bluuebunny/crossref_metadata_2025 huggingface dataset:
Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam.
Authors: Cohen AF , Ashby L. , Crowley D. , Land G. , Peck AW , Miller AA
Published: July 2012

Twelve healthy male volunteers received phenytoin 0.5 and 1 g, lamotrigine (a new anticonvulsant) 120 and 240 mg, diazepam 10 mg and placebo orally in a double‐blind, cross‐over, randomized trial. Maximum drug concentrations at 4 h, measured in plasma were 11.5 +/‐ 2.2 micrograms ml‐1 for phenytoin and 2.7 +/‐ 0.4 micrograms ml‐1 for lamotrigine. These levels were in the therapeutic range for phenytoin and the putative therapeutic range for lamotrigine. Side effects after diazepam (mainly sedation) and phenytoin (mainly unsteadiness) differed markedly from lamotrigine which produced no important side effects. Subjective effects as measured by visual analogue scales were caused by phenytoin and diazepam but not by lamotrigine. Diazepam impaired eye movements, adaptive tracking and body sway. Phenytoin impaired adaptive tracking, increased body sway and impaired smooth pursuit eye movement. Lamotrigine produced only a possible slight increase in body sway. There were significant correlations between performance and saliva levels of phenytoin and diazepam. It was concluded that the tests used were suitable for monitoring CNS effects of anticonvulsants and that lamotrigine possibly could have a more favourable CNS side effect profile than phenytoin.
Comparison of the effects of therapeutic doses of meptazinol and a dextropropoxyphene/paracetamol mixture alone and in combination with ethanol on ventilatory function and saccadic eye movements.
Authors: Ali NA , Marshall RW , Allen EM , Graham DF , Richens A.
Published: July 2012

The respiratory and psychomotor effects of a single oral dose of meptazinol (200 mg) and dextropropoxyphene (65 mg)/paracetamol (650 mg) mixture, was compared alone and in combination with ethanol (0.8 g kg‐ 1). Peak saccade velocity following meptazinol or the dextropropoxyphene/paracetamol mixture was not significantly different from placebo. When each of the treatments was followed by ethanol administration, a significant decrease in saccade velocity (P less than 0.01) was seen. Given alone, neither of the analgesic drugs produced a significant change in the slope of the ventilatory response to hypercapnia. Ethanol did not affect the ventilatory response to hypercapnia when given alone or in combination with meptazinol, but when given with the dextropropoxyphene/paracetamol mixture, a significant reduction in the slope of the ventilatory response to hypercapnia occurred at 1.5 h (P less than 0.05) and 2 h (P less than 0.01) after administration of the analgesic drug. No pharmacokinetic interaction was demonstrated between ethanol and meptazinol or the dextropropoxyphene/paracetamol mixture in the doses used. In contrast to meptazinol, the dextropropoxyphene/paracetamol mixture interacts with ethanol on the ventilatory function.
Terfenadine and placebo compared in the treatment of chronic idiopathic urticaria: a randomised double‐blind study.
Authors: Ferguson J. , MacDonald KJ , Kenicer KJ
Published: July 2012

Terfenadine, a potent and non‐sedative antihistamine, was shown to be effective in chronic idiopathic urticaria in a double‐blind crossover placebo controlled trial. An oral twice daily 60 mg dose of terfenadine was given and itch and wheal parameters were assessed daily. Despite the overall effectiveness of terfenadine, a variable response was noted which was similar to that shown in previous studies with other antihistamines.
Aminophylline and mucociliary clearance in patients with irreversible airflow limitation.
Authors: Pearson MG , Ahmad D. , Chamberlain MJ , Morgan WK , Vinitski S.
Published: July 2012

Were aminophylline to improve mucociliary function, it might prove useful in the management of irreversible airflow limitation. Eight subjects with irreversible airflow limitation due to emphysema inhaled an aerosol of 99mTc sulphur‐colloid particles on each of 2 days. On day 1 aminophylline was administered intravenously, while on the other nothing was given. Particle clearance was measured by recording posterior gamma‐camera images sequentially over a 24 h period. No significant differences were recorded between aminophylline and control studies, but there were marked variations in clearance between study days and between individuals. These differences were compatible with the known effects of airways obstruction and breathing pattern on the sites of particle deposition within the bronchial tree. The latter factors appeared to exert a far greater influence on the observed mucociliary clearance than did aminophylline.
Pharmacokinetics of ranitidine in acute upper gastrointestinal haemorrhage.
Authors: Varoquaux O. , Trawale JM , Doll J. , Andrieu J. , Grosbuis S. , Pays M. , Advenier C.
Published: July 2012

A pharmacokinetic study of ranitidine was performed in 14 patients with haematemesis divided into two groups according to the severity of blood loss. Pharmacokinetic values were calculated from plasma concentrations after the first of three daily injections (100 mg) and compared with those obtained in five healthy volunteers (50 mg i.v.). There were no significant differences between patients in the two haemorrhage groups and controls. The low, or even questionable, effectiveness of histamine H2‐receptor antagonists in the treatment of upper gastrointestinal haemorrhage does not seem to be due to pharmacokinetic factors.
Plasma concentrations, information and therapy adherence during long‐ term treatment with antidepressants.
Authors: Altamura AC , Mauri M.
Published: July 2012

