bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudoephedrine and triprolidine in plasma and breast milk of nursing mothers.
Authors: Findlay JW , Butz RF , Sailstad JM , Warren JT , Welch RM
Published: July 2012

Plasma and milk concentrations of pseudoephedrine and triprolidine were determined (by radioimmunoassay) in three lactating mothers over 12‐48 h after ingestion of a combination medication containing 60 mg of pseudoephedrine hydrochloride and 2.5 mg of triprolidine hydrochloride monohydrate. Pseudoephedrine concentrations in milk were consistently higher than those in plasma. The total amount of drug in milk, as judged by areas under the respective curves (AUC), was two to three times greater than in plasma. Triprolidine concentrations in milk and plasma were more variable between subjects than those of pseudoephedrine. AUC values for milk and plasma were similar for one subject, while the plasma value exceeded that for milk in another woman. The fraction of the dose excreted in milk was estimated to be 0.4‐0.7% for pseudoephedrine and 0.06‐0.2% for triprolidine.
A chemically stable analogue, 9 beta‐methyl carbacyclin, with similar effects to epoprostenol (prostacyclin, PGI2) in man.
Authors: O'Grady J , Hedges A , Whittle BJ , Al‐Sinawi LA , Mekki QA , Burke C , Moody SG , Moti MJ , Hassan S
Published: July 2012

The effects of 9 beta‐methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta‐methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta‐methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen‐aggregated platelet rich plasma (PRP), 9 beta‐methyl carbacyclin being 0.01 times as active as epoprostenol. The anti‐aggregatory potencies of the two compounds were comparable in PRP and whole blood. The phosphodiesterase inhibitor isobutyl methyl xanthine enhanced the anti‐aggregatory activity of both compounds in vitro. 9 beta‐methyl carbacyclin and epoprostenol elevated platelet cyclic AMP, 9 beta‐methyl carbacyclin being 0.04 times as active as epoprostenol. In a placebo controlled trial both drugs produces significant headache and facial flushing when compared with placebo. Nasal stuffiness, abdominal discomfort and nausea were reported on all three treatments. Both drugs caused significant and comparable increase in heart rate and decrease in pre‐ejection (PEP) and PEP/left ventricular ejection time (LVET) ratio compared with placebo. Systolic and diastolic blood pressure, LVET and QS2 index were unchanged. Platelet aggregation responses to ADP were significantly inhibited by all three doses of both drugs compared with placebo. Bleeding time was significantly longer during epoprostenol infusion than either placebo or 9 beta‐methyl carbacyclin infusion. Neither drug had significant effect, compared with placebo, on kaolin activated clotting time in PPP, PRP or in PRP in the presence of heparin, prothrombin time, partial thromboplastin time, thrombin clotting time, fibrinogen, fibrinogen degradation products or euglobulin clot lysis time. The pharmacodynamic effects and duration of action of 9 beta‐methyl carbacyclin and of epoprostenol are similar; 9 beta‐methyl carbacyclin is approximately 100 times less potent than epoprostenol in man.
Serum protein binding and the role of increased alpha 1‐acid glycoprotein in moderately obese male subjects.
Authors: Benedek IH , Blouin RA , McNamara PJ
Published: July 2012

Serum protein and lipid concentrations as well as the serum protein binding of propranolol, diazepam and phenytoin were measured in normal weight and obese volunteers. Concentrations of alpha 1‐acid glycoprotein (AAG) in the obese subjects were double that of the lean controls. Conversely, concentrations of high density lipoproteins (HDL) were decreased in the obese group. The serum binding of propranolol was increased in the obese subjects and correlated with serum AAG concentrations. Diazepam binding was slightly decreased in the obese as a result of lower serum albumin concentrations and elevated free fatty acids. The binding of phenytoin was comparable in all of the volunteers. These findings point out some of the complex pathophysiologic changes associated with obesity which may in turn influence drug disposition and hence drug therapy in the obese patient.
The first pass metabolism of nifedipine in man.
Authors: Waller DG , Renwick AG , Gruchy BS , George CF
Published: July 2012

Oral administration of nifedipine (20 and 30 mg tablets) to six volunteers was associated with a bioavailability of 0.43 and the presence of its nitropyridine analogue in the plasma. This metabolite was present in only trace amounts in samples taken from the same volunteers following i.v. administration of nifedipine. The peak plasma concentrations and area under the plasma concentration‐time curve suggest that the nitropyridine analogue is a major, first pass, metabolite of nifedipine.
Attention tasks as skills performance measures of drug effects.
Authors: Moskowitz H
Published: July 2012

