bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of the uptake and elimination of chloroquine in children with malaria.
Authors: Adelusi SA , Dawodu AH , Salako LA
Published: July 2012

1 Ten children with Plasmodium falciparum malaria were treated with 25 mg/kg chloroquine over 3 days and observed for 7 days. 2 Chloroquine was determined in the red blood cells and plasma, and the red blood cell/plasma chloroquine concentration ratio was correlated with the disappearance of the parasites from the blood. It was found that this ratio decreased with the disappearance of the parasites and remained almost steady after the parasites had disappeared completely from the blood. 3 The half‐life (t1/2) and the elimination rate constant of the ‘terminal’ elimination slope (lambda beta) of the plasma log concentration‐time curve were estimated to be 135.9 +/‐ 9.92 h and 0.005 +/‐ 0.001 h‐1 (s.d.) respectively. 4 The t1/2 and lambda beta calculated from the red blood cell log concentration‐time curve were not significantly different from the corresponding values calculated from the plasma log concentration‐time curve.
Nalidixic acid kinetics in renal insufficiency.
Authors: Cuisinaud G , Ferry N , Pozet N , Zech PY , Sassard J
Published: July 2012

1 A pharmacokinetic study of nalidixic acid (NA) and metabolites was carried out in 23 patients with differing renal function so as to determine the influence of renal insufficiency on the excretion and biotransformation rate of this antibacterial agent. Plasma and urine concentration of NA and of its 7‐hydroxy (HNA) and 7‐carboxy (CNA) derivatives were measured after a single oral administration. 2 Renal insufficiency did not markedly affect the renal clearance of NA while it significantly decreased the elimination rate of HNA, a compound which largely excreted into the urine. 3 Interestingly, CNA which could never be detected in the plasma of patients with normal renal function appeared in that of patients with renal insufficiency. Plasma concentrations of CNA and creatinine were positively related, and the amount of urinary CNA increased with the renal impairment. 4 These results suggest that HNA can still be biotransformed into CNA by the impaired kidney. Since CNA cannot be easily excreted in the urine of patients with renal insufficiency it is hypothesized that this compound back diffuses into the plasma. 5 Finally, the study of the urinary concentrations of NA and metabolites shows that a standard NA dosage can be used, at least in patients with mild renal insufficiency.
The acute effects of ethanol on acetanilide disposition in normal subjects, and in patients with liver disease.
Authors: McKay J , Rawlings MD , Cobden I , James OF
Published: July 2012

1 The effects of single doses (25 g and 50 g) oral ethanol on the disposition of acetanilide (50 mg/kg metabolic active mass) has been studied in normal subjects, and in patients with chronic non‐alcoholic liver disease. 2 In normal subjects, ethanol produced a dose‐dependent increase in acetanilide half‐life, and a decrease in acetenilide clearance. There was a significant correlation (rs = 0.71, P less than 0.01) between the 90 min blood ethanol concentration and the reduction in acetanilide clearance. 3 In patients with liver disease, ethanol produced a similar proportional change in acetanilide half‐life and clearance, but these were less consistent. Moreover, liver disease itself was associated with an increase in acetenilide half‐life, and a reduction in clearance. 4 It is concluded that single oral doses of ethanol, comparable to those consumed during social drinking, may inhibit some forms of microsomal oxidation and thus have important clinical implications.
Tiaramide–a new oral drug for the treatment of asthma.
Authors: Berkin KE , Kerr JW
Published: July 2012

1 TIaramide, an anti‐inflammatory drug, inhibits the action of mediators released from mast cells and has direct smooth muscle relaxant properties. It may therefore have a beneficial effect in asthma. 2 A double‐blind crossover trial comparing the bronchodilator activity of tiaramide and placebo over 16 days was undertaken in 13 patients with asthma. 3 Peak expiratory flow rate (PEFR) was recorded on three separate occasions every day and frequency of salbutamol aerosol usage was noted on a diary card. 4 During treatment with tiaramide the mean mid‐morning PEFR (362 1/min) was higher than mean PEFR on placebo (328) (P less than 0.001) as was the evening PEFR (378) compared with placebo (388) (P less than 0.001). 5 There was a significant reduction in daily use of the salbutamol inhaler whilst on tiaramide (1.8) compared with placebo (2.3) (P less than 0.05). 6. Tiaramide may be a useful addition to existing prophylactic treatment for asthma.
Nifedipine in the treatment of hypertension: report of a double‐blind controlled trial.
Authors: Bayley S , Dobbs RJ , Robinson BF
Published: July 2012

1 The effect of oral nifedipine has been examined in patients with hypertension in whom arterial pressure was not adequately controlled by the combination of a beta‐adrenoceptor antagonist (or alpha‐methyldopa) and a diuretic. 2 In 42 patients, nifedipine (10 mg capsules) was added to the existing therapy in a final dose of 20‐60 mg daily. Six patients had to stop the drug on account of side‐effects. In the 36 patients who continued treatment, arterial pressure fell by an average of 24/9 mmHg supine and 26/10 mmHg standing. 3 In 11 of these patients who subsequently completed a double‐blind, cross‐over, placebo controlled trial, nifedipine (30‐60 mg daily) was found to reduce arterial pressure by an average of 19/11 mmHg supine and 21/12 mmHg standing. 4 In all 11 patients who were changed to a sustained release preparation of nifedipine, control of arterial pressure was at least as good as it had been when taking the capsules.
Urinary excretion of aspirin.
Authors: Cham Elliot B , Dykman JH , Bochner F
Published: July 2012

