bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of beta‐adrenoceptor blockade on heart rate and physiological tremor in diabetics with autonomic neuropathy. A comparative study of epanolol, atenolol and pindolol.
Authors: Reid W , Ewing DJ , Harry JD , Smith HJ , Neilson JM , Clarke BF
Published: July 2012

Eight diabetics with autonomic neuropathy were given single oral doses of epanolol (200 mg), atenolol (50 mg), pindolol (5 mg) and placebo in a double‐blind randomised order at weekly intervals. Supine resting heart rate, physiological tremor and blood glucose were measured before, 2 and 4 h after dosing, and ambulatory heart rate monitored for 24 h. Supine resting heart rate was significantly lowered by atenolol both at 2 and 4 h, and increased on pindolol at 4 h. Heart rate was unaffected by epanolol compared with placebo. Heart rate during the ‘waking’ period (14.00‐23.00 h) was lower than placebo after epanolol and atenolol but unaffected by pindolol. During the ‘sleeping’ period (23.00 h‐08.00 h) heart rate was significantly increased by pindolol, lowered with atenolol and unaffected on epanolol. Pindolol significantly increased physiological tremor at 4 h. No differences were seen between epanolol, atenolol and placebo. Plasma glucose was significantly increased by pindolol 2 h after dosing. These results suggest that pindolol probably produces its partial agonist activity at both beta 1‐ and beta 2‐adrenoceptors, while the partial agonist activity of epanolol is beta 1‐selective. Despite abnormal cardiovascular reflex tests in these diabetics, the heart rate responses obtained in this study after beta‐adrenoceptor blockade were surprisingly normal, and suggest that the concept of ‘cardiac denervation’ in diabetes requires modification.
Adenosine‐induced respiratory stimulation in man depends on site of infusion. Evidence for an action on the carotid body?
Authors: Watt AH , Reid PG , Stephens MR , Routledge PA
Published: July 2012

Adenosine is an endogenous nucleoside which stimulates respiration in man and other mammals. In animals adenosine appears to initiate respiratory stimulation within the carotid body, but whether this is the site of action in man is not known. We administered adenosine by intra‐aortic infusion to 12 subjects undergoing cardiac catheterisation. When adenosine was infused at three sites proximal to the carotid circulation, minute ventilation was significantly higher than baseline values or those during adenosine infusion at a more distal site. These results support the hypothesis that adenosine‐ induced respiratory stimulation in man is mediated in the carotid body.
Sorbinil pharmacokinetics in male and female elderly volunteers.
Authors: Scott AK , Webster J , Petrie JC
Published: July 2012

Sorbinil pharmacokinetics were studied, following a single oral dose, in eight male and eight female healthy, elderly volunteers. Elimination half‐life tended to be longer in males than in females. There was no sex difference in AUC or renal clearance. The long elimination half‐ life of sorbinil in the elderly suggests that accumulation is likely to occur with chronic dosing.
Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers.
Authors: Walley TJ , Heagerty AM , Woods KL , Bing RF , Pohl JE , Barnett DB
Published: July 2012

Two studies of the pharmacokinetics and pharmacodynamics of intravenous nifedipine infusion were performed: the first, a randomised double‐ blind crossover study of nifedipine and its vehicle in eight subjects, the second a dose ranging study in nine subjects. Nifedipine pharmacokinetics did not vary with dose or duration of infusion up to 8 h, and are similar to those reported for other nifedipine preparations. Nifedipine increased heart rate and forearm blood flow and decreased blood pressure after bolus injection but not during prolonged infusion. The vehicle decreased blood pressure and increased forearm blood flow after bolus injection but not during prolonged infusion. It did not affect heart rate. The vehicle's haemodynamic activity has not been previously recognised and is of potential importance in the study of this and similar preparations of calcium antagonists.
Food increases the bioavailability of propafenone.
Authors: Axelson JE , Chan GL , Kirsten EB , Mason WD , Lanman RC , Kerr CR
Published: July 2012

The effect of food intake on the bioavailability of propafenone, a new antiarrhythmic agent, was evaluated by comparing its kinetics in 24 healthy volunteers in a fasted state and after a standard breakfast. With food, the maximum plasma drug concentration was reached earlier and was significantly increased. When data from ‘slow’ metabolizers were excluded, there was an average increase of 147% in the area under the concentration‐time curve (AUCo) following the standard breakfast. There was a significant correlation (r = 0.946) between [(AUCo fed ‐ AUCo fasted)/AUCo fasted] and propafenone intrinsic clearance in the fasted state. Food intake, however, does not appear to affect the bioavailability of propafenone in ‘slow’ metabolizers. Patients should be advised to take propafenone in a constant relationship to food to assure consistent bioavailability.
Quality of life during antihypertensive therapy: techniques for clinical assessment and evaluation.
Authors: Testa MA
Published: July 2012

Assessment of the impact of antihypertensive therapy upon the quality of life of the hypertensive patient can provide practical data associated with patient acceptance of therapy. For measurement purposes, quality of life is the organizing concept around which the major components relating to the patient's subjective evaluation of symptoms, functions and perceptions revolve. Substantive evaluation of quality of life involves the organization of psychometric items or questions which form the basic scales underlying these major components including, symptom distress, well‐being, vitality, depression, anxiety, work performance, sexual functioning, cognition and life satisfaction.
Rationale for combination therapy.
Authors: Hansson L
Published: July 2012