Both empirical epidemiological data on the causes of traffic accidents and conceptual models of skilled human performance stress the central role of perception and cognition. This paper examines the effects of drugs on two major components of cognitive perceptual performance, namely, concentrated attention or vigilance and divided attention. It is demonstrated that these two types of attention tasks are differentially affected by various drugs, so that sometimes one and sometimes another of these tasks is impaired. Various experimental paradigms to investigate these two attention functions are presented. It is demonstrated that attention tasks are frequently highly sensitive to drug effects, suggesting the importance of examining these functions when investigating the effects of drugs on skills performance.
Visual motor co‐ordination and dynamic visual acuity.
Authors: Borland RG , Nicholson AN
Published: July 2012

Data on the effect of an antihistamine (triprolidine 10 mg) on visuo‐ motor coordination and dynamic visual acuity were used to establish interactions between these skills. Analysis of covariance and principal component analysis were used. The analyses suggested two main effects‐ an effect on the activity of the neuromuscular system and one which impaired ability to anticipate target movement. Detection of impaired performance by any task may have wider implications to the effectiveness of the individual than that obviously suggested by the skill itself.
Saccadic eye movement analysis as a measure of drug effects on human psychomotor performance.
Authors: Griffiths AN , Marshall RW , Richens A
Published: July 2012

Analysis of human horizontal saccadic eye movements can provide measurements of central nervous system depression and stimulation. Effects on saccadic eye movements have been observed in normal volunteers with barbiturates, benzodiazepines, opiates and related compounds, carbamazepine, amphetamine and ethanol. A suite of programmes have been developed to allow the generation, collection and analysis of saccadic eye movements using a CBM 3032, 8032 or BBC B microcomputer. The system allows almost continuous sampling and rapid analysis of movements.
Ambulatory motor activity monitoring to study the timecourse of hypnotic action.
Authors: Borbely AA
Published: July 2012

A solid state activity monitor worn on the wrist was used to study the effect of flunitrazepam, flurazepam, temazepam, triazolam and midazolam. All compounds reduced motor activity in the first half, but only flunitrazepam and flurazepam had an effect during the second half of the bed rest period. Ambulatory activity monitoring is an unobtrusive and simple method for investigating timecourse of action.
Postural instability as a measure of sedative drug response.
Authors: Swift CG
Published: July 2012

Methods of varying complexity have been devised to measure movements involved in the control of posture (sway). Dose‐related effects of centrally acting drugs on postural sway have been demonstrated.
Driving performance under the influence of drugs: rationale for, and application of, a new test.
Authors: O'Hanlon JF
Published: July 2012

This paper offers the rationale for developing an over‐the‐road test for assessing drug effects on actual driving performance. It describes the development of such a method and results obtained in three separate experiments where the method was applied. The results support the claim that the test provides a valid measure of drug effects on one type of actual driving performance. The test may eventually find a place in the screening of psychoactive drugs for licensing.
Potentials and limitations of angiotensin converting enzyme inhibition in the treatment of hypertension.
Authors: Menard J , Michel JB , Dussaule JC , Alhenc‐Gelas F , Corvol P
Published: July 2012

To appreciate the advantages of inhibiting the renin‐angiotensin system in the treatment of hypertension it is necessary to be aware of four major failures in today's therapy of the disease: The theoretical blood pressure target (supine diastolic blood pressure of 90 to 95 mmHg) is not reached in every patient. The number of adverse effects affecting the quality of life is not acceptable. Today's antihypertensive medications have no basic physiological rationale. Although the mechanical risks of blood pressure elevation are avoided with today's therapy, coronary heart disease, the most common cardiac complication, is not significantly reduced. Converting enzyme inhibition could theoretically provide a solution to each of these failures but its advantages will have to be balanced against the potential risks. The risk of iatrogenic disease with any compound introduced chronically into a living organism for therapeutic reasons. The lack of substrate specificity and the unknown overall physiological effect of angiotensin converting enzyme.
The chemistry of enalapril.
Authors: Patchett AA
Published: July 2012