Six human volunteers were each given single oral doses of aspirin (ASA) ranging from 300‐1,500 mg. The unchanged ASA excreted in the urine was proportional to dose and urinary pH. The mean percent (+/‐ s.d.) of dose excreted was 1.9 +/‐ 0.67. The clearance for ASA was 1.42 +/‐ 0.28 1/h. The rate of in vitro hydrolysis of ASA to salicylic acid in urine at 37 degrees C was 4 micrograms/min for an initial ASA concentration of 7.5 mg in 100 ml human urine.
Pharmacokinetics and plasma steady state levels of doxycycline in undernutrition.
Authors: Raghuram TC , Krishnaswamy K
Published: July 2012

1 The kinetics of doxycycline were studied in well nourished and undernourished male subjects. 2 The area under the curve after an intravenous dose was reduced and total body clearance was significantly elevated with a shorter/beta‐phase half life of the drug in undernourished subjects. 3 The percentage of total drug excreted in urine in 48 h and renal clearance of the drug were similar in both groups. 4 Plasma protein binding was significantly reduced and gamma‐ glutamyltransferase levels tended to be higher in the undernourished as compared to normals. 5 Increased total body clearance of the drug appeared therefore to be due to higher metabolism of drug in undernourished subjects. This increased metabolism is probably due to lower protein binding of the drug and/or induction of drug metabolism. 6 Plasma Cmin concentrations of doxycycline determined at steady state were lower in undernourished subjects. However, they were within the therapeutic range. 7 The observed alterations in kinetics of doxycycline therefore do not warrant a change in dosage regimen in undernourished subjects.
Differences of sympathomimetic and anticholinergic action of OH‐ maprotiline and its R (‐)‐enantiomer.
Authors: Schmidlin O , Gundert‐Remy U , Maurer W , Weber E
Published: July 2012

1 C 49802 B‐Ba and CGP 12103/A are the racemate and the R (‐)‐ enantiomer respectively of the hydroxylated derivative of the tetracyclic antidepressant maprotiline, which differed in their ability to block noradrenaline‐uptake and in their anticholinergic activity in animal models. 2 The sympathomimetic and anticholinergic activities of both substances were evaluated in eight healthy subjects and compared with the treatment with placebo and amitriptyline. 3 Heart rate, pupillary diameter, stimulated salivary flow rate and blood pressure were measured over a 15 h period keeping a very strict protocol. Plasma catecholamine levels were determined. 4 Saliva production was diminished following the administration of C 49802 B‐Ba, CGP 12103/A and amitriptyline. 5 A moderate, but significant increase in heart rate and mean arterial blood pressure in the recumbent position was observed when C 49802 B‐Ba was given. 6 The results in man are in agreement with the different activities found in animal experiments. 7 It can be concluded that the S (+)‐enantiomer which the racemate contains is more active than the R (‐)‐enantiomer as to the anticholinergic and the sympathomimetic property.
Oral piretanide in chronic renal failure.
Authors: Henderson IS , Beattie TJ , Kennedy AC , Dombey SL
Published: July 2012

1 The effects of high doses of piretanide, a new diuretic agent chemically related to frusemide and bumetanide were evaluated in twelve patients with severe chronic renal insufficiency (creatinine clearance below 25 ml/min). 2 Patients received either 30 mg or 60 mg piretanide orally after a water load of 11. Urine volume and the excretion of electrolytes, creatinine, urea and uric acid were measured over the subsequent 24 h. 3 Piretanide produced an effective diuresis and natriuresis in these patients, its action being broadly similar to those of bumetanide and frusemide observed in previous studies.
Effects of cold exposure on blood pressure, heart rate and forearm blood flow in normotensives during selective and non‐selective beta‐ adrenoceptor blockade.
Authors: Houben H , Thien T , Wijnands G , Van't Laar A
Published: July 2012

Haemodynamic effects of a cold pressor test (foot immersion for 6 min in water at 5 degrees C) without medication and after the non‐selective beta‐adrenoceptor blocker propranolol and the selective beta‐ adrenoceptor blocker metoprolol were studied in 17 volunteers. In the control study as well as in the study with the beta‐adrenoceptor blockers cold exposure caused comparable changes, namely a blood pressure rise and a reduction of forearm blood flow. The increase in heart rate during cold exposure was clearly and equally reduced by both beta‐adrenoceptor blockers. Plasma noradrenaline rose significantly by 47%, plasma adrenaline did not change. It is concluded, that as to this kind of stress, beta 1‐selective‐adrenoceptor blockade confers no important advantage over non‐selective beta‐adrenoceptor blockade.
Racial differences in response to low‐dose captopril are abolished by the addition of hydrochlorothiazide.
Authors: Silberbauer K , Stanek B , Templ H
Published: July 2012