Cardiovascular morbidity and mortality is higher in treated hypertensive patients than in normotensive subjects of the same age, sex and from the same populations. A possible and logical explanation for this could be that arterial pressure in treated hypertensive patients usually is significantly higher than in matched normotensive subjects. For these reasons it would appear logical to identify a therapeutic goal in the treatment of hypertension: to obtain normotensive blood pressure levels. In order to obtain this goal, combined treatment with more than one antihypertensive drug would appear to be required. Therapeutic combinations consisting of an ACE‐ inhibitor plus a diuretic or an ACE‐inhibitor plus a calcium antagonist constitute two examples of antihypertensive drug combinations that would appear to offer potent antihypertensive efficacy and good tolerability.
Pharmacokinetics and biological effects of captopril and hydrochlorothiazide after acute and chronic administration either alone or in combination in hypertensive patients.
Authors: Giudicelli JF , Richer C , Mattei A
Published: July 2012

The pharmacokinetics of free unchanged captopril, total captopril and hydrochlorothiazide (HCTZ) were investigated in three groups of patients with moderate essential hypertension and normal renal function on the first and on the 45th days of an oral treatment with either captopril (50 mg once daily, n = 7) or HCTZ (25 mg once daily, n = 10) or their combination captopril 50 mg + HCTZ 25 mg once daily, n = 8. Simultaneously, the effects of the three treatments on plasma converting enzyme activity (PCEA) and plasma renin activity (PRA) were measured. Elimination half‐lives of total captopril after acute (7.8 +/‐ 2.3 h) or chronic (7.0 +/‐ 0.5 h) captopril dosing were similar to those of HCTZ after acute (6.5 +/‐ 1.0 h) or chronic (8.0 +/‐ 2.5 h) HCTZ dosing. Elimination half‐life of free unchanged captopril was 0.81 +/‐ 0.09 h after acute and 0.96 +/‐ 0.03 h after chronic captopril dosing. Addition of HCTZ to captopril induced no major change in free and total captopril pharmacokinetic parameters, in PCEA inhibition and in PRA increase (as they were determined after captopril alone) on acute as well as on chronic treatment. Addition of captopril to HCTZ induced no major change in HCTZ pharmacokinetic parameters and in PRA increase compared with those determined after HCTZ alone. Chronic treatment with captopril + HCTZ resulted, like chronic captopril treatment, in no accumulation of captopril, in no significant modification of free and total captopril pharmacokinetic parameters and of PCEA inhibition (as determined after acute administration) but led to a significant enhancement of the acutely induced increase in PRA. Chronic treatment with captopril + HCTZ resulted, like chronic HCTZ treatment, in no accumulation of HCTZ, in no significant modification of HCTZ pharmacokinetic parameters (as determined after acute administration) but also led to a significant enhancement of the acutely induced increase in PRA. Thus, the longer duration of the antihypertensive action of captopril + HCTZ as compared to that of captopril cannot be ascribed to a pharmacokinetic or biological interaction between captopril and HCTZ.
Comparison of once and twice daily administration of captopril plus hydrochlorothiazide on 24 h blood pressure levels.
Authors: Poggi L , Vaisse B , Bernard F , Drivet‐Perrin J , Sambuc R
Published: July 2012

The anti‐hypertensive effect of captopril 50 mg plus hydrochlorothiazide 25 mg, given once or twice daily, was investigated by 24 h monitoring in hypertensive patients in a controlled, randomized, double‐blind, cross‐over trial. Ten patients with blood pressure (BP) greater than 160 and/or 95 mm Hg after a 15 day placebo period, were randomly assigned to one of two treatments, in which they either received the combination once daily in the first month, twice daily in the second and once daily in the third (Treatment Group A) or twice daily in the first month, once daily in the second month and twice daily in the third month (Treatment Group B). The anti‐ hypertensive effect of the drug combination was assessed by 24 h monitoring using a Dinamap 845 to establish mean BP levels and circadian curves. After 1 month the twice daily administration was more effective than the once daily, but after 2 months, and throughout the third month, there was no difference in the anti‐hypertensive efficacy of the combination given either once or twice daily.
Captopril + hydrochlorothiazide 24 h ambulatory monitoring effects.
Authors: Asmar RG , Pannier BM , Hugue CJ , Laurent S , Safavian A , Safar ME
Published: July 2012

The purpose of this study was to evaluate over a 24 h period the antihypertensive effect of captopril 50 mg + hydrochlorothiazide (HCTZ) 25 mg once a day in mild to moderate hypertension. Ambulatory recordings over 24 h of the blood pressure using the Spacelabs system were performed, at the end of a 15‐day placebo period and after giving captopril + HCTZ for 45 days. Captopril + HCTZ significantly decreased (P less than 0.001) systolic and diastolic blood pressures for both the diurnal period (8 h to 22 h) and the nocturnal period (22 h to 8 h). No change in heart rate was observed. For further analysis, the mean hour values of blood pressure and heart rate were calculated. A constant decrease of the systolic and diastolic blood pressure throughout the 24 h was obtained after captopril + HCTZ without any change in heart rate and in nyctohemeral variations. The study provided evidence that, in patients with mild to moderate essential hypertension, captopril + HCTZ once a day decreased systolic and diastolic blood pressure all day long without any change in the heart rate and the blood pressure nyctohemeral cycle.
Captopril plus hydrochlorothiazide once daily normalizes 24 h blood pressure in patients with essential hypertension.
Authors: Meijer JL , Ardesch HG , Van Rooijen JC , de Bruijn JH
Published: July 2012

