kg^-1 (meani ± S.E.M., n = 14). The drug is secreted by the renal tubules at a maximum rate of 20 μg/min. at a plasma concentration of about 200 μg/l. Compared with other quaternary ammonium compounds, this is an easily saturated mechanism with a low capacity. The renal clearance constitutes about 30 % of the plasma clearance at a plasma concentration of 200 μg/l. The biliary excretion rate increases proportionally to a plasma concentration up to 100 μg/l and then reaches a maximal rate which is dependent on the bile flow. The biliary clearance decreases from 7 to 2 ml.min.^-1.kg^-1 when the bile flow changes from 7 to 4 g/ hour and the plasma concentration is 200 μg/l. Experiments with bile diversion and saline perfusion of isolated intestinal segments reveal an intestinal route of elimination of both emepronium and metabolites. The bile diversion experiments indicate that about 5-15% of an intravenous dose is excreted through the gastrointestinal epithelium. Perfusion of isolated intestinal loops indicates an apparent clearance of 4-5 ml. min^-1.m^-1 over a wide range of steady state plasma concentrations (20-1200 μ/l). An apparent total intestinal clearance could be calculated to about 7 ml. min.^-1.kg^-1. The remaining part of the plasma clearance (about 8 ml. min.^-1. kg^-1 in an anaesthetized dog) is accounted for by metabolism. The degree of protein binding has been shown to be low, about 20 per cent, and the red blood cell penetration in vitro is only 1-10% of the total amount present in whole blood.     

Effects of thyrotrophin-releasing hormone, and methionine-enkephalin on gastric acid and pepsin secretion in the cat

1 The effect of intravenous administration of thyrotrophin-releasing hormone (TRH) and methionine-enkephalin on gastric acid and pepsin secretions was investigated in conscious cats prepared with chronic gastric fistulae.

2 TRH, 20 μg kg^-1 h^-1, did not influence unstimulated gastric acid secretion, nor gastric acid secretion stimulated by submaximal doses of pentagastrin or histamine. Pepsin secretion stimulated by pentagastrin was not influenced by TRH.

3 TRH, 20 μg kg^-1 h^-1, significantly reduced the gastric acid and pepsin responses to intravenous infusion of insulin. TRH also significantly reduced the degree of hypoglycaemia seen in response to insulin. TRH, 20 μg kg^-1 h^-1, but not 5 μg kg^-1 h^-1, infused alone resulted in a significant hyperglycaemia.

4 It is concluded that the reduction of insulin-stimulated gastric secretion by TRH is not dependent on the hyperglycaemic action of the peptide. The mechanism of action of TRH on insulin-stimulated secretion is discussed with respect to its site of action.

5 Methionine-enkephalin or the potent analogue, D-Ala², Met-enkephalinamide were without effect on unstimulated gastric secretion, or secretion stimulated by pentagastrin, histamine, and insulin. The opiate receptor antagonist, naloxone, did not significantly alter the gastric acid or pepsin response to insulin.

6 It is concluded that there is no evidence that opiates stimulate oxyntic glands directly, nor that the oxyntic cells may possess high affinity binding sites for opiates, nor that endogenous opiates are involved in the control of gastric secretion.

     

Population pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets

Aims

Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson''s disease (PD).

Methods

A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients (n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG.

Results

The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants (LCIG = 9.2 h^–1 vs. LC-oral = 2.4 h^–1; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml⁻¹ additive error) vs. LC-oral (29% proportional error, 0.59 μg ml⁻¹ additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h⁻¹ and 131 l, respectively.

Conclusions

LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.     

The disposition of debrisoquine in hypertensive patients

1 The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers.

2 Incremental doses and prolonged administration led to a proportionately greater urinary recovery and higher plasma concentration of D but the proportion recovered as HD fell while its plasma concentration remained unchanged. Dividing a dose or administering a single oral dose of D resulted in the formation of proportionately more HD and a lower urinary recovery of D. These findings suggest that the metabolism of D to HD may be partially saturated or inhibited by D itself or by HD.

3 Peak urinary excretion rates and plasma concentrations of both D and HD occurred 2 h after a single dose suggesting rapid absorption and presystemic metabolism.

4 HD was eliminated more rapidly than D. Mean (± s.d.) elimination half-life from the urine for HD was 9.6 ± 3.7 h and for D was 16.2 ± 5.7 h. Reasons for this are discussed.

5 Renal clearance of D and HD was not constant. A fall was observed with time after a single dose but on multiple dosing the clearance fell with increasing plasma concentrations. Mean (± s.d.) renal clearance values during multiple administration were D 282 ± 88 ml/min and HD 371 ± 178 ml/min. It is suggested that active saturable tubular secretion of D and HD may be responsible for their renal elimination.