1 In a randomised study, 475 men with diastolic blood pressures of 92‐ 109 mm Hg received either placebo or captopril 37.5 mg, 75 mg or 150 mg/day for 7 weeks. 2 After 7 weeks patients taking placebo were given hydrochlorothiazide 25 mg twice daily, as were two‐thirds of each group taking captopril and they were observed for 7 additional weeks. 3 Captopril reduced blood pressure by 12.2 +/‐ 0.8/9.4 +/‐ 0.4 mm Hg at 7 weeks (n = 323) and captopril plus placebo reduced it by 10.3 +/‐ 1.9/10.2 +/‐ 0.9 mm Hg at 14 weeks (n = 83); placebo by 2.0 +/‐ 1.7/3.4 +/‐ 0.8 mm Hg (n = 76); and captopril plus hydrochlorothiazide by 24.4 +/‐ 1.1/16.2 +/‐ 0.6 mm Hg (n = 173). The effect of low‐dose captopril was similar to that of high doses. 4 White patients responded better than blacks, with a blood pressure reduction of 14.7 +/‐ 1.1/10.7 +/‐ 0.6 mm Hg (n = 170) v 9.1 +/‐ 1.2/8.0 +/‐ 0.7 mm Hg (n = 151). This difference was abolished by the addition of hydrochlorothiazide. 5 Only 15/384 (3.9%) of patients were dropped from the study because of adverse effects. 6 The prescription of low‐dose captopril might be extendable to patients with mild to moderate hypertension.
Long‐term captopril therapy in severe refractory congestive heart failure.
Authors: Steingo L , Pocock WA , Flax H , Stein M , Barlow JB
Published: July 2012

1 The favourable haemodynamic effects of captopril in patients with congestive heart failure have been reported. 2 We have treated 25 patients with severe chronic congestive heart failure with captopril in doses of 75‐450 mg daily. Before entering the study all patients remained in New York Heart Association functional class IV despite high‐ dose diuretic and vasodilator therapy. 3 Mean cardiothoracic ratio was 60%, and all patients had a shortening fraction of 18% or less on echocardiography (normal 25 to 40%). 4 Five patients died within one month of captopril and five between four and seven months, three of whom had improved to class IIM and one to IIS before death. 5 Of the 15 survivors one was referred for a heart transplant when he had improved to class IIM. The remaining 14 patients were followed for 8‐16 months. Ten improved to New York Heart Association class I or IIS and four to class IIM or III. Diuretic requirements were decreased considerably in all 14. Side effects were common but captopril did not have to be withdrawn. Captopril is a highly effective drug in the treatment of patients with congestive heart failure refractory to currently accepted therapy.
Clinical and haemodynamic responses to captopril and hydralazine in chronic congestive heart failure: the importance of preload reduction.
Authors: Fitzgerald DJ , O'Callaghan WG , O'Malley K , Horgan J , O'Brien E
Published: July 2012

1 Although many vasodilators are effective in the treatment of severe congestive heart failure, there have been few comparative studies of these drugs. We compared the acute haemodynamic effects of captopril and hydralazine in 11 patients with congestive cardiac failure unresponsive to diuretics and digoxin. Both drugs increased resting cardiac index, although this effect appeared more pronounced for hydralazine (33% v 23%). Captopril reduced pulmonary capillary wedge pressure (‐8 mm Hg, p less than 0.01) which decreased only slightly on hydralazine. 2 Long‐term treatment was then started on the dose found effective during acute administration. Each drug was given for eight weeks. Exercise tolerance improved with both drugs, the increase during the hydralazine phase correlating with the increase in cardiac index at rest (r = 0.75; p less than 0.05). Clinical improvement appeared more definite on captopril than on hydralazine, however. This improvement was maintained during the captopril phase only in those patients who had a greater than 25% reduction in pulmonary capillary wedge pressure in the acute study.
Short and long‐term effects of treatment with low dose captopril in patients with severe congestive heart failure.
Authors: Dahlstrom U , Karlberg BE
Published: July 2012

1 In an open study the clinical short‐term and long‐term effects of low‐ dose captopril (mean daily dose 45 +/‐ 15 mg) were evaluated in 20 patients with severe congestive heart failure refractory to conventional treatment with digitalis and diuretics. 2 After two weeks' treatment 16 out of 20 patients showed an improvement in New York Heart Association functional class, followed by a significant reduction in body weight and heart volume. The ratio between urinary sodium and potassium excretion was significantly increased and the urinary aldosterone excretion was significantly decrease. In 10 of the patients the initial effects were sustained during long‐term treatment (6 +/‐ 2 months). 3 In conclusion, captopril may be a useful therapeutic adjunct for the long‐term treatment of patients with severe heart failure or when conventional treatment has failed.
A comparison of the effects of chlormezanone and nitrazepam on sleep.
Authors: Adam K. , Oswald I.
Published: July 2012