The hypotensive effect of captopril 50 mg twice daily and of captopril 50 mg + hydrochlorothiazide (HCTZ) 25 mg once daily was studied in 12 patients with mild to moderate essential hypertension, whose blood pressure was not normalized by captopril 25 mg twice daily alone. Both captopril 50 mg twice daily and captopril 50 mg + HCTZ 25 mg once daily caused a significant reduction of outpatient blood pressures as compared with placebo (P less than 0.001). Captopril 50 mg + HCTZ 25 mg once daily also reduced outpatient blood pressures significantly when compared with captopril 25 mg twice daily (P less than 0.01). Both captopril 50 mg twice daily and captopril 50 mg + HCTZ 25 mg once daily significantly reduced 24 h blood pressure (P less than 0.001) without disturbance of its normal circadian rhythm. This effect was more pronounced while on captopril + HCTZ. Captopril 50 mg + HCTZ 25 mg once daily normalizes 24 h blood pressure in most patients with mild to moderate essential hypertension, whose blood pressure is not controlled by captopril 25 mg twice daily alone.
Captopril in combination with hydrochlorothiazide: comparative efficacy vs perceived best therapy.
Authors: Holzgreve H , Osterkorn K , Runge J
Published: July 2012

An open, randomized, multicentre, comparative trial on 2128 patients with mild‐to‐moderate hypertension, treated with so‐called perceived best therapy or a combination of captopril plus hydrochlorothiazide (HCTZ), was conducted over a period of 10 weeks. Both regimens lead to significant blood pressure reductions within the initial 6 weeks, with a difference of 3 mmHg systolic and 2 mmHg diastolic in favour of the captopril plus HCTZ regimen as compared to the perceived best therapy. Both an increase in the daily dose of captopril in uncontrolled patients receiving initial treatment with captopril plus HCTZ and treatment with captopril plus HCTZ in uncontrolled patients receiving the perceived best therapy was followed by improved blood pressure control. There were more withdrawals mainly due to side effects and non‐ compliance in the captopril plus HCTZ group as compared to the perceived best therapy group. By contrast, there were fewer side effects and a tendency towards a more pronounced improvement of complaints and general well‐being in the captopril plus HCTZ group. The study has yielded no clear evidence of an increased number of side effects known to be associated with captopril. Changes of the treatment regimen and dosages according to diastolic blood pressure during the study are difficult to achieve in a study of this type and size.
Studies on the effects of angiotensin II on human chorionic plate arteries and their modification by a calcium antagonist, nitrendipine.
Authors: Odum CU , Pipkin FB
Published: July 2012

1 Six‐point concentration‐response curves were initially established for the contractile effect of angiotensin II (AII), at final concentrations of 10(‐11) to 10(‐6) M, on helically‐cut strips of human chorionic plate arteries. The strips were then randomly allocated to one of four treatment groups: a control group and three treatment groups (n = 10 in each group) which were exposed to carrier or nitrendipine 10(‐11), 10(‐10) or 10(‐9) M final concentration respectively, before the establishment of second concentration‐response curves. 2 The initial responses of the tissues to AII were very similar in the four treatment groups with median EC50s ranging between 2.51 × 10(‐10) and 4.04 × 10(‐10) M (P greater than 0.8). The addition of nitrendipine was associated with significant (P less than 0.005) dose‐ related inhibition of AII‐induced contractions. The median EC50 of the control group during the second half of the experiment was 1.77 × 10(‐7) M, while that of the 10(‐11) M nitrendipine treatment group was 2.16 × 10(‐7) M. The EC50 for the other treatment groups could not be calculated from the curves due to the markedly blunted responses. 3 It is thus suggested that nitrendipine might be effective in vivo in the relief of vasospasm of the placental vascular system in pregnancy‐ induced hypertension.
Enprofylline disposition in the presence and absence of amoxycillin or erythromycin.
Authors: Sitar DS , Aoki FY , Hoban DJ , Hidinger KG , Montgomery PR , Mitenko PA
Published: July 2012

1 The kinetic disposition of a novel xanthine bronchodilator, enprofylline, was determined in young healthy male volunteers in the presence and absence of amoxycillin or erythromycin. These data were compared to those derived from a similar study of theophylline disposition in the presence and absence of erythromycin. 2 Erythromycin inhibited theophylline disposition only in those subjects in whom the control kinetic study was done after antibiotic ingestion, but the effect was modest. Erythromycin had no effect on enprofylline disposition. 3 Amoxycillin reduced the renal clearance of enprofylline, but the change was not statistically significant.
The pharmacokinetics of sustained release tiaprofenic acid in elderly arthritic patients.
Authors: Hosie GA , Hosie J
Published: July 2012

Tiaprofenic acid is a non‐steroidal anti‐inflammatory drug which is highly protein bound and excreted mainly by the kidneys. Previous pharmacokinetic studies with tiaprofenic acid in conventional formulations in elderly arthritic patients have shown no evidence of accumulation of this drug over periods of up to 12 weeks. A sustained release formulation of the drug was given to 14 elderly arthritic patients over 4 weeks and plasma profiles obtained at the beginning and end of treatment over a 24 h period. Area under the curve (AUC), maximum plasma concentration (Cmax) and plasma concentration at 24 h (C24) were calculated and elimination half life (t1/2) was estimated. AUCs to infinity at week 0 were compared with AUCs to infinity at week 4 as a measure of drug accumulation. No significant differences were found for any of these parameters between the beginning and end of treatment. The mean t1/2 for both weeks was approximately 4.4 h. There was no evidence of any accumulation.
Thymoxamine: lack of antihistaminic effects in clinical doses in man.
Authors: Al‐Damluji S , Grossman A , Turner P , Besser GM
Published: July 2012