The influence of information on drug plasma monitoring during long‐term antidepressant therapy in fourteen ambulant, depressed patients was evaluated as variation in the L/D ratio time course. A larger variability in L/D ratio, with higher coefficient of variation and a poorer clinical outcome, was found in non‐informed patients. The data support the hypothesis that verbal information on long‐term drug monitoring of antidepressants could improve patients' adherence to therapy.
Nicardipine in models of myocardial infarction.
Authors: Alps BJ , Calder C. , Wilson A.
Published: July 2012

In a dog model of partial myocardial ischaemia, superimposed ST segment elevations in epicardial ECGs were inhibited by nicardipine over a cumulative i.v. dose range of 1‐20 micrograms kg‐1. Over the cumulative i.v. dose range of 0.5‐166.5 micrograms kg‐1, nicardipine had little overall effect on gross cardiac conduction, at spontaneous heart rate. Dogs that received oral 1‐2 mg kg‐1 nicardipine daily for 16 weeks and then survived 1 week occlusion of the left anterior descending coronary artery (LAD) developed a superior coronary collateral circulation compared with untreated animals. Nicardipine given by three different dosing schedules to baboons markedly limited myocardial infarction over a 6 h period of LAD occlusion. Compared with a group of completely untreated dogs, there was protection of the myocardium in the animals given nicardipine that survived 3 months occlusion of the LAD.
Nicardipine hydrochloride in essential hypertension‐a controlled study.
Authors: Asplund J.
Published: July 2012

Fifty patients with mild essential (primary) hypertension entered a double‐blind, parallel‐group study with either nicardipine 30 mg three times daily or placebo, randomly assigned as monotherapy for 6 weeks. At the end of 6 weeks, the nicardipine‐treated group had a statistically significant reduction in mean supine systolic/diastolic pressure of 21.2/15.0 mm Hg (P less than 0.001) compared with the nonsignificant reduction of 0.7/2.9 mm Hg in the placebo‐treated group. The difference in mean response between the nicardipine‐ and placebo‐ treated groups was significant (P less than 0.001). In the nicardipine‐ treated group, the reduction in mean standing systolic/diastolic blood pressure, 17.9/13.8 mm Hg, was significant (P less than 0.001), whereas in the placebo‐treated group the change was +3.0/‐1.5 mm Hg. The difference between the two treatment groups was significant (P less than 0.001). In both treatment groups, changes in pulse rate were minor, and there was no evidence of tachyphylaxis occurring with nicardipine. Adverse experiences were minor in all cases except for one patient with muscle pain during treatment with nicardipine. Patients who received nicardipine showed a mean increase of 52% in plasma renin activity (PRA) after 6 weeks (P less than 0.01). Initial basal or stimulated PRA did not correlate with blood pressure reduction on nicardipine. Nicardipine 30 mg three times daily is a well‐tolerated and effective antihypertensive agent.
Anti‐hypertensive dose‐response effects of nicardipine in stable essential hypertension.
Authors: Taylor SH , Frais MA , Lee P. , Verma SP , Jackson N. , Silke B.
Published: July 2012

The dose‐response effects of oral nicardipine on the systemic blood pressure were examined in 54 patients with uncomplicated essential hypertension (DBP greater than or equal to 100 mm Hg). The study was designed in four sequential stages. A 2 week single‐blind placebo run‐ in period was followed by dose titration with nicardipine at 2 week intervals. Patients achieving the target DBP less than or equal to 95 mm Hg were then crossed over to placebo for 2 weeks, following which the previous dose of nicardipine was readministered for 6 weeks. Forty‐ eight patients completed the dose‐titration phase. The target DBP 95 mm Hg was achieved in 33; in eight after 10 mg three times daily, in 21 after 20 mg three times daily, in three after 30 mg three times daily and in one after 40 mg three times daily. In the 48 patients, systolic blood pressure was reduced from 188 +/‐ 25 to 158 +/‐ 21 mm Hg (P less than 0.001) and diastolic blood pressure from 111 +/‐ 9 to 93 +/‐ 13 mm Hg (P less than 0.001); heart rate increased from 81 +/‐ 7 to 87 +/‐ 13 beats min‐1 (P less than 0.01). Thirty‐one of the 33 patients completed the crossover to placebo, which was accompanied by a significant increase towards pretreatment blood pressure levels. Reinstitution of nicardipine at the previous dose resulted in a reduction of SBP and DBP to levels not significantly different from those at the end of the dose‐ titration stage.(ABSTRACT TRUNCATED AT 250 WORDS)
Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long‐acting rifamycin derivative.
Authors: Durand D Vital , Hampden C , Boobis AR , Park BK , Davies DS
Published: July 2012

The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. Administration of rifapentine (600 mg 48 h‐1) for 10 days resulted in a significant reduction in antipyrine half‐life (from 13.2 +/‐ 1.0 h to 7.7 +/‐ 0.4 h) and a corresponding increase in its total body clearance (from 41.8 +/‐ 5.5 ml min‐1 to 67.4 +/‐ 5.6 ml min‐1). Twelve days after stopping rifapentine administration, these values had largely returned to base‐line. 24‐Hour excretion of 6 beta‐ hydroxycortisol was significantly increased, by approximately three‐ fold, following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6 beta‐hydroxycortisol excretion had returned to pretreatment values. Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3‐hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.
D‐glucaric acid excretion in critical care patients‐comparison with 6 beta‐hydroxycortisol excretion and serum gamma‐glutamyltranspeptidase activity and relation to multiple drug therapy.
Authors: Heinemeyer G , Roots I , Lestau P , Klaiber HR , Dennhardt R
Published: July 2012