1 Twelve volunteers, of mean age 60 years, took part in a double‐blind, balanced cross‐over study, to compare effects of chlormezanone 400 mg and nitrazepam 5 mg on electrophysiologically‐recorded and subjectively‐ rated sleep. 2 In the first week of administration nitrazepam caused a significant shortening of the time to fall asleep, but following withdrawal subjects took longer to fall asleep than during the baseline period. 3 Both chlormezanone and nitrazepam initially caused increase of sleep duration and less interruption of sleep by wakefulness. By the third week, for chlormezanone this effect was no longer significant, and for nitrazepam there was a significant decline in the effect. There was no statistically significant difference between the two drugs for these measures. 4 The drugs differed little in their effects on the amount of the various sleep stages, except that nitrazepam significantly reduced the duration of slow wave sleep, whereas chlormezanone had no significant effect on slow wave sleep. Both drugs reduced the amount of REM sleep in the first 6 h of sleep but only nitrazepam reduced the percentage of the time spent in REM sleep of the whole night. 5 Subjects' own ratings of sleep quality showed that both of the drugs improved sleep, but following withdrawal it was only after nitrazepam that there was impairment of the quality of sleep. Neither drug affected subjective alertness in the morning.
The influence of food on the oral and intravenous pharmacokinetics of a high clearance drug: a study with labetalol.
Authors: Daneshmend TK , Roberts CJ
Published: July 2012

1 The effects of food on the pharmacokinetics of orally and intravenously administered labetalol were assessed in six healthy volunteers. 2 Food caused a 38% increase in the mean systemic bioavailability of labetalol: from 0.26 +/‐ 0.03 (mean +/‐ s.e. mean) to 0.36 +/‐ 0.05 (P less than 0.05). 3 Food caused 20% increases in the volume of distribution of labetalol: (from 567 +/‐ 63 to 685 +/‐ 76) and in plasma clearance (from 1923 +/‐ 417 to 2344 +/‐ 566 ml/min. These changes did not reach statistical significance. Food did not alter the plasma half‐life of labetalol after oral or intravenous dosing. 4 Food appears to increase labetalol bioavailability by decreasing its first pass metabolism. It is suggested that this change results from transient alteration of hepatic blood flow. The drug should therefore be taken at a standard time in relation to meals to minimise intraindividual variation in bioavailability.
Reversal of clonidine induced miosis by the alpha 2‐adrenoreceptor antagonist RX 781094.
Authors: Clifford JM , Day MD , Orwin JM
Published: July 2012

Clonidine given i.v. at a dose of 0.1 mg and 0.2 mg was found to cause miosis in a placebo controlled double‐blind study in six healthy volunteers. In a further single‐blind placebo controlled study in three of these volunteers, the alpha 2‐adrenoreceptor antagonist RX 781094 at a dose of 0.1 mg/kg i.v. reversed the miosis induced by i.v. clonidine 0.2 mg. At a dose of 0.05 mg/kg the miosis was partially reversed.
A comparative study of saliva and serum paracetamol levels using a simple spectrophotometric method.
Authors: Adithan C. , Thangam J.
Published: July 2012

The relationship between saliva and serum paracetamol levels was investigated in ten healthy male volunteers. The salivary and serum paracetamol levels showed significant correlation with each other. The salivary and serum paracetamol concentration ratio was highly dependent on sampling time. The salivary and serum paracetamol half‐lives showed significant correlation with each other while the area under curve of paracetamol concentration in saliva and serum failed to show significant correlation.
Sustained release aminophylline in asthma and its interaction with rimiterol.
Authors: Monie RD , Rocchiccioli KM , White JP
Published: July 2012

Twenty chronic asthmatics who completed a double‐blind cross‐over study comparing sustained release aminophylline tablets with placebo had a significant improvement in airways obstruction. Inhaled rimiterol and the aminophylline tablets were shown to act in an additive manner. There was a significant reduction in asthmatic symptoms on active tablets. A further nine patients had to be withdrawn from the study because of adverse side effects.
Ipratropium bromide and fenoterol by aerosolized solution.
Authors: Jenkins CR , Chow CM , Fisher BL , Marlin GE
Published: July 2012

Ipratropium bromide (0.5 mg) and fenoterol (2 mg) produced equivalent peak bronchodilatation between 1 and 2 h after administration to eight patients with chronic partially reversible airways obstruction. The duration of action compared with saline was 6 h for ipratropium and 4 h for fenoterol. Both drugs in combination produced greater bronchodilatation than either drug alone. The increase in FVC was disproportionately greater than FEV1 with both drugs and saline, suggesting relief of obstruction of small airways.
The effects of cimetidine on serum calcium and parathyroid hormone levels in primary hyperparathyroidism.
Authors: Fisken RA , Wilkinson R. , Heath DA
Published: July 2012

1 Cimetidine has been reported to reduce serum calcium and parathyroid hormone (PTH) levels in primary hyperparathyroidism, but some studies have reported negative findings. 2 A double‐blind, controlled trial of cimetidine in this condition was, therefore, conducted. Eight patients were given cimetidine and placebo for 2 months each, in random order. Only one patient showed a significant fall in serum calcium on cimetidine and no patient showed a fall in PTH levels. 3 In addition, eight patients were studied during a 48 h continuous intravenous infusion of cimetidine. The first five patients exhibited no effect of the drug on either calcium of PTH levels, but in the sixth there appeared to be a dose‐dependent suppression of PTH. The seventh and eighth patients were, therefore, given a higher dose of the drug but it failed to suppress calcium or PTH values. 4 It is concluded that cimetidine is not of value in primary hyperparathyroidism.
The selectivity of the beta‐adrenoceptor for ventilation in man.
Authors: Butland RJ , Pang JA , Geddes DM
Published: July 2012