The purpose of this study was to investigate whether the alpha 1‐ adrenoceptor antagonist thymoxamine possesses antihistaminic activity in clinical doses in man, as has been reported on the guinea pig ileum in vitro. Five normal subjects were given on three separate occasions intravenous infusions of thymoxamine (0.15 mg kg‐1 loading dose followed by 0.15 mg kg‐1 h‐1), chlorpheniramine (1.5 mg loading dose followed by 1.5 mg h‐1) and normal saline (placebo). Intravenous bolus doses of histamine (1 and 2 micrograms kg‐1) were given after pretreatment with propranolol 10 mg to block the beta‐adrenoceptor agonist effects of the catecholamines released by the histamine injections. Histamine caused a dose‐dependent reduction of FEV1 and FVC that was antagonised by chlorpheniramine but not by thymoxamine, suggesting that thymoxamine has no antihistaminic activity in the doses used in man. Thymoxamine caused a small enhancement of the bronchoconstrictor effect of the lower dose of histamine. The relatively selective action of thymoxamine makes it a suitable agent for the investigation of alpha 1‐adrenoceptors.
Placebo does not lower ambulatory blood pressure.
Authors: Dupont AG , Van der Niepen P , Six RO
Published: July 2012

The effects of 4 weeks of placebo on clinic and on ambulatory blood pressure, measured non‐invasively using the Remler M 2000 portometer, were studied in 46 hypertensive patients who were included in three consecutive double‐blind randomized placebo‐controlled trials with antihypertensive drugs. Placebo significantly reduced clinic blood pressure, but had no significant effect on ambulatory blood pressure.
Ethanol and platelet intracellular free calcium concentrations.
Authors: Lees KR , Barr SM , Butters L , Rubin PC
Published: July 2012

The effect of 0.8 g kg‐1 absolute ethanol orally on platelet intracellular free calcium was assessed in a random order study in 24 normotensive subjects with an isocaloric control. Platelet calcium was measured 90 min and 12 h after treatment by the Quin 2 method. The study had 90% power of detecting a 16.5% change. After 90 min, breath ethanol was 37 +/‐ 9 micrograms 100 ml‐1, blood pressure was unchanged and heart rate rose slightly. Platelet calcium was unchanged by ethanol after 90 min or 12 h.
Chloroquine excretion following malaria prophylaxis.
Authors: Gustafsson LL , Lindstrom B , Grahnen A , Alvan G
Published: July 2012

Urinary excretion of chloroquine and its desethyl‐metabolite was monitored for up to 395 days after the last dose of oral chloroquine (300 mg base) taken once weekly for 10 weeks as malaria prophylaxis. Concentrations in plasma could be followed for up to 70 days after the last dose. A three exponential decay was applied to the urinary excretion data. The half‐life of the terminal phase varied from 45 to 55 days for chloroquine and from 59 to 67 days for the metabolite. Mean residence time was approximately 20 days for the parent compound and 35 days for the metabolite, indicating that the terminal phases are of less importance for the effective half‐lives.
The accuracy of a pharmacokinetic theophylline predictor using once daily dosing.
Authors: Chrystyn H , Mulley BA , Peake MD
Published: July 2012

1. The accuracy of a computer based pharmacokinetic prediction method based on Bayesian analysis has been evaluated for an oral show release form of theophylline. 2. In 83 patients from seven centres 24 h serum theophylline concentration‐time profiles were measured under a variety of circumstances. 3. Revised predictions of 24 h serum theophylline concentration profiles were generated by Bayesian analysis using single serum drug concentrations taken before, during and after the study days in different subgroups of those patients. Comparing the predicted and measured profiles the mean prediction error (bias) was 0.05 mg l‐1 for peak concentrations and 0.04 mg l‐1 for trough concentrations during once daily dosing. The corresponding root mean squared prediction errors (precision) were 2.59 and 1.17 mg l‐1, respectively. 4. This accuracy is considered more than adequate for clinical purposes. 5. The technique can be used with a variety of other drugs and can form a valuable part of a routine therapeutic drug monitoring service.
Calcium absorption and excretion in patients treated with verapamil.
Authors: Sjoden G , Rosenqvist M , Kriegholm E , Haglund K
Published: July 2012

1. The effect of verapamil on the intestinal absorption of calcium was studied using a single isotope technique. Serum calcium and urinary excretion of calcium in the urine were followed in nine patients during treatment with verapamil for 2 months. 2. A dose of 80‐120 mg (three times daily) resulted in a significant reduction of systolic and diastolic blood pressure. 3. There was no change in the intestinal calcium absorption (alpha) expressed as the fraction of given activity absorbed per hour (alpha = 0.82 +/‐ 0.19 vs alpha = 0.83 +/‐ 0.25; +/‐ s.d., NS) or of the excretion of calcium in urine (Ca/creatinine ratio 0.35 +/‐ 0.20 vs 0.31 +/‐ 0.33; NS). 4. Serum calcium was not significantly different before and during treatment (2.43 mmol l‐1 +/‐ 0.10 vs 2.47 mmol l‐1 +/‐ 0.14; NS). 5. This study demonstrates that verapamil, at doses recommended for clinical use, does not seem to affect the intestinal absorption of calcium, the serum calcium concentration or the excretion of calcium in urine.
Lack of effect of topical indomethacin on psoriasis.
Authors: Green CA , Shuster S
Published: July 2012