The design origins of the potent non‐mercapto angiotensin converting enzyme inhibitors enalaprilat and its mono ethyl ester enalapril are described. Lactam analogues of enalaprilat have provided some insight into the conformation of this inhibitor when it is bound to converting enzyme. X‐ray crystallographic studies of a related enzyme/inhibitor complex offer an explanation for the high potency and specificity of these and related inhibitors.
ACE inhibition and brachial artery haemodynamics in hypertension.
Authors: Simon AC , Levenson JA , Safar AM , Bouthier JD , Safar ME
Published: July 2012

Brachial artery haemodynamics, including arterial diameter, blood flow velocity, blood flow and compliance of the brachial artery may be evaluated non‐invasively in man, using pulsed Doppler methods. In patients with sustained untreated essential hypertension, brachial artery diameter is increased, blood flow is normal and arterial compliance is reduced independently of the level of blood pressure. Converting enzyme inhibition may reverse the large artery abnormalities, causing an increase in arterial diameter, blood flow and arterial compliance both in acute and long‐term investigations. These changes in large arteries may contribute towards improved cardiovascular morbidity and less mortality in treated hypertensive patients.
The effect of the non‐steroidal anti‐inflammatory drug choline magnesium trisalicylate on gastric mucosal cell exfoliation.
Authors: Mitchell KG , Hearns J. , Crean GP
Published: July 2012

Gastric mucosal cell exfoliation was measured in 10 normal subjects taking choline magnesium trisalicylate (CMT), aspirin and placebo. Both drugs resulted in significantly elevated rates of exfoliation although the serum salicylate levels achieved with aspirin were lower than those achieved by CMT. Side‐effects of tinnitus, nausea and increased faecal blood loss were more common while subjects were taking CMT.
Central effects of single oral doses of propranolol in man.
Authors: Salem SA , McDevitt DG
Published: July 2012

The central effects of propranolol, a lipophilic beta‐adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.
Comparison of the effect of a conventional heparin and a low molecular weight heparinoid on platelet function.
Authors: Mikhailidis DP , Barradas MA , Mikhailidis AM , Magnani H. , Dandona P.
Published: July 2012

In a study comparing the in vitro effects of heparin and a low molecular weight heparinoid (Organon 10172) on aggregation of platelets from normal subjects, we have demonstrated that whereas heparin markedly enhances platelet aggregation induced by other aggregators and inhibits the anti‐aggregatory effect of epoprostenol (prostacyclin, PGI2), heparinoid does not produce such effects. The use of heparinoid may thus have a significant advantage over that of heparin in situations where enhanced platelet aggregation is the main factor leading to thrombosis or where heparin treatment is followed by thrombocytopaenia.
Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid.
Authors: Tokola RA , Neuvonen PJ
Published: July 2012

The effect of acute migraine attack and rectally given metoclopramide on the absorption of orally given tolfenamic acid (300 mg) was investigated in seven female patients in a crossover study consisting of four phases, two without migraine and two during migraine. Metoclopramide hydrochloride (20 mg) or placebo was given double‐blind. Migraine attacks delayed the absorption of tolfenamic acid. Serum concentrations of tolfenamic acid 1.5 and 2 h after drug administration remained smaller, the peak serum concentration (tmax) occurred later and the area under the serum concentration‐time curve between zero and 2 h (AUC0‐2 h) remained decreased during migraine. Metoclopramide pretreatment in migraine attacks increased the serum concentration of tolfenamic acid at 1.5 h, but its peak concentration, time to peak concentration and the AUC0‐5 h remained unchanged as compared with the values obtained with tolfenamic acid alone. Between the absorption of tolfenamic acid without migraine and after metoclopramide pretreatment during migraine no significant differences existed. When the patients were studied without migraine the serum concentrations of tolfenamic acid 45 min and 60 min after its administration were higher after metoclopramide than after placebo pretreatment. During migraine attacks the serum concentrations and the AUC0‐5.5 h of metoclopramide were slightly lowered. The impairment of drug absorption by migraine was not related to the duration or severity of the attack. The observed changes in drug absorption during migraine attacks are obviously due to the delay in gastric emptying. Rectally administered metoclopramide accelerates the absorption of orally given tolfenamic acid.
Bronchodilator responses to nebulised ipratropium and salbutamol singly and in combination in chronic bronchitis.
Authors: Chan CS , Brown IG , Kelly CA , Dent AG , Zimmerman PV
Published: July 2012

