Short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols; the detailed pharmacokinetics of budesonide, formoterol, and terbutaline

There is an increasing interest in using the lung as a route of entry for both local and systemic administration of drugs. However, because adequate technologies have been missing in the preclinical setting, few investigators have addressed the detailed disposition of drugs in the lung following short inhalation exposures to highly concentrated dry powder aerosols. New methods are needed to explore the disposition of drugs after short inhalation exposures, thus mimicking a future clinical use. Our aim was to study the pulmonary disposition of budesonide, formoterol, and terbutaline, which are clinically used for the treatment of bronchial asthma. Using the recently developed DustGun aerosol technology, we exposed by inhalation for approximately 1 min the isolated and perfused rat lung (IPL) to respirable dry particle aerosols of the three drugs at high concentrations. The typical aerosol concentration was 1 mug/mL, and the particle size distribution of the tested substances varied with a MMAD ranging from 2.3 to 5.3 mum. The IPL was perfused in single pass mode and repeated samples of the perfusate were taken for up to 80 min postexposure. The concentration of drug in perfusate and in lung extracts was measured using LC-MS/MS. The deposited dose was determined by adding the amounts of drug collected in perfusate to the amount extracted from the tissues at 80 min. Deposited amounts of budesonide, formoterol fumarate, and terbutaline sulphate were 23 +/- 17, 36 +/- 8, and 60 +/- 3.2 mug (mean +/- SD, n = 3), respectively. Retention in lung tissues at the end of the perfusion period expressed as fraction of deposited dose was 0.19 +/- 0.05, 0.19 +/- 0.06, and 0.04 +/- 0.01 (mean +/- SD, n = 3) for budesonide, formoterol, and terbutaline, respectively. Each short inhalation exposure to the highly concentrated aerosols consumed 1-3 mg powder. Hence, this system can be particularly useful for obtaining a detailed pharmacokinetic characterization of inhaled compounds in drug discovery/development.     

The effects of a beta-2 selective adrenergic agonist and a beta-nonselective antagonist on theophylline clearance

Beta-adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 +/- 12.9 vs 40.6 +/- 9.9 mL/min/1.73m2; P less than .01) increased half-life (8.37 +/- 1.77 vs 12.32 +/- 2.70 hours; P less than .05), and increased postinfusion theophylline concentration (13.5 +/- 2.7 vs 18.95 +/- 2.5 micrograms/mL; P less than .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 +/- 13.0 vs 75.0 +/- 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 +/- 12.7 vs 36.1 +/- 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta-2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta-adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.     

The effect of propranolol on paracetamol metabolism in man.

Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.     

特普他林对大鼠烟雾吸入伤后肺泡液体清除功能的影响

目的　观察特普他林对大鼠烟雾吸入伤后肺泡上皮液体清除能力变化的影响。方法　采用大鼠烟雾吸入性损伤模型。伤后 2 4h经气管滴注特普他林 ( 10 -4 mol·L-1)溶液 5ml·kg-1;1h后检测肺泡内液体清除率 (ALC)、总肺水量 (TLW )、肺血管外肺水量 (EVLW)和动脉血气指标。结果　大鼠伤后 2 4hALC降低 46 8% ,TLW和EVLW明显增加 ,出现严重的低氧血症。特普他林组ALC增高 5 7 6 % ,TLW和EVLW显著减少 ,低氧血症明显改善。钠转运特异性抑制剂阿咪洛利或哇巴因能部分抑制特普他林刺激肺泡内液体清除的作用。结论　特普他林通过上调钠主动转运机能 ,促进肺水肿液的吸收 ,从而改善换气功能 ,对吸入伤后肺水肿有一定的治疗作用     

Effect of inhaled terbutaline sulphate in relation to its deposition in the lungs

We studied the effects of inhaled terbutaline on FEV₁ and gas exchange, and the pattern of deposition within the lungs. To document this and to estimate the dose of terbutaline administered to the lungs, [^99mTc]DTPA was added to nebulised terbutaline solution. The aerosol was deposited preferentially in large or small airways by using aerosols with different particle mass median diameters (1.5 and 4.8 μm) and different inhalation flow rates (0.25 and 1.01/s). The patients inhaled placebo and then three increasing doses of terbutaline (0.006, 0.02 and 0.08 mg to the lungs). Finally, 2 mg terbutaline was inhaled from a metered dose inhaler via a spacer. After each inhalation FEV₁, PaO₂ and PaCO₂ was measured. The inhalation of small particles at a low flow resulted in a fairly uniform lung deposition, while larger particles at a higher flow resulted in heavy central deposition. Penetration index for small and large particles were 1.3 ± 0.2 and 0.8 ± 0.3 (P < 0.001), respectively. In both groups FEV₁ increased similarly with each dose, and at 0.02 and 0.08 mg the increase was significant (P < 0.01). After eight metered doses of terbutaline sulphate (0.25 mg per dose) inhaled via a spacer, there was a further increase in FEV₁ (P < 0.001). Gas exchange did not differ between the two groups but if they were combined the Da-aO₂ was significantly lower after metered doses than control (P < 0.05). Thus, it appears that the site of deposition is not important for the bronchodilator effect of terbutaline, and gas exchange tended to improve with both modes of administration.     

Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury

We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.     

Alterations in the metabolism of oestrogens during treatment with aminoglutethimide in breast cancer patients. Preliminary findings

In this small study, the effect of aminoglutethimide on the disposition of oestrogens in women with advanced breast cancer was investigated using bolus injections of 4-[14C]-oestradiol and 6,7-[3H]-oestrone sulphate, alone or in combination. No alterations in oestrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-[14C]-oestradiol clearance was not changed. 14C-Oestrone sulphate AUC was reduced by 43% at a low dose of aminoglutethimide (125 mg twice daily) and by 65% at a high dose (250 mg 4 times daily) with hydrocortisone acetate 25 mg twice daily. The oestrone sulphate terminal elimination rate constant (lambda z) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens). A possible increase in oestrone sulphate clearance during long term treatment was tested for by injecting 6,7-[3H]-oestrone sulphate. These studies revealed a marked increase (mean 104%) in oestrone sulphate clearance in patients receiving the high dose aminoglutethimide schedule. Following injection of 4-[14C]-oestradiol plus 6,7-[3H]-oestrone sulphate, the fraction of 4-[14C]-oestradiol metabolised to oestrone sulphate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of 14C-oestriol was observed after 4-[14C]-oestradiol administration. Our results, although preliminary, suggest that aminoglutethimide is a potent inducer of aminoglutethimide metabolism, thereby producing a significant reduction in plasma bioavailability of oestrone sulphate. These effects may have a role in the action of aminoglutethimide, a finding which warrants further investigation.     

The role of sulphate conjugation in the metabolism and disposition of oral and intravenous paracetamol in man.

The effects of paracetamol dose (5 and 20 mg/kg) and route of administration (intravenous and oral) on the urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were studied in five healthy subjects. The fractional urinary excretion of unchanged paracetamol and its conjugates was independent of the route of administration at both dose levels, suggesting that the gastrointestinal tract is not an important site for paracetamol metabolism. The percentage of the dose excreted as the sulphate conjugate was significantly higher after 5 than after 20 mg/kg (37.7% and 33.3% respectively) and this is consistent with saturation of sulphate conjugation. No significant effect of paracetamol dose upon the area under the plasma concentration-time curve (AUC), corrected for dose, was found for the sulphate or glucuronide conjugates. The total plasma clearance of paracetamol and the renal clearance of the sulphate conjugate were significantly higher after the 5 than the 20 mg/kg dose (331 +/- 42 ml/min and 295 +/- 48 ml/min; 273 +/- 74 ml/min and 205 +/- 46 ml/min respectively). The oral systemic availability of paracetamol was 80% and independent of dose.     

The challenges of quantitative measurement of lung deposition using 99mTc-DTPA from delivery systems with very different delivery times.

In quantifying aerosol delivery, the drug is often mixed with a radiolabel such as (99m)Tc-DTPA whose deposition is used as a proxy for the drug. (99m)Tc-DTPA deposited in the lung is cleared by a combination of absorption into the pulmonary circulation and mucociliary clearance. If administration is not instantaneous, the image will not include that clearance during administration, a problem raised if comparing devices with different administration times. However, if rates of clearance are measured, it will be possible to "correct" the initial image for the clearance that occurred during administration and before counting. Five adult males inhaled a 5-mL solution containing (99m)Tc-DTPA from a breath enhanced jet nebulizer (LC Plus)over the course of 10 min and a 1.25-mL solution from a vibrating membrane device (eFlow), which was delivered in 2.5 min. Quality assurance was the radioactivity count balance (RCB) defined as the difference in the total radioactivity pre-nebulization less post, divided by pre, and expressed as a percentage. Attenuation calculations used a (57)Co flood source (Macey and Marshall). The "correction" for the clearance of (99m)Tc-DTPA was 0.91 +/- 0.04 (mean +/- SD) for the LC Plus) and 0.96 +/- 0.02 for the eFlow). RCB was -0.6 +/- 3.5% for the LC Plus and -4.7 +/- 6.4% for the eFlow, implying acceptable accuracy. For the LC Plus, lung deposition was 15.9(13.4, 18.4)% (mean and 95% CI) of the charge dose, and for the eFlow it was 32.0(29.0, 35.0)%. This technique gave an acceptable level of accuracy for quantitative planar imaging and allowed the comparison of delivery from devices with very different rates of delivery.     