Topical 1% indomethacin had no effect on chronic stable plaque psoriasis in an open controlled study using subjective clinical scores nor in a randomised double‐blind inert base controlled study using both subjective and objective measurements of lesional response; nor did it initiate or affect the development of psoriasis after cold injury. Previous studies are reviewed and it is concluded that the evidence does not support the hypothesis which relates psoriasis to eicosanoids produced by lipoxygenase activity.
The effect of a new inotropic agent, DPI 201‐106, on systolic time intervals and the electrocardiogram in healthy subjects.
Authors: Ruegg PC , Nuesch E
Published: July 2012

1. DPI 201‐106 (DPI) is a novel inotropic agent, with Na+ channel agonistic action combined with a sensitization of contractile proteins to Ca++. In a double‐blind trial in healthy volunteers (n = 20) cardiovascular effects (blood pressure, heart rate, ECG) of single oral doses were studied. In addition systolic time intervals (STIs) were assessed in 10 of these subjects. DPI plasma concentrations were measured by h.p.l.c. 2. Preejection period was shortened by 14 ms (P less than 0.01) and 30 ms (P less than 0.01) 1 h after 30 and 60 mg, respectively, suggesting a dose‐dependent inotropic effect. Heart rate was slightly reduced after both doses. Mean blood pressure remained unchanged. 3. Corrected QT interval duration (QTc) was prolonged by a mean of 7 ms (NS) and 22 ms (P less than 0.001) 1 h after 30 and 60 mg, respectively. PQ and QRS intervals remained unaffected. 4. Peak plasma levels were attained at 1‐2 h and the terminal elimination half‐life was approximately 15 h. 5. It is concluded that DPI has positive inotropic and negative chronotropic properties which make it potentially useful for the treatment of heart failure.
Control of hypertension in elderly patients with felodipine and metoprolol: a double‐blind, placebo‐controlled clinical trial.
Authors: Freeling P , Davis RH , Goves JR , Burton RH , Orme‐Smith EA
Published: July 2012

1. Forty‐nine patients aged 65‐80 years, whose Phase V diastolic blood pressure (dBP) was above 95 mmHg after 4 weeks open treatment with metoprolol 50 mg twice daily were randomized to receive, double‐blind, the calcium antagonist felodipine (n = 32) 2.5 mg twice daily or placebo (n = 17) in addition to metoprolol for 2 weeks. If the dBP remained greater than 95 mmHg, the dose of felodipine or placebo was doubled for a further 2 weeks; if the dBP was still greater than 95 mmHg, the dose of felodipine was doubled again to 10 mg twice daily or the corresponding placebo dose given. The duration of the double‐blind period was 6 weeks, all patients receiving metoprolol 50 mg twice daily throughout. 2. At the end of the double‐blind period, the seated dBP was reduced from 103 +/‐ 5 (mean +/‐ s.d.) to 88 +/‐ 7 mmHg (P less than 0.001) by felodipine and from 105 +/‐ 100 +/‐ 11 mmHg (NS) by placebo. The differences between these reductions (P less than 0.01) and between the final dBPs (P less than 0.001) were significant. Eighty‐ nine per cent of patients receiving felodipine and 33% of those receiving placebo (P less than 0.001) had controlled (dBP less than or equal to 95 mmHg) BPs. Half (14/27 completing) of the patients receiving felodipine required 2.5 mg throughout; 9/27 needed 5 mg and 4/27 10 mg twice daily. Adverse events occurred with equal frequency in the two groups, but the profile was different.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of the airway response to eye drops of timolol and its isomer L‐714,465 in asthmatic subjects.
Authors: Richards R , Tattersfield AE
Published: July 2012

1. The inadvertent administration of timolol to asthmatic patients continues to cause occasional severe and even fatal attacks of asthma. The (R)‐enantiomer of timolol, L‐714,465, is four times less potent than timolol in reducing intraocular pressure in man. It is 49 times less potent than timolol on beta 2‐adrenoceptors in animals and 13 times less potent on the airways of normal subjects. These findings suggested that L‐714,465 might be a safer alternative for the treatment of glaucoma. 2. Ten subjects with mild asthma who bronchoconstricted to timolol eye drops (0.25 or 0.5%) were studied. Airway dose‐response curves to timolol (0‐2%), L‐714,465 (0‐4%), and placebo (methyl cellulose) eye drops were performed in a double‐blind randomised study in which airway response was measured as change in FEV1 and specific airway conductance (sGaw). 3. L‐714,465 and timolol caused dose dependent falls in sGaw and FEV1 with L‐714,465 being approximately four times less potent than timolol. The geometric mean dose ratio was 3.89 for FEV1 (95% confidence interval (CI) 1.7‐8.7) and 3.93 (95% CI 2‐ 7.8) for sGaw. Since the difference in potency is similar to the reported difference in potency of the two drugs on intraocular pressure we conclude that L‐714,465 would not have a greater safety margin than timolol. 4. After completion of the dose‐response study eight subjects inhaled ipratropium bromide (72 micrograms) and this caused an increase in FEV1 from 74% to 80% of baseline.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of nedocromil sodium, a new drug for the treatment of reversible obstructive airways disease, in human volunteers and patients with reversible obstructive airways disease.
Authors: Neale MG , Brown K , Foulds RA , Lal S , Morris DA , Thomas D
Published: July 2012

