British Journal of Clinical Pharmacology

Park, BK; Coleman, JW

doi: 10.1111/j.1365-2125.1988.tb05287.xpmid: 3207559

Vincent, J.; Liminana, R.; Meredith, PA; Reid, JL

doi: 10.1111/j.1365-2125.1988.tb05288.xpmid: 2905150

1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal elimination half‐life was 10.6 +/‐ 2.6 and 12.5 +/‐ 1.9 h respectively after 10 and 50 mg of ebastine. 4. Antihistamine (H1‐receptor) activity was examined with intradermal histamine (2 micrograms). Oral ebastine reduced the histamine wheal area for up to 24 h and also reduced subjective local pain. 5. Antihistamine activity correlated well with plasma levels of carebastine in individual subjects. 6. Ebastine appears to have potential as an antihistamine for once a day dosing.

Vincent, J.; Sumner, DJ; Reid, JL

doi: 10.1111/j.1365-2125.1988.tb05289.xpmid: 2905151

1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1‐receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long‐lasting antihistamine effects can be demonstrated.

Ferner, RE; Ward, C.; Kelly, C.; Connolly, M.; Bateman, DN; Rawlins, MD

doi: 10.1111/j.1365-2125.1988.tb05290.xpmid: 2905152

1. The rate of onset and magnitude of the effect of levocabastine, a potent H1‐receptor antagonist, in reversing histamine‐induced bronchoconstriction were determined in a double‐blind cross‐over trial against saline placebo. Histamine was administered by nebuliser so that forced expiratory volume in 1 second (FEV1) was reduced to 80‐75% of baseline FEV1 in 10 men with mildly or moderately responsive airways and the effects of intravenous injection of saline or saline + 200 micrograms levocabastine were studied. 2. The maximum rate of recovery of FEV1 was 7[2‐10]% min‐1 (median [range]) in the first 5 min after levocabastine injection, but only 4[1‐7]% min‐1 after saline alone (P less than 0.05). 3. The median area under the recovery curve of FEV1 from 0 to 30 min after injection was 405 [228‐498]% basal FEV1 X min after levocabastine and 301[98‐502]% basal FEV1 X min after saline alone (P less than 0.002). 4. FEV1 returned to 90% of baseline within 30 min in all subjects after levocabastine, but not after saline alone (P less than 0.002). 5. Histamine‐induced bronchoconstriction was relieved more quickly by levocabastine than saline alone. This model may have application to the study of drugs used in the treatment of anaphylaxis.

Gould, CA; Ollier, S.; Aurich, R.; Davies, RJ

doi: 10.1111/j.1365-2125.1988.tb05291.xpmid: 2905153

1. The effect of 4.4 mg azelastine administered orally on airway responsiveness, skin prick testing, daily peak expiratory flow rates and symptoms of asthma was compared with placebo in a 7 week double‐ blind, parallel group study of 24 patients with extrinsic asthma. The study was in two parts: a 2 week assessment period, during which all patients received placebo tablets but recorded daily peak flow rates (PEFRs) and symptoms, preceding the 7 week double‐blind comparison. 2. Azelastine, 4.4 mg, significantly decreased airway responsiveness to histamine compared with placebo both after a single dose (P less than 0.001), and following 7 weeks continuous treatment (P less than 0.02). Airway responsiveness to methacholine was not altered by administration of azelastine compared with placebo. 3. Skin prick test weal diameters to both allergen and histamine were significantly reduced after both a single dose and following 7 weeks continuous therapy treatment with azelastine. 4. There was a significant improvement in both the mean of the morning and the evening peak flow rates recorded during the last week compared with the first week of the study in the group receiving 4.4 mg of azelastine twice daily compared with placebo. Scores for wheeze were significantly reduced during the final 3 weeks of the study in patients receiving azelastine compared both with those receiving placebo and with the first week of the study (P less than 0.05, P less than 0.01). Consumption of inhaled bronchodilators fell significantly during the study in the group receiving azelastine therapy (P less than 0.05); no such fall occurred in the placebo treated patients. 5. A bitter metallic taste was reported by 58% of patients who received azelastine therapy.