The incidence of increased drug metabolism activity as a consequence of multiple drug therapy at a surgical intensive care ward has been studied non‐invasively by determinations of daily urinary D‐glucaric acid (GA) excretion rates. Among 165 randomly selected patients, GA excretion was stimulated in 76 cases (= 46%). Exploratory data analysis showed that increases in GA excretion are primarily due to administration of barbiturates (pentobarbitone, Nembutal), miconazole (Daktar) and, to a lesser extent, neuroleptics. Surprisingly, the large number of simultaneously administered additional drugs failed to increase GA excretion. Urinary 6 beta‐hydroxycortisol (6 beta‐OHF) and 17‐hydroxycorticosteroid (17‐OHCS) excretion rates were correlated in 34 patients with GA excretion; patients not receiving known enzyme inducers showed low GA values but high 6 beta‐OHF and 17‐OHCS values, however, with a ratio of 6 beta‐OHF/17‐OHCS in the normal range. Patients receiving high dose pentobarbitone treatment failed to exhibit significantly increased 6 beta‐OHF and 17‐OHCS or 6 beta‐OHF/17‐OHCS values. Miconazole treatment resulted in a significantly increased ratio of 6 beta‐OHF/17‐OHCS. gamma‐Glutamyltranspeptidase activity in serum showed no correlation with GA excretion (n = 91).
A simple borohydride/GC method for measuring sparteine metabolites in man.
Authors: Inaba T , Vinks A , Otton SV
Published: July 2012

A simple borohydride/GC method was developed for phenotyping sparteine oxidation in man. The major metabolites of sparteine found in human urine, 2‐ and 5‐dehydrosparteine, were converted quantitatively back to sparteine by sodium borohydride reduction. The amount of sparteine metabolites can be estimated from the difference of sparteine concentrations between the borohydride‐treated and untreated urine samples. The coefficient of variation of this assay was estimated from repeated analyses to be +/‐ 3% within a day (intra‐assay) and +/‐ 8% between days (inter‐assay).
Domperidone treatment in man inhibits the fall in plasma renin activity induced by intravenous gamma‐L‐glutamyl‐L‐dopa.
Authors: Worth DP , Harvey JN , Brown J , Worral A , Lee MR
Published: July 2012

The dopamine pro‐drug gamma‐L‐glutamyl‐L‐dopa (gludopa) was administered intravenously to six normal subjects at a dose of 12.5 micrograms min‐1 kg‐1, either with or without the dopamine antagonist domperidone. A control was provided by the intravenous infusion of domperidone and saline on a separate occasion. Intravenous gludopa produced a significant natriuresis, whether administered alone or in combination with domperidone. After gludopa infusion, there was a significant fall in plasma renin activity, an effect which was attenuated significantly by concomitant treatment with domperidone. These observations suggest that blockade of renal DA2 dopamine receptors has little or no effect on gludopa‐induced natriuresis, but that at least part of the dopaminergic inhibition of renin release is mediated by renal DA2 receptors.
Transient bradycardia and subsequent sinus tachycardia produced by intravenous adenosine in healthy adult subjects.
Authors: Watt AH , Routledge PA
Published: July 2012

Adenosine was administered in increasing intravenous bolus doses to nine healthy volunteers. A transient decrease in heart rate was observed which occurred about 20 s after injection. This was due to a reduction in sinus rate and/or transient block of conduction through the atrioventricular node, and lasted less than 10 s. An increase in sinus rate which followed any transient bradycardia was also observed. The maximum bradycardia and maximum tachycardia were each significantly related to the logarithm of adenosine dose.
Captopril and opiate antagonism in essential hypertension.
Authors: Ajayi AA , Rubin PC , Reid JL
Published: July 2012

Six patients maintained on 50‐100 mg captopril, for 2‐25 months, were administered captopril 50 mg orally, together with either naloxone or 0.9% saline vehicle (placebo) given intravenously, in a double‐blind crossover study. Naloxone did not appear to modify the circulatory effects of captopril in these patients, in contrast to earlier findings after acute captopril administration in normotensives. The results do not support an important endogenous opioid role in the chronic antihypertensive effect of captopril, but provide evidence that different mechanisms may contribute to the early short term falls in blood pressure, compared to the later long term effects.
Antihypertensive effect of doxazosin in hypertensive patients: comparison with atenolol.
Authors: Baez MA , Garg DC , Jallad NS , Weidler DJ
Published: July 2012

The antihypertensive effect of doxazosin 1‐16 mg once‐daily was compared with that of atenolol 50‐100 mg once‐daily, and placebo, utilizing a double‐blind parallel group (12 patients each) design. Blood pressure (BP) and pulse rate were determined in out‐patients who returned for clinic visits every 2 weeks for 14 weeks. During the first 4 weeks, all patients received single‐blind placebo therapy. During the subsequent 10 weeks, patients were randomized to placebo, atenolol or doxazosin treatment. After 2 weeks of doxazosin therapy 16 mg daily, there was a significant decrease from baseline (single‐blind placebo period) in supine diastolic BP (P less than 0.01) and standing diastolic BP (P less than 0.001). The decreases in supine and standing diastolic BPs in the doxazosin 16 mg daily group were significantly (P less than 0.01) different from the corresponding BPs of the placebo group. At weeks 12 and 14, heart rates in the doxazosin group were not significantly different from baseline or from those in the placebo group. After 4 and 6 weeks of atenolol 100 mg daily, there was a significant decrease from baseline in both supine (P less than 0.001 and P less than 0.05) and standing (P less than 0.05) diastolic BPs and heart rates (P less than 0.05). However, when the atenolol group was compared with the placebo group, a significant decrease occurred only with supine diastolic BP at week 12 (P less than 0.01) and not at week 14; but significant decreases occurred in supine and standing heart rates at weeks 12 and 14 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Double‐blind comparison of the effects of long‐term treatment with doxazosin or atenolol on serum lipoproteins.
Authors: Lehtonen A , Himanen P , Saraste M , Niittymaki K , Marniemi J
Published: July 2012