1. The plasma concentrations and urinary excretion of nedocromil sodium have been determined following single dose administration in six healthy volunteers dosed orally (1 mg kg‐1) and intravenously (0.2 microgram kg‐1 for 30 min). Similar parameters were measured in six volunteers and twelve asthmatic patients dosed by inhalation (4 mg). Multiple dose kinetic measurements were also made. 2. The intravenous data demonstrated that nedocromil sodium is a high clearance drug (10.2 +/− 1.3 ml min‐1 kg‐1). The data were fitted by a two compartment model with very rapid elimination from the central compartment (k10 = 0.088 +/− 0.021 min‐1; beta = 0.013 +/− 0.002 min‐1). 81% of the dose was excreted in the urine. 3. Oral absorption was low (2‐3% of the dose) and contributed negligibly to the plasma profile after inhalation. 4. After inhalation of single doses of 4 mg in volunteers and patients plasma concentration rose rapidly, plateaued and then fell monoexponentially with a half‐life of approximately 2 h. The data fitted a ‘flip‐flop’ model with two absorption components. The extent of absorption was up to 6% of the dose with less in patients. 5. After multiple dosing with 4 mg four times daily for 7 days in volunteers negligible accumulation was observed. The pattern was similar in patients treated with 4 mg four times daily after 1, 6 and 12 months.
Inhibition of artificially induced cough in man by bronchodilators.
Authors: Lowry R , Higenbottam T , Johnson T , Godden D
Published: July 2012

1. The antitussive properties of bronchodilators were evaluated in a total of 47 normal volunteers. 2. Cough was induced by inhalation of ultrasonically nebulized solutions of distilled water and hypotonic saline. 3. Inhaled fenoterol hydrobromide (360 micrograms; 20 volunteers) and inhaled ipratropium bromide (72 micrograms; 14 volunteers) both significantly reduced couch compared with placebo (P less than 0.01). Oral salbutamol sulphate (4 mg; 11 volunteers) and oral pirenzepine hydrochloride (50 mg; 14 volunteers) had lesser effects. 4. Cough inhibition correlated with a small but statistically significant degree of bronchodilatation as measured by specific airway conductance (sGaw) and forced expiratory volume in one second (FEV1) in six normal subjects studied with each treatment in a placebo controlled, double blind study (r = 0.67, P less than 0.001). 5. Small reductions in airway tone are associated with a reduced cough response elicited by inhaled ultrasonically nebulized distilled water.
Evaluation of a microcomputer program (OPT) for parameter optimisation in clinical pharmacokinetics: gentamicin and tobramycin.
Authors: Zantvoort FA , Wagenvoort JH , Derkx FH , Michel MF
Published: July 2012

1. Several nomograms and computer programs are available to aid in aminoglycoside dosing. 2. Due to the variability in the relationship between dosage and serum drug levels, monitoring through the acquisition of serum drug levels is mandatory. 3. All clinical data, including serum drug levels, are subject to errors. 4. The program we have evaluated, OPT, calculates the most likely set of pharmacokinetic parameter estimates for individual patients by applying Bayes' theorem and the principle of Maximum Likelihood Estimation. Through a feedback process all available data are used, taking possible errors into account. 5. Our study shows that OPT is able to predict serum aminoglycoside levels accurately in the routine clinical setting. It may thus contribute to the quality of aminoglycoside therapy.
Apparently normal phenytoin metabolism in a patient with phenytoin‐ induced rash and lymphadenopathy.
Authors: Maguire JH , Wettrell G , Rane A
Published: July 2012

A 10‐year old female on phenytoin therapy developed a rash and lymphadenopathy. H.p.l.c. assays of urinary metabolites indicated no differences in stereoselective metabolism of phenytoin to phenolic and dihydrodiol metabolites as compared with volunteers given the drug or with pediatric patients without adverse reactions. This suggests that no obvious difference in stereoselective metabolism of phenytoin to potentially toxic arene oxides exists between this patient and other patients on phenytoin. Our results are consistent with the hypothesis that differences in peripheral detoxication of phenytoin arene oxides and not differences in hepatic metabolism of phenytoin may be responsible for such adverse reactions.
Effects of graded oral doses of a new 5‐hydroxytryptamine/noradrenaline uptake inhibitor (Ro 15‐8081) in comparison with 60 mg codeine and placebo on experimentally induced pain and side effect profile in healthy men.
Authors: Stacher G , Steinringer H , Schneider S , Mittelbach G , Gaupmann G , Abatzi TA , Stacher‐Janotta G
Published: July 2012

1. Ro 15‐8081 (Hoffmann‐La Roche, Basle, Switzerland) is a novel mixed 5‐HT/noradrenaline uptake inhibitor producing potent antinociceptive effects in animal pain models. 2. In healthy man, two models with electrically and thermally induced pain, respectively, have been shown to reliably discriminate between the effects of opioid as well as of antipyretic analgesics and placebo. 3. This study investigated the effects of single oral doses of 10, 25, and 50 mg Ro 15‐8081 in comparison with 60 mg codeine and placebo on threshold and tolerance to electrically induced pain and on threshold to thermally induced pain. Furthermore, the effects on psychomotor function, self‐rated subjective feelings, and side effect profile were studied. 4. Twenty healthy males participated each in five experiments in which they received, in random double‐blind fashion, each of the treatments. Every experiment comprised two series of measurements before and twelve after drug administration, carried out at 30 min intervals. 5. Ro 15‐8081 produced marked elevations of threshold and tolerance to electrically and of threshold to thermally induced pain. The effects of all doses of Ro 15‐ 8081 were significantly superior to those of placebo. Threshold and tolerance to electrically induced pain were not affected differently by the three doses of Ro 15‐8081, whereas the threshold to thermally induced pain was elevated significantly more by 50 mg than by 10 and 25 mg Ro 15‐8081. 6. Codeine 60 mg had a more rapid onset of action and greater maximal effects than Ro 15‐8081.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypokalaemia and other non‐bronchial effects of inhaled fenoterol and salbutamol: a placebo‐controlled dose‐response study in healthy volunteers.
Authors: Scheinin M , Koulu M , Laurikainen E , Allonen H
Published: July 2012