1 Minute ventilation, alveolar PCO2, CO2 production and heart rate were measured in eight normal subjects before and during infusions of noradrenaline 0.2, 1.0 and 5.0 micrograms min‐1 and isoprenaline 0.04, 0.2 and 1.0 microgram min‐1. 2 These measurements were repeated after propranolol 3.5 mg, atenolol 8 mg or metoprolol 7 mg by intravenous injection. 3 Noradrenaline 5.0 micrograms min‐1 and isoprenaline 1.0 microgram min‐1 significantly increased ventilation and CO2 production and decreased alveolar PCO2. These changes were attenuated by propranolol, atenolol and metoprolol. There was no significant difference between the blocking effects of the three beta‐adrenoceptor blockers for these three variables but propranolol was more effective than atenolol or metoprolol in blocking isoprenaline induced tachycardia (P less than 0.001). 4 The hyperventilatory response to catecholamines is predominantly a beta1‐effect.
Comparative pharmacological and pharmacokinetic observations on propranolol (long acting formulation) and bendrofluazide administered separately and concurrently to volunteers.
Authors: Nicholls DP , Harron DW , McAinsh J. , Castle WM , Barker NP , Shanks RG
Published: July 2012

1 The effect of long‐acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise tachycardia was studied in ten normal volunteers. 2 The preparations were given in random order, double‐blind, on three separate study weeks. Observations were made 0, 1, 3, 6, 8, 24, 33 and 48 h after drug administration. 3 The three preparations produced a significant reduction in exercise tachycardia up to 48 h after drug administration, and the effects of the three preparations were not significantly different from each other. 4 Following LA propranolol, LA propranolol and bendrofluazide, and the combined formulation the mean reductions in exercise heart rate 24 h after drug administration were 16.7 +/‐ 2.1%, 13.0 +/‐ 1.8% and 16.2 +/‐ 1.7% respectively. 5 Plasma levels of propranolol and bendrofluazide were measured at 0, 1, 2, 3, 6, 8, 10, 12, 24, 33 and 48 h after dose administration. 6 There was no significant difference in plasma propranolol levels, Cmax propranolol or AUCo‐x following the three preparations. The mean apparent t1/2 beta of propranolol after LA propranolol alone was significantly shorter than following the other two preparations (P less than 0.05), but this was not associated with a different pharmacodynamic response. 7 There was no significant difference in the pharmacokinetic parameters of bendrofluazide following the two preparations containing bendrofluazide. No bendrofluazide was detected in plasma after LA propranolol alone. 8 The new combined formulation produces similar pharmacodynamic and pharmacokinetic responses to LA propranolol and bendrofluazide given separately, and to LA propranolol given alone, and so may be of value in the treatment of hypertension.
The acute and chronic effect of oxprenolol and propranolol on peripheral blood flow in hypertensive patients.
Authors: Vandenburg MJ
Published: July 2012

1 The effects of oxprenolol and propranolol on peripheral blood flow were compared in patients with mild and moderate essential hypertension. 2 In an acute double‐blind crossover study in which eight patients participated there was a significant reduction in resting forearm blood flow (RFBF) 2 h after 80 mg propranolol (mean +/‐ s.e. mean) (‐0.87 +/‐ 0.13 microliter min‐1 100 g‐1) and after 80 mg oxprenolol (‐0.30 +/‐ 0.12) but not after placebo. This reduction was significantly greater after propranolol (P = 0.022). 3 Seven patients continued into a double‐blind crossover study comparing the above dose of the two drugs twice a day. On both the beta‐adrenoceptor blockers there was a significant reduction in blood pressure after 2 weeks of treatment and also a significant reduction in RFBF. 4 After 6 weeks treatment with propranolol the reduction in RFBF persisted and was significantly less (P = 0.04) than after 6 weeks treatment of oxprenolol, at which time RFBF was back to control. 5 There were no consistent changes in skin temperature. 6 Neither propranolol nor oxprenolol should be used in patients with severe peripheral vascular disease. 7 If beta‐adrenoceptor blockade is necessary in patients with mild peripheral vascular disease oxprenolol should be used in preference to propranolol but should be prescribed with caution.
LOW, SINGLE DAILY DOSES OF GUANFACINE IN THE AMBULATORY TREATMENT OF HYPERTENSION
Authors: JERIE P.
Published: July 2012

Low dose treatment with guanfacine was tested in three open‐field national studies (Belgium, France, West Germany) under general practice conditions.

Of 11,270 patients originally selected, 4,627 were evaluated after 6 weeks, 1,234 after 8 weeks and 3,504 after 12 weeks of treatment. The patients studied suffered from various forms of hypertension, classified from mild to severe. The patients' ages ranged from 16 to 93 years (mean 60 ± 12), the male/female ratio being 45: 55.

With daily doses of 1 mg and 2 mg, 85–92% of the patients were adequately controlled; in 58–70% the blood pressure was normalised. The mean reduction of both systolic and diastolic blood pressure was 16%. The heart rate did not show any significant change.

The most common side effects were dryness of the mouth (14–22% of all patients treated), drowsiness (in 5–9%), tiredness (in 3–12%) and dizziness (4–9.4%).