The effects on plasma lipids and apoproteins A‐I and B of oral administration of doxazosin and atenolol over a 20‐week period were studied in 42 patients with mild to moderate essential hypertension. Total plasma cholesterol decreased by 8.9% (P less than 0.01) and LDL cholesterol by 16.9% (P less than 0.01) after 20 weeks' treatment with doxazosin. Total HDL cholesterol and HDL2 cholesterol concentrations increased slightly during doxazosin treatment and the increase in HDL2 level at 4 weeks was statistically significant (P less than 0.05). At 20 weeks, the levels of total HDL cholesterol and HDL2 were significantly (P less than 0.05) lower with atenolol than with doxazosin. The ratio HDL/total cholesterol increased during doxazosin treatment (P less than 0.05 at 4, 12 and 20 weeks). The HDL/total cholesterol ratio was significantly higher after 20 weeks with doxazosin than with atenolol (P less than 0.05). The levels of VLDL cholesterol and triglycerides increased significantly (P less than 0.01) during atenolol treatment. The concentrations of apoproteins A‐I and B did not change significantly during treatment with doxazosin or with atenolol but at 20 weeks the ratio of apo A‐I to apo B was significantly (P less than 0.05) lower with atenolol than with doxazosin. On the basis of these results, doxazosin would seem to have significant favourable effects on the serum lipid profile.
Once a day verapamil in essential hypertension.
Authors: Muller FB , Ha HR , Hotz H , Schmidlin O , Follath F , Buhler FR
Published: July 2012

Pharmacodynamic and therapeutic studies with a new slow release 240 mg verapamil formulation were performed in a total of 73 patients with essential hypertension (WHO I‐II, diastolic greater than or equal to 100 mm Hg). Chronic administration of slow release 240 mg verapamil, one or two tablets in the morning, resulted in 24 h plasma concentration profiles with trough levels greater than 40 ng ml‐1 in 14 of 16 patients and good 24 h blood pressure control. There was no correlation between plasma verapamil or norverapamil concentration and blood pressure response. Monotherapy with slow release verapamil was well tolerated and resulted in good blood pressure control (less than or equal to 95 mm Hg diastolic) in 46 of the 57 patients. Responses were best in older patients and those with low plasma renin or higher control blood pressure. Slow release 240 mg verapamil given once daily is a simple and effective regimen.
Combination therapy with beta‐adrenoceptor blockers and calcium antagonists.
Authors: Dargie HJ
Published: July 2012

Verapamil and nifedipine enhance the hypotensive and anti‐anginal effects of beta‐adrenoceptor blocking drugs. The combination of beta‐ adrenoceptor blocking drugs with nifedipine may pose fewer safety problems than the combination with verapamil especially in ischaemic heart disease when left ventricular function is suspect. Verapamil as a single agent may be as effective as a beta‐adrenoceptor blocking drug in angina and provide a suitable alternative. Careful supervision is required when verapamil is combined with beta‐adrenoceptor blockers for both angina and hypertension but reported clinical problems in hypertension are few.
Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.
Authors: Looareesuwan S , White NJ , Chanthavanich P , Edwards G , Nicholl DD , Bunch C , Warrell DA
Published: July 2012

Chloroquine diphosphate (3 mg base kg‐1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml‐1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/‐ s.d.) first order rate constant 0.65 +/‐ 0.14 min‐1, and an estimated apparent volume of the central compartment of 0.18 +/‐ 0.15 l kg‐1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/‐ 9.5 to 101 +/‐ 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/‐ 15 to 92 +/‐ 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.
The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects.
Authors: Bruce M , Scott N , Lader M , Marks V
Published: July 2012

The effects of single doses of anhydrous caffeine (250 mg and 500 mg) and placebo on physiological, psychological measures and subjective feelings were studied in a double‐blind, cross‐over study in nine healthy subjects who had abstained from caffeine‐containing beverages for 24 h before each occasion. Caffeine and caffeine metabolites in plasma and urine were assayed. Peak plasma concentrations were observed at 1 to 2 h with an approximate half‐life of 5 h. The concentrations of the metabolite 1,7‐dimethylxanthine increased during the 5 h. The major urine metabolite was 1‐methyluric acid. The EEG showed a dose‐related decrease in log ‘theta’ power and a decrease in log 'alpha' power. Other dose‐related effects were an increase in skin conductance level (sweat‐gland activity) and self rating of alertness. Ratings of headache and tiredness were decreased by the caffeine. The study illustrates the complexities of studying a drug which is widely taken and which is often associated with withdrawal effects.
Ethoxyresorufin O‐deethylation by human liver microsomes.
Authors: Williams FM , Mutch E , Woodhouse KW , Lambert D , Rawlins MD
Published: July 2012