1. The hypokalaemia‐inducing effects of two widely used inhaled antiasthmatic beta 2‐adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2. Each drug was administered in three different doses, 400, 600 and 800 micrograms, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 micrograms in 1 h). The treatments were given at 1 week intervals in random order in a single‐blind fashion. 3. The concentration of potassium in plasma was dose‐dependently reduced by both drugs with peak effects 75‐90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average +/‐ s.d. reductions of 1.13 +/‐ 0.32 and 0.67 +/‐ 0.25 mEq l‐1, respectively, after the highest doses, P less than 0.05). Concomitantly, decreases were noted in the amplitude of the T‐wave on the ECG. 4. The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic beta 2‐adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5. Plasma renin activity, noradrenaline in plasma and heart rate were also dose‐ dependently increased by the treatments, whereas blood pressure remained unaltered. 6. While the clinical significance of hypokalaemia induced by inhaled beta 2‐adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non‐bronchial effects.
The effect of angiotensin II on endogenous noradrenaline release in man.
Authors: Seidelin PH , Coutie WJ , Struthers AD
Published: July 2012

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg‐1 min‐1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.
Once daily amlodipine in the treatment of mild to moderate hypertension.
Authors: Webster J , Robb OJ , Jeffers TA , Scott AK , Petrie JC , Towler HM
Published: July 2012

1. The antihypertensive efficacy of once‐daily amlodipine was studied in a group of 30 patients with mild to moderate hypertension in a double‐blind, placebo controlled parallel group study. The dose range of amlodipine was 2.5‐10 mg daily titrated at 2 weekly intervals for a total treatment period of 8 weeks. 2. Amlodipine produced a significant reduction in blood pressure compared with placebo, the mean difference between baseline and 8 weeks (corrected for placebo effect) being 16/12 mm Hg supine, 14/4 mm Hg standing. 3. Blood pressure returned to baseline values during a terminal 4 week washout period on placebo. 4. There were no significant effects on heart rate. 5. Two patients experienced slight ankle oedema while receiving amlodipine 10 mg daily but the active drug was otherwise well tolerated. 6. Plasma concentration of amlodipine, sampled 24 h after the preceding dose, increased as the dose titration sequence was followed, averaging 2.5 ng ml‐1 on 2.5 mg, 4.9 ng ml‐1 on 5 mg and 10.5 ng ml‐1 on 10 mg.
Effects of silybin on histamine release from human basophil leucocytes.
Authors: Miadonna A , Tedeschi A , Leggieri E , Lorini M , Froldi M , Zanussi C
Published: July 2012

1. Effects of a naturally occurring flavonoid, silybin, on histamine release from human basophils were examined, in order to assess the potential utility in the treatment of allergic disorders. 2. The f‐met peptide and anti‐IgE‐induced histamine release was significantly (P less than 0.05) inhibited in a concentration‐dependent fashion. Conversely, no significant (P greater than 0.05) effect on calcium ionophore A23187‐induced histamine secretion was documented. The inhibitory activity was significantly (P less than 0.05) reversed by elevating extracellular calcium concentrations. 3. The anti‐allergic properties of silybin can be reasonably ascribed to a membrane‐ stabilizing activity, possibly related to an interference in calcium influx. These results indicate that an in vivo evaluation of the anti‐ allergic activity of silybin would be worthwhile.
Lack of effect of antacids on plasma concentrations of omeprazole given as enteric‐coated granules.
Authors: Tuynman HA , Festen HP , Rohss K , Meuwissen SG
Published: July 2012

Twelve male volunteers were studied after a single oral dose of 20 mg omeprazole given as enteric‐coated granules with and without concomitant administration of 10 ml of a potent liquid antacid (buffering capacity 56.6 mmol 10 ml‐1) under fasting conditions. No statistically significant differences were detected in median Cmax (0.41 approximately equal to 0.53 mumol l‐1), the geometric mean AUC (0.80 approximately equal to 0.81 mumol l‐1 h) or median tmax (1.25 h), with and without antacid.
Large arteries in hypertension: heterogeneous haemodynamic response to beta‐adrenoceptor antagonists with and without intrinsic sympathomimetic activity.
Authors: Simon AC , Levenson J , Pithois‐Merli I
Published: July 2012