The results indicate that 1–2 mg guanfacine given once daily control BP in more than 80% of patients with mild to moderate hypertension when given as monotherapy and in moderate to severe hypertension when given in combination with a diuretic.

Guanfacine can be used safely in hypertensive patients with heart failure, renal failure, diabetes mellitus or coronary heart disease.
CLINICAL ASPECTS OF BLOOD PRESSURE CRISIS DUE TO WITHDRAWAL OF CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS
Authors: HANSSON L.
Published: July 2012

Sudden cessation of antihypertensive therapy, in particular centrally acting drugs such as clonidine, may cause a withdrawal syndrome characterised by a rapid increase in blood pressure, headaches, tremor, restlessness and nausea.

The withdrawal syndrome is associated with a marked increase in sympathetic activity, as indicated by the increased levels of urinary and plasma catecholamines.

The clonidine withdrawal syndrome is reproducible.

The crisis can be managed acutely either by reinstituting the drug which has been withdrawn or by giving α‐ and β‐adrenoceptor blocking drugs, either separately or in the form of labetalol.

The withdrawal syndrome can now be reproduced in animal models, but in spite of extensive studies, the exact underlying mechanism remains to be elucidated.
THE INFLUENCE OF GUANFACINE ON BLOOD PRESSURE AND LUNG FUNCTION IN HYPERTENSIVE PATIENTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE
Authors: WEVER A.M.J. , VAN BRUMMELEN P.
Published: July 2012

The effects of guanfacine, given once daily in dosages of 0.5‐3 mg, on blood pressure and lung function were investigated in a placebo controlled single‐blind trial in 10 patients with hypertension and chronic obstructive lung disease.

Six of the 10 patients also received a thiazide diuretic in an unchanged dose throughout the study.

Guanfacine lowered diastolic blood pressure to less than 95 mm Hg in 9/10 patients.

Lung function was not influenced by guanfacine.

A dry mouth was the most frequent side effect.
Changes in heart rate and forearm blood flow following intravenous boluses of isoprenaline in the presence of practolol and propranolol.
Authors: Arnold JM , Allen JA , Shanks RG , McDevitt DG
Published: July 2012

1 Increases in heart rate and forearm blood flow following graded intravenous bolus injections of isoprenaline sulphate, were measured in a double‐blind randomised study of six subjects who received either placebo, practolol 50 mg, practolol 200 mg, propranolol 10 mg or propranolol 40 mg. 2 Dose related increases in forearm blood flow were produced by the graded boluses of isoprenaline sulphate. 3 Practolol 50 mg attenuated the heart rate response to isoprenaline but did not significantly affect the changes in forearm blood flow. Practolol 200 mg further attenuated the heart rate responses but also decreased the forearm blood flow responses. 4 Propranolol 10 mg and propranolol 40 mg significantly attenuated both the heart rate and forearm blood flow responses. The effect on forearm blood flow tended to be greater than the effect on heart rate. 5 Practolol 200 mg had the same effect on heart rate responses as propranolol 10 mg but a significantly smaller effect on the forearm blood flow responses. 6 The measurement of forearm blood flow following intravenous bolus injections of isoprenaline provides useful information about the beta 2‐adrenoceptor antagonism of propranolol and practolol. However, application of the technique may be limited by the magnitude of the heart rate response and by the short‐lived nature of the increase in forearm blood flow.
A link between liver microsomal enzyme activity and thyroid hormone metabolism in man.
Authors: Ohnhaus EE , Studer H
Published: July 2012

1 The effect of different combinations of liver microsomal enzyme inducing drugs on thyroidal hormone steady state concentrations was investigated. Three groups of healthy volunteers were given daily either antipyrine 1200 mg together with phenobarbitone 100 mg, antipyrine 1200 mg combined with rifampicin 600 mg or rifampicin 600 mg alone for a period of 14 days. 2 Before and after each treatment the total body clearance of antipyrine, gamma‐glutamyl transferase (gamma‐ GT), 6 beta‐OH‐cortisol as in vivo parameters of liver microsomal enzyme activity were measured. In addition, thyroxine (T4), free thyroxine (FT4), T3 resin uptake, tri‐iodothyronine (T3) reverse T3 (rT3) and TSH were estimated. 3 After rifampicin administration there was a 60% increase in antipyrine clearance while following combinations of antipyrine‐phenobarbitone or antipyrine‐rifampicin an 80% and 128% increase respectively occurred. 4 A marked decrease of T4, FT4 and rT3 was seen in all groups while T3 remained stable in all groups investigated. This effect may be partly due to an increase in extrathyroidal metabolism of T4 as found previously by a kinetic turnover study using 125I‐T4. It also depends on the extent of the liver microsomal enzyme inducing capacity rather than on the nature of the drugs used. The striking disparity of liver enzyme induction of T4 and rT3 disposal on the one hand and T3 metabolism on the other is a unique phenomenon whose pathogenesis is not clear at the present time.
Protein binding of non‐steroidal anti‐inflammatory drugs in plasma and synovial fluid of arthritic patients.
Authors: Wanwimolruk S , Brooks PM , Birkett DJ
Published: July 2012