A placebo controlled study compared the magnitude and duration of bronchodilatation produced by nebulised salbutamol (5 mg) and ipratropium (0.5 mg) singly and in combination in twenty patients with chronic bronchitis (mean baseline FEV1 was 33% predicted). The onset of action, of both nebulised salbutamol and ipratropium given singly, occurred within 15 min. Both agents produced a similar degree of bronchodilatation. In combination both the magnitude and duration of the bronchodilatation produced was significantly greater than with either agent alone.
Astemizole, a potent histamine H1‐receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels.
Authors: Howarth PH , Emanuel MB , Holgate ST
Published: July 2012

The efficacy of astemizole, a new, long acting, oral histamine H1‐ receptor antagonist was compared to placebo for the treatment of allergic rhinitis and conjunctivitis during the grass pollen season of 1982. Sixty‐three patients with a positive skin prick test to grass pollen and current symptoms participated in an 8 week, double‐blind, randomized study. Astemizole, 10 mg, was significantly better than placebo in alleviating both nose (P less than 0.05) and eye (P less than 0.01) symptoms despite significantly greater use of the reserve medication, clemastine, by the placebo group (P less than 0.003). There was a lag period of 5 days after initiation of therapy before treatment benefit became manifest. Subdivision of nasal symptoms indicated significant improvement compared to placebo over the 8 weeks for sneezing (P less than 0.05) and runny nose (P less than 0.05) but not blocked nose. The absence of effect on nasal blockage was confirmed by parallel measurement of nasal calibre by body plethysmography. The antihistaminic potency of astemizole was indicated by an 80% inhibition of the histamine induced skin weal response after 8 weeks therapy. A positive correlation was found between serum drug levels and % inhibition of histamine skin weal (r = 0.64, P less than 0.001). Astemizole was free from adverse sedative or anticholinergic effects but did cause a mean increase in weight of 1.3 kg (P less than 0.01) after 8 weeks therapy, not found with placebo.
Pharmacokinetic and pharmacodynamic studies with a new controlled‐ release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations.
Authors: Perucca E. , Grimaldi R. , Gatti G. , Caravaggi M. , Crema F. , Lecchini S. , Frigo GM
Published: July 2012

The kinetics and dynamics (inhibition of exercise tachycardia) of two controlled‐release preparations of propranolol (Elanolol and Inderal LA) were examined in six normal volunteers. Conventional propranolol (Inderal) was also studied for comparison purposes. As compared to conventional propranolol (120 mg), single doses of Elanol (120 mg) and Inderal LA (160 mg) produced a smoother serum level profile, with lower and delayed peak times. Dose‐corrected AUC0‐24 values were greater after Elanol than after Inderal LA (651 +/‐ 147 vs 402 +/‐ 159 ng ml‐1 h, means +/‐ s.e. mean, P greater than 0.05). The profile of inhibition of exercise tachycardia mirrored closely that of the serum levels. At steady state, all regimens studied (Inderal 40 mg three times daily; Elanol 120 mg once daily; Inderal LA 160 mg once daily) ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose‐corrected AUC0‐24 values were 797 +/‐ 148 ng ml‐1 h after Inderal, 908 +/‐ 113 ng ml‐1 h after Elanol and 602 +/‐ 122 ng ml‐1 after Inderal LA. The bioavailability of Inderal LA was significantly lower than that of the other preparations. These results demonstrate that long‐acting formulations of propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first‐pass metabolism.
Enalapril in essential hypertension: a comparative study with propranolol. Enalapril in Hypertension Study Group (UK).
Authors: De Blasi A. , Cortellaro M. , Costantini C.
Published: July 2012

We report the first comparative study on enalapril maleate, a new angiotensin converting enzyme inhibitor, in patients with uncomplicated mild to moderate essential hypertension. Fifty‐four patients were randomly assigned to treatment with enalapril or propranolol for 16 weeks following a placebo run‐in‐phase. The study was double‐blind. Enalapril and propranolol both reduced blood pressure, though the changes were significantly treated with enalapril were normotensive at the end of the study. Enalapril treatment was associated with a significant reduction in weight. Both drugs raised plasma potassium and urea. No haematological abnormalities occurred with enalapril and there were no reports of rash, taste disturbance or proteinuria. At the end of the trial the mean daily dose of enalapril was 20 mg and that of propranolol was 180 mg.
Beta 1‐selective and non‐selective beta‐adrenoceptor blockade, anaerobic threshold and respiratory gas exchange during exercise.
Authors: McLeod AA , Knopes KD , Shand DG , Williams RS
Published: July 2012