1. Hypertension is associated with a distension of the large arteries and consequently a marked reduction in arterial compliance, which does not result merely from the mechanical effects of elevated arterial pressure but also from early functional and/or structural changes in the arterial walls. This suggests that one of the aims of antihypertensive therapy should be to reverse these arterial abnormalities in the hope of protecting the patient from the atherosclerotic complications of hypertension. 2. Studies have been carried out to compare the effects of equieffective antihypertensive doses of pindolol and propranolol on the arterial circulation in patients suffering from essential hypertension. After 3 months therapy pindolol produced a dilatation of the brachial artery with an increase in arterial compliance and blood flow. In contrast, propranolol, despite comparable antihypertensive effects, did not influence brachial artery circulation. 3. These different effects on the arterial circulation presumably reflect the differing pharmacological properties of the two beta‐adrenoceptor antagonists and suggest that the intrinsic sympathomimetic activity of pindolol may be responsible for the qualitative differences in the arterial responses to the two drugs. 4. The results reviewed here reveal that even when two drugs of the same class are used to treat patients with essential hypertension the effects of these agents on arterial haemodynamics can vary greatly and are unrelated to the degree of blood pressure lowering. Thus, pindolol, in contrast to propranolol, not only lowers blood pressure but also reverses some of the changes in arterial haemodynamics which are characteristic of hypertensive disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.
Authors: Macphee GJ , Mitchell JR , Wiseman L , McLellan AR , Park BK , McInnes GT , Brodie MJ
Published: July 2012

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg‐1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6 beta‐ hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady‐state concentration (90 +/− 6 mg 1(‐1)) well within the target range (50‐100 mg 1(‐1)) for the drug. 3 VPA pre‐treatment did not alter total CBZ area under the concentration‐time curve (AUC 0‐59 h) but did prolong CBZ elimination half life by 12% (P less than 0.01). AUC 0‐59 h for free plasma CBZ was 13% higher (P less than 0.02) and half‐life of unbound CBZ 16% longer (P less than 0.02) during VPA treatment. CBZ‐ 10,11 epoxide (CBZ‐E) levels (52%) and CBZ‐E/CBZ ratios (45%) were both elevated by concurrent VPA (P less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ‐related side effects were reported as more severe when VPA was also taken (P less than 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)
N‐acetylation phenotyping with dapsone in a mainland Chinese population.
Authors: Horai Y , Zhou HH , Zhang LM , Ishizaki T
Published: July 2012

1 The N‐acetylation of dapsone (DDS) was studied in 108 unrelated Chinese subjects residing in the mainland of China. 2 The frequency of slow acetylators determined using the plasma monoacetyldapsone to DDS ratio (MADDS/DDS, slow acetylators less than 0.30 and rapid acetylators greater than 0.35) at 3 h after an oral dose of DDS (100 mg) was 13.0% (14 of the 108 subjects) with a 95% confidence interval of 7.9 to 20.6%. 3 The mean plasma concentration of MADDS was about three times lower in the slow than in the rapid acetylators and there was a highly significant correlation (rs = 0.886, P less than 0.001) between plasma MADDS concentration and acetylation ratio. 4 Urinary acetylation ratios (MADDS/DDS) and cumulative urinary excretion of MADDS were significantly (P less than 0.001) lower in slow acetylators compared with rapid acetylators. In addition, there was a significant relationship (rs = 0.510 to 0.718, P less than 0.001) between plasma and urinary acetylation ratios. However, the distribution of the urinary acetylation ratio was not bimodal. 5 The urinary acetylation ratio after an oral dose of DDS is not a discriminative index for determining acetylation phenotype.
The effect of carbidopa and indomethacin on the renal response to gamma‐ L‐glutamyl‐L‐dopa in normal man.
Authors: Jeffrey RF , MacDonald TM , Marwick K , Lee MR
Published: July 2012

1. The renal response to gamma‐L‐glutamyl‐L‐dopa (gludopa, 25 micrograms kg‐1 min‐1) was investigated in seven normal male volunteers. The effects of oral carbidopa (100 mg) and indomethacin (100 mg) on the response to gludopa were studied in the same group. 2. Gludopa at this dose level produced a 900‐fold increase in urine dopamine excretion and caused a natriuresis and suppression of plasma renin activity with only minor effects on pulse rate and blood pressure. 3. Carbidopa inhibited the increase in dopamine excretion by 97% and abolished the renal actions of gludopa. 4. The increase in urine dopamine produced by gludopa was not altered by indomethacin and the urine sodium output was similar to that caused by gludopa alone. 5. Gludopa is an effective renal dopamine prodrug whose activity can be blocked by the dopa decarboxylase inhibitor carbidopa. The results with indomethacin suggest that dopamine and the prostaglandins form separate natriuretic systems in the kidney.
(+)‐sulpiride antagonises the renal effects of gamma‐L‐glutamyl‐L‐dopa in man.
Authors: MacDonald TM , Jeffrey RF , Freestone S , Lee MR
Published: July 2012

1. gamma‐L‐glutamyl‐L‐dopa (gludopa) was given by intravenous infusion to six healthy salt‐replete men on two occasions, with and without pretreatment with (+)‐sulpiride. 2. Gludopa increased sodium excretion, glomerular filtration rate and effective renal plasma flow whilst decreasing plasma renin activity. 3. (+)‐sulpiride had no significant effect on baseline natriuresis, renal haemodynamics or plasma renin activity, but significantly attenuated the rise in sodium excretion, glomerular filtration rate and effective renal plasma flow produced by gludopa. 4. (+)‐sulpiride abolished the acute fall in plasma renin activity seen with gludopa. 5. (+)‐sulpiride raised serum prolactin concentration but did not affect the ris in urine dopamine excretion rate caused by gludopa. 6. Gludopa exerts its renal effects by stimulating specific dopamine receptors which are principally of the DA1 subtype.