1 The protein binding of seven non‐steroidal anti‐inflammatory drugs (indomethacin, tolmetin, salicylic acid, ibuprofen, flurbiprofen, naproxen and GP53,633) and warfarin was investigated by equilibrium dialysis in simultaneous samples of synovial fluid and plasma from 12 arthritic patients. 2 The protein binding of all drugs studied except warfarin and flurbiprofen was significantly lower in synovial fluid than in plasma. 3 The decreased protein binding of these drugs is likely to explain the lower total drug concentrations found in synovial fluid in comparison to plasma. 4 The lower albumin concentration plays an important role in determination of reduced drug binding in synovial fluid compared to plasma and the fatty acid concentration in synovial fluid may also influence the protein binding of some of these drugs.
Effect of sodium acetyl salicylate on cholesterol saturation of fasting gall bladder bile, with and without chenic acid.
Authors: Kupfer RM , Northfield TC
Published: July 2012

The aims of this study were (a) to determine whether sodium acetyl salicylate by itself or in combination with chenodeoxycholic (chenic) acid would decrease the cholesterol saturation index (SI) of fasting gall bladder bile in man; and (b) to confirm prospectively that 8 mg kg − 1 day −1 chenic acid given at bedtime together with a low cholesterol diet reduces gall bladder bile SI to a level where consistent gallstone dissolution would be expected. Seven patients were studied on each of the following regimens given in random order for 1 month each: bedtime chenic acid alone 8 mg kg −1 day −1; sodium acetyl salicylate alone 600 mg four times daily; bedtime chenic acid together with sodium acetyl salicylate; no treatment. Gall bladder samples were taken by nasoduodenal intubation at the end of each regimen and SI determined. SI (mean +/− s.e. mean) on low cholesterol diet with no drug treatment was 1.14 +/− 0.06. On bedtime chenic acid 8 mg kg‐1 day‐1 plus low cholesterol diet it fell to 0.83 +/− 0.03 (P less than 0.05). Sodium acetyl salicylate did not alter gall bladder bile SI. 95% confidence limits for the effect of sodium acetyl salicylate on SI were +0.03 and − 0.05. We conclude that (a) sodium acetyl salicylate does not lower SI of gall bladder bile in man; (b) an adequate fall in SI for gallstone dissolution can be achieved with a reduced dose (8 mg kg‐1 day‐1) of chenic acid given at bedtime with a low cholesterol diet.
Standardised isoprenaline sensitivity tests‐a comparison of existent methods.
Authors: Arnold JM , McDevitt DG
Published: July 2012

1 Six healthy subjects (four male, two female, aged 19‐24 years) received intravenous boluses of isoprenaline sulphate by two standardised methods of injection (Cleaveland et al., 1972; George et al., 1972). Heart rate changes were analysed by three different methods. 2 The I25 (dose of isoprenaline required to increase the heart rate by 25 beats/min) was not significantly altered by either the method of injection or the method of heart rate measurement. 3 The slope of the heart rate dose response curve was significantly steeper when isoprenaline was injected in a fixed 2 ml volume through a three‐ way tap, and when the heart rate was measured from the shortest three R‐ R intervals. 4 However the differences in method of injection and heart rate measurement between the two techniques do not appear to produce major alterations in the results obtained, particularly the I25.
Acute effects of combined vasodilation and beta‐adrenoceptor blockade with prizidilol on renal function.
Authors: Boehringer K , Weidmann P , Link L , Bianchetti MG , Schiffl H , Reubi FC
Published: July 2012

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.
Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.
Authors: Eichelbaum M , Bertilsson L , Sawe J
Published: July 2012

Thirty‐five healthy subjects who had been classified as extensive or poor metabolizers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine. The clearance of antipyrine by the formation of 4‐hydroxy‐antipyrine and 3‐ hydroxy‐antipyrine respectively were closely correlated (r = 0.83, P less than 0.001) and both were significantly higher in smokers than in non‐smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations.
Human platelet phenolsulphotransferase M and P: substrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide.
Authors: Carter Bonham SM , Rein G , Glover V , Sandler M , Caldwell J
Published: July 2012

Human platelet phenolsulphotransferase exists in two functional forms. M and P. In this study the substrate specificity of the two forms has been further delineated by correlating activities in different individuals with various substrates. m‐Tyramine, noradrenaline, adrenaline, 5‐hydroxytryptamine, p‐hydroxyamphetamine, isoprenaline, salbutamol and l‐naphthol were all specific substrates for the M form of the enzyme. Paracetamol, a mixed substrate, was predominantly metabolized by the M form. Salicylamide at 5 microM was a substrate for the P form but became and M substrate at higher concentration. Phenol itself, a specific substrate for phenolsulphotransferase P at 10 microM, also became an M substrate at 1 mM concentration. These substrate specificities were confirmed with the selective inhibitor, dichloronitrophenol. In this study, we measured phenolsulphotransferase activity in platelets from 13 individuals selected on the basis of their wide variation in ability to sulphoconjugate paracetamol and salicylamide in vivo. There was no significant relationship between the in vivo pattern with either drug and the activity of platelet phenolsulphotransferase assayed with paracetamol or salicylamide respectively.
Effect of cephapirin on tubular reabsorption of amino acids, uric acid and beta 2‐microglobulin in man.
Authors: Arvidsson A , Alvan G , Borga O , Eklof R
Published: July 2012