Assessment of different methods of inhalation from salbutamol metered dose inhalers by urinary drug excretion and methacholine challenge

AIMS: Methods to determine the lung delivery of inhaled bronchodilators from metered dose inhalers include urinary drug excretion 30 min post inhalation and methacholine challenge (PD20). We have compared these two methods to differentiate lung delivery of salbutamol from metered dose inhalers using different inhalation methods. METHODS: In phase 1 of the study, on randomized study days, 12 mild asthmatics inhaled placebo, one and two 100 microg salbutamol doses from a breath actuated metered dose inhaler, in randomized fashion on different days. In phase 2, they inhaled one 100 microg salbutamol dose from a metered dose inhaler using a SLOW (20 l min(-1)) and a FAST (60 l min(-1)) inhalation technique and a slow inhalation delayed until after they had inhaled for 5 s (LATE). Urinary excretion of salbutamol (0-30 min) and PD20 were measured after each dose. RESULTS: Following placebo, one and two 100 microg salbutamol doses, the geometric mean for PD20 was 0.10, 0.41 and 0.86 mg respectively and the mean (SD) urinary drug excretion after one and two doses was 2.25 (0.65) and 5.37 (1.36) microg, respectively. After SLOW, FAST and LATE inhalations the geometric mean for PD20 was 0.50, 0.40 and 0.42 mg, respectively, and mean (SD) salbutamol excretion was 2.67 (0.84), 1.90 (0.70) and 2.72 (0.67) microg, respectively. Only the amount of drug excreted during the FAST compared with the SLOW and LATE inhalations showed a statistical difference (95% confidence interval on the difference 0.12, 1.54 and 0.06, 1.59 microg, respectively). CONCLUSIONS: Urinary salbutamol excretion but not PD20 showed differences between the inhalation methods used. When using a metered dose inhaler slow inhalation is better and co-ordination is not essential if the patient is inhaling when they actuate a dose of the drug.     

Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans

AIMS: Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans. METHODS: Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2-40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed. RESULTS: ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62% vs 4% during placebo, P < 0.05, for Study 1 and in 42% vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at approximately 1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 +/- 1 vs 19 +/- 1, 18 +/- 2 vs 23 +/- 3, 15 +/- 1 vs 17 +/- 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 +/- 2 vs 84 +/- 3, 80 +/- 4 vs 90 +/- 5, 75 +/- 3 vs 79 +/- 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level). CONCLUSIONS: The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease.     

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

1. The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2. The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 +/- 1.2 and 4.2 +/- 0.7 ml min-1 for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration 11.4 +/- 3.1 and 9.9 +/- 2.0 ml min-1 for the 250 and 500 mg single doses, respectively). 3. The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (greater than 50%) after multiple dose administration. 4. The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 +/- 2.8 and 9.1 +/- 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 +/- 3.1 and 15.9 +/- 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5. The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentration-dependent plasma binding.     

Factors affecting the response to inhibition of drug metabolism by cimetidine--dose response and sensitivity of elderly and induced subjects

The effect of cimetidine on oxidative drug metabolism was characterised using antipyrine clearance in a group of healthy volunteers. In six subjects cimetidine produced a dose dependent reduction of antipyrine clearance: 400 mg/day (16.8 +/- 2.2%, mean +/- s.e. mean), 800 mg/day (26.3 +/- 1.5%) and 1600 mg/day (33.5 +/- 2.4%). The effect of cimetidine (800 mg/day) was of similar magnitude (approximately 25%) in two groups of six young (21-26 years) and six elderly (65-78 years) subjects. The effect of pretreatment begun just 1 h before administration of antipyrine was similar to that of 24 h pretreatment and that reported for chronic cimetidine pretreatment. The percentage reduction in antipyrine clearance produced by cimetidine 800 mg/day was greater (44 +/- 5 vs 24 +/- 3%; P less than 0.05) in six subjects who had been pretreated with the hepatic enzyme inducer rifampicin (600 mg/day for 21 days) than in the control uninduced state. Although cimetidine was capable of rapidly reversing the effect of rifampicin on antipyrine clearance, following withdrawal of both rifampicin and cimetidine there was still evidence of enzyme induction. These results suggest that the effect of cimetidine on oxidative metabolism is dose dependent, is more marked in enzyme induced subjects, is independent of the duration of pretreatment and is of similar magnitude in young and elderly subjects.     

Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction.

Mucociliary dysfunction results in mucus accumulation, airway obstruction, bacterial colonization, recurrent infective exacerbations, and an increase in morbidity and mortality. Studies in patients with cystic fibrosis, established that inhalation of hypertonic saline (HS) increases clearance of mucus acutely in a dose-dependent manner. Clearance over 90 min was 23.8 +/- 4.0% and 26.0 +/- 3.1% in response to 7% and 12% saline, which was significantly enhanced compared to 12.7 +/- 1.4% and 19.7 +/- 3.1% in response to 0.9% and 3% saline. Mannitol (approximately 300 mg) inhaled as a dry powder had a marked acute effect in patients with bronchiectasis. Clearance over 75 min was 34.0 +/- 5.0% with mannitol, 17.4 +/- 3.8% with control, and 11.7 +/- 4.4% at baseline. Further studies in patients with bronchiectasis showed that mannitol reduces the 24-h retention of radiolabeled mucus, suggesting that the effect of mannitol extends beyond the acute phase. Mannitol helped patients to clear mucus within 2 h that would have taken 24 h to clear without mannitol. A further study in CF patients showed that mannitol was equally effective as 6% HS at improving ciliary and cough clearance. The total clearance over 120 min with mannitol (27.6 +/- 3.7%) and with HS (31.0 +/- 5.5%) was significantly increased compared to their respective controls (18.6 +/- 3.8% and 20.9 +/- 3.6%). These preliminary results suggest that long-term treatment with HS or mannitol may benefit patients with mucociliary dysfunction.     

Effects of pexid on liver cell cultures ultrastructural and histoenzymological studies

Summary A double blind, placebo-controlled study of the ventilatory effects of three new beta₁-selective adrenoceptor blockers was carried out in eight asthmatic patients. Measurements were performed before and 2, 3 and 4 h after ingestion of a single oral dose of placebo, atenolol 100 mg, metoprolol 100 mg or acebutolol 400 mg. At each time ventilatory indices and heart rate were assessed before, during and 15 min after an exercise test. The ventilatory indices were re-assessed after challenge with terbutaline 1.5 mg by inhalation. The three beta-blocking agents caused equal falls in exercise heart rate two hours after ingestion, indicating the equipotency of the cardiac effects. The three agents reduced significantly and to the same extent FEV₁ and PEFR both before and after exercise. The respiratory indices clearly improved after stimulation with terbutaline. The response to terbutaline was less marked after acebutolol, which may indicate that it has a lower degree of beta₁-selectivity. The beta-blockers did not show any influence on bronchodilatation during exercise, or on exercise-induced bronchospasm.     

Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.

1. The effect of dose (100 mg, 250 mg, 500 mg, 750 mg and 1000 mg) on the glucuronidation and sulphation of diflunisal was studied in six healthy volunteers. 2. Total urinary recovery ranged from 78.9 +/- 11.9% to 91.5 +/- 18.7% of the administered dose. Urinary recovery (normalized for total urinary recovery) of diflunisal sulphate (DS) significantly increased with dose from 9.3 +/- 3.7% to 18.1 +/- 4.8%. 3. Normalized urinary recovery for diflunisal phenolic glucuronide (DPG) was unaffected by dose (range: 30.6 +/- 3.8% to 40.6 +/- 6.6%). Normalized urinary recovery for the acyl glucuronide (DAG) significantly decreased from 52.3 +/- 4.6% to 40.2 +/- 3.4% as the dose increased. 4. Total plasma clearance of diflunisal significantly decreased from 14.4 +/- 1.4 ml min-1 to 8.7 +/- 1.4 ml min-1 as the dose increased from 100 mg to 750 mg. A further increase in dose to 1000 mg resulted in an unexplained increase in total plasma clearance to 10.3 +/- 1.8 ml min-1. 5. Dose-dependent plasma clearance of diflunisal was caused mainly by saturation of the formation of DAG, whereas the formation of DS and DPG were relatively unaffected by dose.     

Determination of the relative bioavailability of salbutamol to the lung following inhalation.