The effect of oral doses of the beta 1‐selective adrenoceptor antagonist atenolol (50 mg), the non‐selective antagonist propranolol (40 mg) and placebo was investigated during exercise in a crossover comparison in six healthy but untrained subjects. Descriptors of ventilation, respiratory gas exchange, and arterialized blood lactate and glucose were obtained during steady state bicycle ergometric exercise at 20% and 60% of the subjects' previously determined maximal oxygen uptake (VO2 max). At these work intensities, the previously reported increase of respiratory exchange ratio (RER) during non‐ selective beta‐adrenoceptor blockade was found to be trivial (placebo = 0.96 +/‐ 0.03 s.e. mean; propranolol = 0.97 +/‐ 0.01; atenolol = 0.97 +/‐ 0.04; 60% VO2 max, 10 min exercise) and only present during the early minutes of effort. Oxygen uptake and carbon dioxide production did not differ between treatments. Both drugs produced highly significant falls in peak expiratory flow (PEF) rates and tidal volume (VT) which were compensated by an increase in respiratory rate. PEF, 60% VO2 max: placebo = 3.8 +/‐ 0.3 l/s; propranolol 3.6 +/‐ 0.3 l/s (P less than 0.03); atenolol 3.1 +/‐ 0.3 l/s (P less than 0.01). VT, 60% VO2 max: placebo 2.0 +/‐ 0.1 l; propranolol 1.8 +/‐ 0.21 (P less than 0.05); atenolol 1.7 +/‐ 0.1 1 (P less than 0.01). Arterialized lactate was significantly elevated during work at 20% and 60% VO2 max, but rose progressively at the 60% VO2 max load. Ventilation, oxygen uptake and ventilatory equivalent for carbon dioxide also rose progressively at this workload. Ventilatory equivalent for oxygen showed no significant rise.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of oral fenoldopam (SKF 82526‐J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man.
Authors: Harvey JN , Worth DP , Brown J , Lee MR
Published: July 2012

The effect of a single oral dose of 100 mg of fenoldopam on renal function and blood pressure was investigated in seven healthy male subjects in a double‐blind placebo controlled study. Mean diastolic blood pressure fell by 10 mm Hg, 45 min after oral dosing and then gradually returned to baseline values. There was an increase in pulse rate and a delayed rise in systolic blood pressure. Measured from 30 to 120 min after drug ingestion, mean effective renal plasma flow increased to 158% of the value observed after placebo; mean glomerular filtration rate rose to 109% of the placebo value. Measured from 120 to 210 min after administration of the drug, effective renal plasma flow and glomerular filtration rate had returned to baseline values. Fenoldopam produced a small increase in the mean sodium excretion rate which was not significantly different from the fall after placebo. No change was detected in urine flow or potassium excretion rate. Mean plasma renin activity increased three‐fold 1 h after oral dosing. Plasma aldosterone did not show a parallel increase although the plasma concentration at 1 h was significantly higher than after placebo. The results show a pronounced renal vasodilator effect lasting about 2 h. The findings are consistent with marked DA1 receptor agonist activity.
Cardiac effects of sodium stibogluconate.
Authors: Henderson A , Jolliffe D
Published: July 2012

Sodium stibogluconate although potentially cardiotoxic is the drug of choice for Kalaazar and cutaneous leishmaniasis due to Leishmania braziliensis. Increasing use of this drug in the British Army has necessitated a formal evaluation of its cardiac side‐effects. Consequently a detailed study of the cardiac effects of sodium stibogluconate was undertaken in 22 male soldiers using for the first time modern non‐invasive techniques. Intravenous sodium stibogluconate 600 mg daily for 10 days did not affect blood pressure, heart rate, left ventricular contractile function or rhythm. Electrocardiography showed a reversible reduction of T wave amplitude.
Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine‐N‐oxide following i.v. and oral administration in healthy volunteers.
Authors: McBurney A , Farrow PR , Ainsworth S , Ward JW
Published: July 2012

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine‐N‐oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/‐ 13.7%. Following intravenous administration, the mean AUC0‐8 h metabolite/AUC 0‐8 h pinacidil ratio was 0.559 +/‐ 0.272 and after oral administration, 0.825 +/‐ 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half‐life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine‐N‐oxide may be a ‘first‐pass’ metabolite of pinacidil. In most patients pinacidil pyridine‐N‐oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.
Strength of the human mixed lymphocyte reaction (MLR) and its suppression by azathioprine or 6‐mercaptopurine.
Authors: Al‐Safi SA , Maddocks JL
Published: July 2012