As a substrate for human liver microsomes, ethoxyresorufin appears to be metabolised by a group of cytochrome P450 isoenzymes which are inducible by cigarette smoking. Kinetic studies in microsomes from four human livers indicate that only one enzyme component is involved over the full substrate range. Ethoxyresorufin O‐deethylation activity at both high and low substrate concentrations correlated with the high affinity component of ethoxycoumarin O‐deethylation and of diphenyloxazole metabolism.
Valpromide inhibits human epoxide hydrolase.
Authors: Pacifici GM , Franchi M , Bencini C , Rane A
Published: July 2012

The effect of antipileptic drug valpromide (VPM) on the activity of epoxide hydrolase was studied in human adult and foetal liver, kidneys, lungs, intestine and in placenta. The activity of the epoxide hydrolase was measured with both styrene oxide and benzo(a)pyrene‐4,5‐oxide as substrates. VPM inhibited the epoxide hydrolase obtained from all organs studied. The degree of inhibition was independent of the substrate used. A lowering of the epoxide hydrolase activity by 50% was observed when the concentration of VPM was similar to that of the substrates. VPM competitively inhibited the activity of adult liver epoxide hydrolase with styrene oxide as substrate.
Relationship between alpha 1‐acid glycoprotein and distribution of disopyramide and mono‐N‐dealkyldisopyramide in whole blood.
Authors: Bredesen JE , Kierulf P
Published: July 2012

The binding of disopyramide (DP) and mono‐N‐dealkyldisopyramide (MND) was measured by equilibrium dialysis in spiked whole blood (10 mumol l‐ 1 DP or MND) from 50 patients having a serum concentration of alpha 1‐ acid glycoprotein (AAG) ranging from 0.40 to 3.14 g l‐1, as well as in whole blood from five healthy subjects, spiked with different concentrations of AAG ranging from 0.61 to 3.33 g l‐1. The binding ratio (moles bound divided by moles unbound) in all samples increased from 1.0 to 8.0 for DP and 0.6 to 3.3 for MND with increasing AAG concentrations. The binding varied according to the AAG concentrations both in patients and healthy subjects. Similarly total and free plasma concentrations of DP and MND were also measured. With increasing AAG concentrations the total concentrations measured increased from 9.0 to 15.9 mumol l‐1 for DP and from 6.8 to 11.8 mumol l‐1 for MND whereas the free concentrations decreased from 3.8 to 0.5 mumol l‐1 for DP and from 5.0 to 2.0 mumol l‐1 for MND. With increasing AAG concentrations the whole blood/plasma concentration ratio decreased from 1.11 and 1.47 to 0.63 and 0.85 for DP and MND respectively. The ratio between their concentration in cells and the unbound concentration in plasma, however, was constant over the whole AAG concentration range. The mean ratios for all samples were 3.0 and 3.1 for DP and MND respectively, indicating that both compounds are bound or distributed to the blood cells. The distribution of the drugs in whole blood changed according to increasing AAG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Flecainide: single and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man.
Authors: Tjandra‐Maga TB , Verbesselt R , van Hecken A , Mullie A , De Schepper PJ
Published: July 2012

The kinetics of flecainide after single intravenous (2 mg kg‐1) and oral (200 mg) dosing, absolute bioavailability, effects of food and aluminium hydroxide on flecainide absorption and steady‐state kinetics following twice daily oral dosing (200 mg) have been evaluated in ten healthy subjects. Absolute bioavailability of oral flecainide averaged 70% (range 60‐86%). Rate and extent of flecainide absorption were not significantly affected by food nor by concomitantly administered aluminium hydroxide. The apparent volume of distribution of 5.5 +/‐ 0.3 l kg‐1 indicates wide distribution of flecainide in tissues. Estimated elimination half‐lives from plasma data averaged 9.3 to 12.4 h (single oral dose studies), 11.8 h (single i.v. dose), and 11.5 h (multiple oral dose). Half‐lives calculated from urinary excretion data corresponded well with those calculated from plasma data. Flecainide elimination takes place both by nonrenal (metabolic) clearance and renal excretion of the intact drug involving glomerular filtration and active tubular secretion. Following i.v. dosing CLNR and CLR averaged respectively 3.24 +/‐ 0.80 and 2.38 +/‐ 0.49 ml min‐1 kg‐1. After 200 mg twice daily oral treatment steady state was reached within 3‐4 days with trough and peak plasma levels on day 8 of 457 and 662 ng ml‐1, which are well within the therapeutic range.
Pharmacokinetics of intravenously administered haem arginate.
Authors: Tokola O , Tenhunen R , Volin L , Mustajoki P
Published: July 2012

The pharmacokinetics of haem were investigated after intravenous administration of a therapeutic dose of haem arginate (3 mg haem kg‐1) to four healthy volunteers and four symptomless porphyric patients. Plasma haem concentrations were measured also during a treatment course of four infusions in six patients with porphyria. Plasma haem concentrations declined monoexponentially over 48 h in both healthy volunteers and porphyric patients, with a mean +/‐ s.e. mean elimination half‐life of 10.8 +/‐ 0.6 h. Other kinetic parameters were also similar in the two groups, total plasma clearance was 3.7 +/‐ 0.4 ml min‐1 and volume of distribution was 3.37 +/‐ 0.34 l. In the multiple dose study the elimination half‐life increased significantly, from 11.3 +/‐ 0.4 h to 18.1 +/‐ 1.4 h over 4 consecutive days. Plasma haemopexin values decreased with time after a single haem arginate dose. The infusion of haem arginate did not cause thrombophlebitis.
A simple method for determining acetylator phenotype using isoniazid.
Authors: Hutchings A , Routledge PA
Published: July 2012