1. The urinary excretion of salbutamol and its sulphate metabolite was measured following oral (4 mg) and inhaled (4 x 100 micrograms) administration of salbutamol. 2. Total urinary recovery of salbutamol and its sulphate conjugate indicated a mean (s.d.) relative bioavailability of 92.2 (24.8) % following inhalation compared with oral administration. 3. The mean (s.d.) elimination half-lives of salbutamol and its sulphate conjugate were 5.7 (1.4) and 4.1 (2.1) h, respectively, after oral administration and following inhalation they were 6.1 (2.1) and 5.1 (1.0) h, respectively. 4. Following oral and inhaled administration it was found that in the first 30 min the mean (s.d.) percentage of the dose excreted in the urine as unchanged salbutamol was 0.18 (0.14) and 2.06 (0.80) %, respectively (P < 0.01). The drug content of a urine sample taken 30 min after inhalation is, therefore, considered to be representative of the amount of drug delivered to the lungs. It is proposed that this method can be used to evaluate the relative bioavailability of salbutamol to the lung following inhalation by different techniques and devices.     

Paracetamol elimination in patients with non-insulin dependent diabetes mellitus.

The pharmacokinetics and metabolism of an intravenous dose (500 mg) of paracetamol were studied in a group of non-insulin dependent diabetic patients (n = 10) and in a group of healthy control subjects (n = 9). Paracetamol clearance, half-life and the partial clearance to paracetamol glucuronide were not significantly different, but the partial clearance to paracetamol sulphate was significantly reduced (62 +/- 18 vs 86 +/- 17 ml h-1 kg-1 (mean +/- s.d.)) and the renal clearance of paracetamol was significantly increased (56 +/- 20 vs 22 +/- 6 ml h-1 kg-1 (mean +/- s.d.)) in the non-insulin dependent diabetic patients, compared with the control group.     

Regular nebulised terbutaline in chronic obstructive airways disease: dose-response studies fail to detect tolerance.

1. To determine the effects of high dose terbutaline on the possible development of tolerance we have examined the influence on dose-response of regular nebulised terbutaline. 2. We studied 10 subjects with severe chronic obstructive airways disease (COAD), mean age 63 years mean (s.e. mean) PEFR 142 l min-1 (19), FEV1 0.77 1 (0.12) and FVC 1.93 (0.19). Cumulative dose-response curves were measured (PEFR, FEV1 and FVC) to six incremental doses of terbutaline (0.5-8 mg) before and 1, 4, 8 and 12 weeks after starting nebulised terbutaline 5 mg four times a day. 3. Maximal bronchodilatation (Emax) was calculated by polynomial regression. Responses were examined by analysis of variance. 4. Mean baseline PEFR increased by 32 l min-1 (P less than 0.05), FEV1 by 0.16 1 (NS) and FVC by 0.54 l (P less than 0.05) after 12 weeks. Initial mean Emax PEFR was maintained throughout the study. The percentage of mean Emax PEFR achieved by each cumulative dose of terbutaline either increased (0.5 mg, 1 mg and 2 mg, P less than 0.01) or was maintained (4 mg, 6 mg and 8 mg) throughout the study. 5. We conclude that in severe COAD regular nebulised terbutaline 5 mg four times a day produces a sustained improvement in baseline lung function without changes in dose-response which would suggest tolerance.     

Effect of a PAF antagonist, BN52063, on PAF-induced bronchoconstriction in normal subjects.

1. The effects of an oral platelet activating factor (PAF) antagonist, BN52063, or matched placebo on inhaled PAF challenge were assessed in a double-blind study in eight normal subjects. 2. PAF (24 micrograms) induced an immediate bronchoconstriction, with a maximum fall in flow at 30% of vital capacity from a partial flow volume manoeuvre (Vp30) of 47.1 +/- 7% (mean +/- s.e. mean) 5 min after inhalation following placebo treatment. Repeated PAF challenges at 15 min intervals resulted in tachyphylaxis of the bronchoconstrictor response. 3. Two hours after the ingestion of BN52063 (120 mg) the maximum bronchoconstriction induced by inhaled PAF was attenuated (35.9 +/- 9% fall at 5 min) with a significant reduction (P less than 0.05) in response after the first and second inhalations. 4. Inhaled PAF induced an immediate neutropenia (73.2 +/- 9% fall 5 min after inhalation) followed by a rebound neutrophilia, which were unaffected by pretreatment with BN52063. 5. Oral ingestion of a dose of BN52063 which is effective in reducing skin responses to PAF gave partial protection against the bronchoconstrictor effect of inhaled PAF in normal subjects.