Azathioprine (36 microM) had a significantly (P less than 0.00003) greater inhibitory effect on human MLR responses below 20,000 counts/min than on responses above 20,000 counts/min. In contrast, 6‐ mercaptopurine (100 microM) had a similar suppressive effect on MLR responses below and above 20,000 counts/min suggesting it has a different mode of action to azathioprine.
Protein binding and CSF penetration of phenytoin following acute oral dosing in man.
Authors: Brodie MJ , Muir SE , Agnew E , MacPhee GJ , Volo G , Teasdale E , MacPherson P
Published: July 2012

Prophylactic phenytoin (DPH) has been evaluated in 20 patients undergoing diagnostic myelography. DPH (0.75 g) was ingested at 20.00 h the night before and 0.5 g at 08.00 h on the morning of the procedure. Total DPH concentrations at myelography (mean +/‐ s.d.: 12.7 +/‐ 4.3 mg l‐1; range 6.3‐21.5 mg l‐1) correlated with CSF values (1.3 +/‐ 0.46 mg l‐1; range 0.7‐2.2 mg l‐1; r = 0.83, P less than 0.001). DPH protein binding at that time varied two‐fold (9.2‐18.5%) and free drug levels (1.7 +/‐ 0.6 mg l‐1) correlated with CSF (r = 0.83, P less than 0.001) and total (r = 0.89, P less than 0.001) plasma DPH concentrations. There were significant negative correlations between patient weight (n = 17) and total (r = 0.57, P less than 0.05) and CSF (r = −0.55, P less than 0.05) DPH concentrations at myelography. Total plasma DPH levels 8 h (14.5 +/‐ 3.9 mg l‐1; range 7.3‐20.6 mg l‐1) and 24 h (12.3 +/‐ 3.8 mg l‐1; range 5.0‐19.8 mg l‐1) after myelography were largely within the ‘therapeutic range’ of 10‐20 mg l‐1 for the drug. No patient suffered a seizure although, in two, spike discharges were seen on a post‐myelography electroencephalogram. A simple regime involving two doses of DPH would provide acceptable plasma CSF concentrations as a basis for controlled studies in seizure prophylaxis following neuroradiological investigations involving intrathecal contrast.
Renal excretion of intravenously infused amoxycillin and ampicillin.
Authors: Sjovall J , Westerlund D , Alvan G
Published: July 2012

The aim of this study was to determine whether concentration‐dependent renal clearance of ampicillin and amoxycillin occurs. The drugs were given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross‐over design. Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion. The renal clearance of the drugs was independent of the plasma concentration. The mean (s.d.) renal clearances of ampicillin and amoxycillin were 167 (24) and 157 (20) ml min‐1 1.73 m‐2 respectively. The net secretion was about 50% of the total renal clearance of both drugs. The plasma concentration and urinary excretion rate versus time curves indicated a polyexponential decline, which could be described by both a biexponential and a triexponential equation. The former proved to be more reliable, especially in the calculation of micro rate constants. There was a tendency to more sustained plasma concentrations after amoxycillin, also illustrated by a significantly lower mean (s.d.) plasma clearance of this drug, viz. 185 (30) ml min‐1 1.73 m‐2, as compared to ampicillin, 210 (24) ml min‐1 1.73 m‐2 (P less than 0.04). There were no major differences in the disposition rate constants and the distribution volumes of ampicillin and amoxycillin. The mean (s.d.) plasma half‐life was 1.7 (0.3) h for both drugs. The urinary excretion rate indicated a slower terminal disposition rate however, with ampicillin and amoxycillin half‐lives of 3.4 (2.0) and 3.9 (1.2) h respectively. The longer half‐life in the terminal phase may be due to increased tubular reabsorption at low urinary concentrations. It was not possible to determine in this study whether the half‐life was affected by changes in clearance or volume of distribution. The urinary solubility of the drugs was dependent on pH. This could explain the massive macroscopic crystalluria seen in one subject after amoxycillin. Three hours after termination of the infusion, crystals could no longer be found in the sediment. There was no clinical or laboratory evidence of renal damage.
Pharmacokinetics of aztreonam in elderly male volunteers.
Authors: Creasey WA , Platt TB , Frantz M , Sugerman AA
Published: July 2012