A comparison was made between the results of acetylator phenotyping by isoniazid (INH) half‐life measurements based on samples taken for 6 h after a single oral dose (200 mg), and by determination of the ratio of acetylisoniazid (Ac.INH) to isoniazid in the 3 h samples. In the 32 subjects, examined, there was complete agreement about classification of the subject as a fast (t1/2 less than 130 min; Ac.INH/INH greater than 1.5) or slow acetylator (t1/2 greater than 130 min; Ac.INH/INH less than 1.5). The single sample test appears to be as reliable as the more time‐consuming isoniazid half‐life method.
Effects of cimetidine and ranitidine on the pharmacokinetics of quinine.
Authors: Wanwimolruk S , Sunbhanich M , Pongmarutai M , Patamasucon P
Published: July 2012

The pharmacokinetics of orally administered quinine were determined in six normal volunteers before and after a 7‐day course of cimetidine (1 g day‐1) or ranitidine (300 mg day‐1). Peak plasma quinine concentration and the time of peak concentration were not altered after cimetidine or ranitidine pretreatment. After cimetidine pretreatment there was a significant reduction in the apparent oral clearance of quinine, from 0.182 +/‐ 0.063 (mean +/‐ s.d.) to 0.133 +/‐ 0.055 1 h‐1 kg‐1 (P less than 0.05). This was reflected in a 49% (range 17 to 90%) increase in the mean elimination half‐life from 7.6 +/‐ 1.3 to 11.3 +/‐ 3.7 h (P less than 0.05). In contrast to cimetidine, ranitidine had no significant effect on the clearance or half‐life of quinine. The apparent interaction between quinine and cimetidine may have therapeutic implications. Special care should be taken in patients taking these two common drugs concomitantly. Additionally, to avoid unnecessary risks due to drug interaction, the use of ranitidine may be preferable in the patients in whom it is desirable to administer an H2‐ receptor antagonist together with quinine.
The pharmacokinetics of sodium cromoglycate in man after intravenous and inhalation administration.
Authors: Neale MG , Brown K , Hodder RW , Auty RM
Published: July 2012

The pharmacokinetics of sodium cromoglycate in four healthy volunteers after slow intravenous infusion have been evaluated following measurement of plasma concentrations by radioimmunoassay. The results confirm earlier findings that sodium cromoglycate is rapidly eliminated from the body and that the data can be fitted to a two compartment open model. The pharmacokinetic parameters derived from the intravenous administration were used to evaluate the pharmacokinetics after inhalation administration via the Spinhaler. A model for absorption from the lungs is described which involves absorption at two different rates; this gives a better fit to the observed data than a single absorption rate. A fast absorption rate constant with a mean value of 0.54 min‐1 and a slower rate constant with a mean value of 0.0097 min‐1 were found. Of a mean total of 2.84 mg absorbed from a 20 mg inhaled dose, 0.68 +/‐ 0.15 (s.e. mean) mg were absorbed at the fast rate and 2.17 +/‐ 0.37 mg at the slower rate. These rates probably reflect absorption from different sites within the lungs. The results may have important implications for interpretation of clinical findings.
Steady‐state pharmacokinetics and effects of a new once‐daily, slow‐ release theophylline capsule preparation in asthma.
Authors: Williams PE , Alwazir YA , Routledge PA , Campbell IA
Published: July 2012

Plasma and saliva theophylline concentrations were measured in 21 asthmatic subjects receiving chronic oral therapy with a new sustained‐ release theophylline capsule (K1B Riker) given as a once daily dose, after titration to achieve a before‐dose concentration of 8 mg l‐1 or greater, or to the maximum dose of 1200 mg of theophylline daily. Plasma concentrations rose from a mean +/‐ s.d. minimum concentration (Cmin) of 7.9 +/‐ 2.3 mg l‐1 to a mean maximum of 13.6 +/‐ 3.3 mg l‐1 at a median time of 10 h after dosing. Saliva theophylline concentrations were closely related to the plasma theophylline concentration both between and within subjects with a mean saliva to plasma concentration ratio between subjects (S/P ratio) of 0.62 (+/‐ 0.05) and a mean within subject coefficient of variation of 8.2% (+/‐ 4.5%). There was a significant but small (10%) change in the mean S/P ratio during the dosing interval. Peak expiratory flow rate (PEFR) changed slightly but significantly during the dosing interval but forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) did not. The drug was well tolerated at the dose used (600‐1200 mg once daily).
Comparison of levocabastine, a new selective H1‐receptor antagonist, and disodium cromoglycate, in a nasal provocation test with allergen.
Authors: Kolly M , Pecoud A
Published: July 2012