6 The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively.

7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.

     

Dose-response relationships in tropicamide-induced mydriasis and cycloplegia

1 Mydriatic and cycloplegic effects of tropicamide in the normal and in the guanethidine-treated human eye have been recorded following prolonged exposure of the eye to drug solutions.

2 Marked effects and satisfactory dose-response relationships were observed at drug concentrations within the range 1.25-40 μg/ml, by comparison with concentrations of 5-10 mg/ml usually applied as eye-drops.

3 The findings are discussed in relation to drug concentrations which produce cholinergic antagonism in vitro.

     

NONMEM法分析肾移植患者环孢素A的群体药动学

用HPLC和FPIA法(单克隆抗体)测定全血中环孢素A(CsA)浓度,收集临床60例肾移植患者牛奶送服CsA后浓度数据281点,应用NONMEM程序一步法估算其群体药动学参数,并定量地分析体重、年龄、性别,长期用药对清除率的影响。按口服吸收一室开放模型估算的群体药动学参数为:清除率CL(L·h^-1)、表现分布容积V_d(L)和口服吸收速率常数K_a(h^-1)分别等于59.8,227及1.28,其个体间变异Q_CL(%),Q_VL(%)及Q_Ka(%)分别为30.27,29.02和75.10,浓度观察值与模型预测值的残差变异Q_E(%)等于31.19固定效应与CL的定量关系为:以体重的0.03倍加法调整,男性较女性患者增加4.31,长期用药患者下降12.7。     

The pharmacokinetic assessment of sodium cromoglycate

The plasma concentration of sodium cromoglycate (SCG) was measured in four healthy subjects by radioimmunoassay after a 4 mg intravenous dose and after inhaling from 20 mg capsules, and from 10 and 30 mg ml^?1 nebulizer solutions. The mean absorption constant (K₁) after inhalation was 0·43 h^?1. The mean elimination constant from the plasma (K_elim) after intravenous administration was 11·5 h^?1, and that after inhalation was similar. The apparent volume of distribution of SCG (V_dβ) was 0·2 litre kg^?1 and the mean plasma clearance was 0·35 litre h^?1kg^?1. The amount of SCG absorbed after inhalation varied according to the method of inhalation and dose. After the inhalation of powder from 20 mg capsules, 1·30–3·96 mg reached the plasma, after inhalation of SCG produced by nebulizing a 10 mg ml^?1 solution for 5 min at 10 psi using a Minineb nebulizer 0·19—0·31 mg reached the plasma and when the solution was increased to 30 mg ml^?1 the figure was 0·33—0·45 mg.     

Plasma concentrations and bioavailability of isosorbide dinitrate and pindolol from a combination formulation

The plasma concentrations and bioavailability of sustained-release isosorbide denigrate and standard-release pindolol have been compared after administration of these drugs in combination and alone. Bioavailability parameters of isosorbide dinitrate and pindolol obtained after administration of the drugs in combination were not significantly different (P>0.05) to those obtained after administration of either drug alone. Two peaks of mean concentrations of isosorbide dinitrate occurred in plasma after administration of 30 mg of this drug in combination with 7.5 mg pindolol (4.4 ng ml^?1 at 1 h and 4.5ng ml^?1 at 5h), or alone (5.9ngml^?1 at 2h and 5.7ng ml^?1 at 5h). In each case, plasma concentrations of isosorbide dinitrate were maintained during at least 8 h, whereas the drug was not detected in plasma at 2.5 h after administration of a standardrelease formulation. The peaks of mean concentrations of pindolol were 39.7ng ml^?1 at l.5h after administration of 7.5 mg drug in combination with isosorbide dinitrate and 38.0 ng ml^?1 at 1 h after administration of the drug alone. Concentrations of pindolol in plasma declined with a half-life of 3 h.     

Comparison of cell death and adenosine triphosphate content as indicators of acute toxicity in vitro

1 Anchorage-independent LS cells, derived from L929 mouse fibroblasts, were used as an in vitro alternative to animals for the assessment of acute toxicity. The two end points were cell death, indicated by fluorescein diacetate and ethidium bromide, and intracellular adenosine triphosphate (ATP) content.

2. Concentrations of 20 test compounds which produced a 50% decrease in the ATP contents of control cells (ATP₅₀) ranged from 17 μg ml^?1 for diethylstilboestrol to 7˙0 mg ml^?1 for sodium chloride.

3. The concentrations which caused 50% cell death ranged from 16 μg ml^?1 for diethylstilboestrol to 8˙0 mg ml^?1 for paracetamol.

4. There was a good numerical correlation (r = 0˙99) between the ranks of ATP₅₀ and CD₅₀ end-points, there being only minor changes in order between the ranks.

5. The slopes of the dose-response plots for individual chemicals were markedly different.