Cephapirin, a beta‐lactam antibiotic, was administered intravenously to five healthy subjects in a dose of 1 g. Renal clearances of cephapirin, beta 2‐microglobulin, uric acid and amino acids were measured during the experiment and compared to timed control data, i.e. when no cephapirin was given. Renal clearance of cephapirin decreased when plasma concentrations declined. As protein binding of cephapirin is constant over a wide plasma concentration range, this finding may indicate that cephapirin is reabsorbed in the kidney by a saturable process. Renal clearance of endogenous amino acids, particularly those belonging to the basic group increased after cephapirin. There was no change in renal clearance of beta 2‐microglobulin which excludes a general toxic effect on tubular reabsorption of endogenous substances caused by cephapirin. A flow dependent increase of uric acid clearance was observed. Our results are suggestive of a competition between cephapirin and amino acids for some common step in the tubular reabsorption process.
Characterization of chloroquine plasma protein binding in man.
Authors: Walker O , Birkett DJ , Alvan G , Gustafsson LL , Sjoqvist F
Published: July 2012

Chloroquine protein binding was determined by equilibrium dialysis of purified plasma proteins and plasma samples from 20 healthy subjects and 14 patients with rheumatoid arthritis. The mean binding was 61 +/‐ 9% in plasma from healthy subjects (range 46‐74%) and 64 +/‐ 7% in plasma from rheumatoid arthritis patients (range 55‐79%). Albumin and alpha 1‐acid glycoprotein at physiological concentrations bound chloroquine to an approximately equal extent. Protein binding is unlikely to be an important determinant of chloroquine pharmacokinetics or response.
Lack of effect of ranitidine on the disposition of lignocaine.
Authors: Feely J , Guy E
Published: July 2012

Cimetidine has been shown to alter the disposition of lignocaine and other drugs that are highly extracted by the liver. In a placebo controlled study ranitidine (150 mg twice daily) did not alter the elimination half‐life, systemic clearance or distribution of lignocaine (mg/kg) in six healthy subjects. The interaction with cimetidine appears to be unrelated to histamine H2‐receptor antagonism.
Acute dose‐response studies in bronchial asthma with a new corticosteroid, budesonide.
Authors: Ellul‐Micallef R , Johansson SA
Published: July 2012

1 Budesonide is an epimeric mixture of a new synthetic non‐halogenated glucocorticoid (16 alpha, 17 alpha,‐(22R,S)‐prophylmethylenedioxypregna‐ 1,4‐diene‐11/3,21‐diol‐3, 20‐dione). 2 Acute dose response studies with three different inhaled doses of budesonide, have been carried out in a group of 12 chronic asthmatic patients. 3 The lowest dose (100 micrograms) of inhaled budesonide produced a more marked effect in relieving airflow obstruction, than a much larger (1600 micrograms) oral dose of the drug. 4 When the area under the curve for peak expiratory flow rate values was calculated, a dose‐response relationship could be seen between the different inhaled doses. 5 It appears that budesonide has a predominantly local anti‐asthmatic action in the lung.
Genetically determined oxidation capacity and the disposition of debrisoquine.
Authors: Sloan TP , Lancaster R , Shah RR , Idle JR , Smith RL
Published: July 2012

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the ‘extensive metabolizer’ (EM; n = 5) and ‘poor metabolizer’ (PM; n = 5) phenotypes. The 4‐ hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity‐limited and displayed significant dose‐dependency over a range of 1‐20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first‐order kinetics over a dose range of 10‐40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post‐dosing, and higher values for areas under the plasma concentration‐time curve (EM: 105.6 +/‐ 7.0 ng ml‐1 h; PM: 371.4 +/‐ 22.4 ng ml‐1 h, 2P less than 0.0001), neither debrisoquine plasma half‐ life (EM: 3.0 +/‐ 0.5 h; PM: 3.3 +/‐ 0.4 h) nor renal clearance of the drug (EM: 152.8 +/‐ 30.3 ml min‐1; PM: 137 +/‐ 4.5 ml min‐1) displayed significant inter‐phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a ‘metabolic ratio’ derived from a single 0‐8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre‐systemic elimination capacity.
Inhibition of food stimulated acid secretion by fenoctimine, a new anti‐ secretory agent.
Authors: Williams JG , Robertson RJ , Milton‐Thompson GJ
Published: July 2012

The effect of fenoctimine, a new anti‐secretory agent, has been studied on food stimulated acid secretion in six normal volunteers. When tested between 2 and 4 h after dosing, and compared with placebo, fenoctimine 50 mg inhibited acid secretion by a mean of 29%, 150 mg by 43% and 250 mg by 47%.
Prediction of optimum oral theophylline dose in patients with obstructive airways disease.
Authors: Taylor DR , Kinney CD , McDevitt DG
Published: July 2012

The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM, CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM, PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration‐time curve were used to establish DM, CALC for a concentration of 10 micrograms/ml. DM, PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained‐release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM, ACT). The correlation between C(6) and log DM, CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM, ACT was found to correlate significantly with DM, PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM, ACT corresponded satisfactorily to DM, PRED. In the remaining five, for whom DM, ACT lay outside the 95% confidence limits for the predicted dose, DM, PRED in general underestimated DM, ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM, PRED was lower than that for DM, CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.