The effect of intranasal administration of levocabastine, a new selective H1‐receptor antagonist, was investigated in a nasal provocation test (NPT) performed with allergens. The NPT allowed a quantitative estimation of the nasal allergic threshold (concentration of allergen necessary to trigger the reaction). In addition, the intensity of the three major rhinitis symptoms (obstruction, rhinorrhea and sneezing) was determined. Twelve adult patients, allergic to grass pollen, underwent a first NPT without pretreatment ('initial NPT'); the NPT was then repeated after the single intranasal administration of either placebo, 8 mg disodium cromoglycate (DSCG) or 0.2 mg levocabastine in a double‐blind random order. The NPTs gave reproducible results since both the threshold and symptom intensities were similar in the initial NPT and in the NPT performed after placebo. The reaction threshold increased in 8/12 patients after DSCG (0.05 less than P less than 0.1) and in 9/12 patients after levocabastine (P less than 0.05). Levocabastine clearly inhibited rhinorrhea (P less than 0.001) and sneezing (P less than 0.02) but did not influence the nasal obstruction. DSCG inhibited rhinorrhea only (P less than 0.01). The intranasal administration of levocabastine might be useful in the treatment of allergic rhinitis.
The effect of glucose on acetylation status.
Authors: Suhardjono D , Boutagy J , Shenfield GM
Published: July 2012

Forty‐nine healthy volunteers (47 male, 2 female) had their sulphadimidine acetylator status determined on a control day and on a second occasion when they were given an oral glucose load. They were classified as fast and slow acetylators using the standard urine method and as fast, slow and intermediate acetylators using calculated metabolic and total body clearances. Twenty‐seven (55%) were slow acetylators and this proportion was not altered by glucose loading either with or before sulphadimidine ingestion. On the control day, five (10%) were fast and 17 (35%) were intermediate acetylators but these sub‐groups were not clearly distinguishable from each other when glucose was given. The glucose load did not cause any individual to change from slow to fast categories. Two type 2 (insulin independent) diabetics also showed no difference in acetylator status when studied with widely different blood glucose concentrations. We conclude that glucose can induce minor increases in sulphadimidine clearance but is unlikely to alter phenotypic acetylation status. Previous observations of an increased incidence of fast acetylators in diabetics may therefore indicate a genetic marker.
Comparison of the analgesic effect of a corticosteroid and paracetamol in patients with pain after oral surgery.
Authors: Olstad OA , Skjelbred P
Published: July 2012

In a double‐blind crossover study identical oral surgical procedures were performed on two separate occasions in 24 patients. After one operation they were given capsules of methylprednisolone. A total of 84 mg was administered in decreasing doses for 4 days, starting with 24 mg 2 h after surgery. After the other operation 1 g paracetamol was given at 2, 6 and 9 h after surgery, then 500 mg four times daily for the next 2 days. Several measurements/assessments were recorded for paired comparisons of the postoperative courses. There was no significant difference in pain scores when comparing the two treatments. However, 3 and 4 h after the operation, there was a tendency towards better pain relief with paracetamol (P greater than 0.05). The results suggest that methylprednisolone, after a delay, may exert analgesic efficacy comparable to a standard regimen with paracetamol. On the third postoperative day methylprednisolone reduced measured swelling by 29% compared to paracetamol (P = 0.03). Overall preference scores evaluated the two treatments as equally efficient on the day of surgery. The first and second postoperative day the scores were in favour of methylprednisolone (P = 0.03). Present and previous results in this model suggest that corticosteroids deserve attention as a means of reducing both pain and inflammation after surgery and trauma.
The pharmacokinetics of dapsone after oral administration to healthy volunteers.
Authors: Pieters FA , Zuidema J
Published: July 2012

After oral administration of 100 mg dapsone (DDS) to 25 healthy volunteers peak serum DDS concentrations between 1.10 and 2.33 mg l‐1 were reached within 0.5 to 4 h. AUCs varied from 20.3 to 75.4 mg l‐1 h, while the elimination half‐lives ranged from 11.5 to 29.2 h. The apparent volumes of distribution were 0.84 to 1.26 l kg‐1 body weight, assuming complete bioavailability. Statistically significant differences in peak drug concentration, peak time and AUC existed between males and females. Absorption and elimination of DDS appeared to be faster than reported in other studies, suggesting differences in DDS kinetics between healthy volunteers and patients.
The plasma protein binding of basic drugs.
Authors: Routledge PA
Published: July 2012

The plasma protein binding of basic drugs appears to vary more than was at first assumed and is related to the marked intra‐and interindividual differences in one of the chief binding proteins, AAG. Changes in AAG concentrations will result in alterations in the distribution and metabolism of basic drugs which will complicate the interpretation of the relationship between total drug concentration and drug efficacy or toxicity. For some drugs, e.g. lignocaine, direct measurement of free concentrations may improve their clinical use but rapid and reliable techniques are as yet not readily available.
Effects of a mu‐opioid receptor agonist (codeine phosphate) on visuo‐ motor coordination and dynamic visual acuity in man.
Authors: Bradley CM , Nicholson AN
Published: July 2012

Effects of codeine (30, 60 and 90 mg) on visuo‐motor coordination and dynamic visual acuity, together with critical flicker fusion, digit symbol substitution, complex reaction time and subjective assessments of mood, were studied from 0.75‐2.0 h after ingestion by six healthy female adults. The study was double‐blind and placebo controlled, and triprolidine (10 mg) was used as the active control. The effect on visuo‐motor coordination was limited and was dose related and linear, and performance was altered on visuo‐motor coordination with 60 and 90 mg codeine, and on dynamic visual acuity with 90 mg codeine (P less than 0.05). No other effect of codeine was detected. Modulated neuromuscular function is likely to be the common denominator of the changes in performance with codeine, though nausea, but not sedation, may be a contributory factor. It is possible that altered performance with codeine may involve interactions with different receptors than those which lead to sedation.
The action of a dopamine (DA1) receptor agonist, fenoldopam in human vasculature in vivo and in vitro.
Authors: Hughes A , Thom S , Martin G , Redman D , Hasan S , Sever P
Published: July 2012