Lipworth, BJ; Clark, RA; Dhillon, DP; Brown, RA; McDevitt, DG

doi: 10.1111/j.1365-2125.1988.tb05292.xpmid: 2849969

1. Fourteen asthmatics (mean +/‐ s.e. mean baseline FEV1 62 +/‐ 6% of predicted) were given cumulative doubling doses of salbutamol by metered‐dose inhaler as follows: 100 micrograms, 200 micrograms, 500 micrograms, 1000 micrograms, 2000 micrograms, 4000 micrograms. 2. Airways, tremor, haemodynamic and cyclic AMP responses were measured at each dose increment (made every 20 min). 3. There was a linear log dose‐ response relationship for each airways parameter (FEV1, VC, sGaw, FEF 50%). The plateau in the dose‐response curve was not reached within our dose range. These changes were also mirrored in cyclic AMP responses. 4. There was a wide range in maximum airways response expressed in terms of absolute increase over baseline (95% confidence intervals: delta FEV1 667‐1483 ml; delta VC 689‐1695 ml; delta sGaw 0.92‐4.50 s‐1 kPa‐1; delta FEF 50% 0.94‐2.15 l s‐1). Patients with a lower baseline showed a greater response in terms of percent increase in FEV1 (r = ‐ 0.83, P less than 0.001). There was however, no correlation between baseline airway calibre and the dose required for maximum bronchodilatation. 5. There were objective increases (mean +/‐ s.e. mean) in both heart rate (maximum delta HR of 14 +/‐ 5 beats min‐1 at 4000 micrograms) and tremor power (maximum delta Tr of 115 +/‐ 44% at 2000 micrograms). These were not dose limiting side‐effects as subjective symptoms were infrequent at higher doses. 6. Higher than conventional doses of salbutamol given by metered‐dose inhaler may produce a distinct improvement in airways response without significant side‐effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Gould, CA; Ollier, S.; Aurich, R.; Davies, RJ

doi: 10.1111/j.1365-2125.1988.tb05293.xpmid: 2905154

1. The antihypertensive efficacy of two different doses of the calcium antagonist felodipine was evaluated in patients with hypertension persisting despite beta‐adrenoceptor blocker therapy. Following a single‐blind placebo period of 4 weeks, patients were randomized to placebo (n = 36), felodipine 5 mg twice daily (n = 39) and felodipine 10 mg twice daily (n = 35) for another 4 weeks. beta‐adrenoceptor blocker therapy remained unchanged throughout the study. 2. Effects on blood pressure (BP) were evaluated after the first dose and after chronic dosing at 2 h after dosing and the end of the dosing interval (12 h). 3. Felodipine decreased systolic and diastolic BP by 30‐35/20‐ 25 mm Hg at 2 h. These decreases were similar after acute and chronic treatment. Twelve hours after dosing, decreases of 15‐20/10‐15 mm Hg were observed compared to 10/5 mm Hg on placebo, and half of the patients still had a controlled BP (supine diastolic BP less than 90 mm Hg). BP responses were rather similar for both doses of felodipine at 2 and 12 h. 4. Multiple regression analysis showed that both initial BP level and plasma felodipine concentrations were significant predictors of the BP response to felodipine, but age was not. 5. Adverse effects attributed to felodipine were mainly related to vascular symptoms (primarily flushing and ankle swelling); these occurred in about 30% of patients, and were pronounced in three patients (4%). 6. Felodipine is therefore highly effective in lowering BP of hypertensive patients on chronic beta‐adrenoceptor blocker therapy, with no evidence for a gradual lowering of the BP or for development of tolerance. Both initial BP level and plasma concentrations are better indicators of antihypertensive efficacy of this calcium antagonist than age.

Belz, GG; Essig, J.; Kleinbloesem, CH; Hoogkamer, JF; Wiegand, UW; Wellstein, A.

doi: 10.1111/j.1365-2125.1988.tb05294.xpmid: 2974715

1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day‐1), cilazapril (2, 5 mg day‐1), and a combination of both in a double‐blind cross‐over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose‐effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose‐ effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin‐stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found.

Hardy, BG; Bartle, WR; Myers, M.; Bailey, DG; Edgar, B.

doi: 10.1111/j.1365-2125.1988.tb05295.xpmid: 3207560

1. We studied the effects of pre‐treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double‐blind four‐ way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration‐response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side‐effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.

Reeves, PT; Hanrahan, P.; Edelman, J.; Ilett, KF

doi: 10.1111/j.1365-2125.1988.tb05296.xpmid: 3207561

1. The disposition of sulphadimidine (15 mg kg‐1 orally) was investigated in six chronic osteoarthritis patients (four slow and two fast acetylators) prior to and 4 days following intra‐articular administration of glucocorticoids. 2. The mean (+/‐ s.e. mean) renal clearance of sulphadimidine was increased from 0.03 +/‐ 0.01 to 0.07 +/‐ 0.02 ml min‐1 kg‐1 (P = 0.01) following the administration of intra‐ articular steroid. 3. Mean metabolic clearance and volume of distribution data were similar on the two study days. However, two of the slow acetylators showed marked increases (63% and 193%) in metabolic clearance following steroid treatment.