This study was designed to investigate dopaminergic mechanisms in human vasculature using the selective vascular dopamine receptor agonist fenoldopam in vivo and in vitro. In vivo, forearm blood flow was measured plethysmographically and in vitro isolated rings of human blood vessels from a variety of sites were used for tissue bath studies. Intra‐arterial fenoldopam markedly increased forearm blood flow, this effect was antagonised by (R) sulpiride, a vascular dopamine (DA1) antagonist, but not by metoclopramide, a neuronal (DA2) antagonist, or by guanethidine, an adrenergic neurone blocking agent. In vitro, fenoldopam relaxed preconstricted human renal, mesenteric and lumbar arteries, but not saphenous vein in a concentration dependent manner. (RS) sulpiride and SCH 23390 competitively antagonised this effect. These studies demonstrate the presence of a vasodilatory vascular dopamine receptor in man both in vivo and in vitro.
Effect of glycopyrrolate and atropine on thermoregulation after exercise.
Authors: Simpson KH , Green JH , Ellis FR
Published: July 2012

The effects of two anticholinergic drugs on heat production (derived from oxygen consumption), sweating and core and skin temperature were compared with saline placebo in five healthy volunteers, before and after exercise. There were no significant differences between the groups in resting and peak heat production after exercise. Sweat evaporation rate increased after exercise in all cases, but there was individual variation in response to the drugs. Sweat evaporation was greater after saline placebo compared with atropine, but not after glycopyrrolate compared with saline placebo or atropine. In the saline placebo group, increased sweat evaporation following exercise was reflected by an initial fall, in skin temperature. Following anticholinergic drugs, skin temperature increased after exercise without an initial decrease. Core temperature increased following exercise, but there were no significant differences between the anticholinergic drugs and saline placebo. Although clinical doses of anticholinergic drugs, when compared with saline placebo, inhibited sweating after exercise, core temperature was not significantly increased. Therefore it is suggested that non‐evaporative heat loss compensated for the reduction in sweating due to anticholinergic drugs.
Topical steroid treatment reduces arachidonic acid and leukotriene B4 in lesional skin of psoriasis.
Authors: Wong E , Barr RM , Cunningham FM , Mistry K , Woollard PM , Mallet AI , Greaves MW
Published: July 2012

Topical clobetasol propionate or vehicle ointment was applied daily for 3 days to psoriatic plaques on eight patients. Skin chamber exudates from untreated, steroid and vehicle treated lesions were assayed for arachidonic acid (AA), leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid (12‐HETE) before, and at 24 h and 72 h after treatment. Significant reductions in AA and LTB4 were observed at 72 h in steroid treated lesions. The reduction in 12‐ HETE levels observed after steroid treatment was not statistically significant. PGE2 levels in lesional psoriatic skin were unaltered. The reduction of AA, and LTB4 was associated with clinical improvement of psoriasis.
The disposition of intravenous L‐tryptophan in healthy subjects and in patients with liver disease.
Authors: Rossle M , Herz R , Mullen KD , Jones DB
Published: July 2012

The disposition of free and of total tryptophan following an intravenous load of 1.5 g of L‐tryptophan was evaluated in eight patients with non‐cirrhotic liver disease, 40 patients with cirrhosis of the liver (21 Child's A, 15 Child's B, 4 Child's C) and in 14 healthy subjects. Cirrhosis affected disposition of tryptophan by (a) decreasing the clearance of both free and total tryptophan by 64% (P less than 0.001) and 34% (P less than 0.01), respectively, (b) by increasing the apparent volume of distribution of total tryptophan by 42% (P less than 0.01) by expansion of the peripheral compartment, resulting in (c) a threefold increase in the half‐life of tryptophan. Apart from a reduction in free tryptophan clearance, these changes in tryptophan disposition were not apparent in patients with non‐cirrhotic liver disease. Elevated fasting free tryptophan plasma concentrations are an indicator of impaired tryptophan metabolism in cirrhosis. They result from a decreased hepatic clearance of tryptophan rather than from a reduction in tryptophan protein binding. This study emphasises the markedly differing pharmacokinetic behaviour of tryptophan in cirrhotic patients compared with normal subjects and with patients with non‐cirrhotic liver disease.
Sedation for gastroscopy: a comparative study of midazolam and Diazemuls in patients with and without cirrhosis.
Authors: Hamdy NA , Kennedy HJ , Nicholl J , Triger DR
Published: July 2012

A double‐blind controlled study comparing the effects of intravenous Diazemuls (0.15 mg kg‐1) with midazolam (0.07 mg kg‐1) in patients with normal liver function and with cirrhosis and portal hypertension is described. The clinical effect of the two drugs was assessed by serial tests of psychomotor function before and at varying intervals after administration. Using this dosage regime, midazolam caused significantly greater impairment in psychomotor function in both cirrhotic and non cirrhotic subjects, and the time taken for recovery of normal function was also significantly prolonged. Patients with cirrhosis showed a significantly prolonged recovery time following administration of either benzodiazepine compared with the controls. Administration of midazolam in a lower dose might reduce the degree of sedation and shorten the recovery time, but this could also lead to a loss of some of the amnesic effect. Caution is recommended in the administration of benzodiazepines to patients with cirrhosis.