The pharmacokinetics of aztreonam were studied in 12 healthy male volunteers aged 65 to 75 years who received 1 g of the antibiotic intravenously. Data were fitted to a two‐compartment open model to yield the following parameters: t 1/2, lambda 1, 0.15 h; t 1/2,z, 2.06 h; area under the 24‐h serum concentration‐time curve, 231.8 micrograms ml‐1 h; Cmax, 120.1 micrograms/ml; V1 area, 0.16 l/kg; and serum clearance, 0.94 ml min‐1 kg. Twenty‐four hour urinary elimination reached 63.1% of dose as aztreonam and 3.1% as the open ring metabolite SQ 26,992. These data were similar to those obtained for healthy males aged 18 to 35 years. Thus, age per se is not a major therapeutic consideration in treating elderly patients, and other factors, primarily the parameters of renal function, should serve as the basis for any dose reduction.
Nicotine pharmacokinetics and its application to intake from smoking.
Authors: Feyerabend C , Ings RM , Russel MA
Published: July 2012

Five subjects were given 25 micrograms/kg nicotine intravenously over 1 min, before and after a loading period involving the smoking of six cigarettes. Plasma nicotine concentrations declined in a biphasic manner, the half‐lives of the initial and terminal phases averaging 9 min and 133 min respectively. Terminal half‐lives before and after the loading period were essentially the same suggesting the absence of saturation kinetics at nicotine concentrations that build up during smoking. The plasma clearance of nicotine and the volume of distribution were very high averaging 915 ml/min and 1731, respectively. Two approaches were used to calculate the nicotine intake from smoking. The average dose of nicotine absorbed from one cigarette was 1.06 mg which was 82% of the standard machine‐smoked yield of 1.3 mg. To illustrate their potential use in ‘nicotine titration’ studies, these approaches were used to compare nicotine intake from smoking a high (2.4 mg) and low (0.6 mg) nicotine cigarette. The dose of nicotine absorbed averaged 1.14 mg and 0.86 mg per cigarette respectively, being 48% and 143% of the machine‐smoked yields.
The effect of dietary supplementation with linoleic and gammalinolenic acids on the pressor response to angiotensin II‐a possible role in pregnancy‐induced hypertension?
Authors: O'Brien PM , Morrison R , Broughton Pipkin F
Published: July 2012

Dietary supplementation with 3 g/day linoleic acid, 32 mg/day gammalinolenic acid and co‐factors for prostaglandin synthesis was given to 10 pregnant and 10 non‐pregnant subjects for a week. Their pressor response to the infusion of three doses of angiotensin II (AII) (pregnant: 4, 8, 16 ng kg‐1 min‐1: non‐pregnant: 1, 2, 4 ng kg‐1 min‐1) was then compared with that of 40 pregnant and 24 non‐pregnant controls who had not been given such supplementation. Dietary supplementation was not associated with changes in basal systolic or diastolic blood pressure or heart rate during the week of treatment in pregnant or non‐ pregnant subjects. Basal systolic blood pressure, diastolic blood pressure and heart rate values did not differ between the treated and untreated subjects in each group. The diastolic pressor response to AII was significantly less after treatment at all doses; the effect was more marked in the pregnant subjects. The systolic response to AII, normally less than the diastolic, was somewhat blunted in the treated pregnant patients at the two higher infusion doses. No significant effect was found in the non‐pregnant group. Evidence from other studies suggests that increasing plasma linoleic acid concentrations leads to increased plasma concentrations of epoprostenol (prostacyclin, PGI2) while increased availability of gammalinolenic acid is associated with a rise in prostaglandin E1 and E2 production. Pregnancy‐induced hypertension is associated with a diminished tissue production of both epoprostenol and E series prostaglandins, and with an enhanced pressor response to AII.(ABSTRACT TRUNCATED AT 250 WORDS)
Verapamil disposition‐effects of sulphinpyrazone and cimetidine.
Authors: Wing LM , Miners JO , Lillywhite KJ
Published: July 2012

The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/‐)‐ verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h‐ 1 kg‐1 (s.e. mean 0.51‐ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h‐1 kg‐1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h‐1 kg‐1) than in females (4.49 to 10.21 l h‐1 kg‐1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25‐250 micrograms l‐ 1) or addition of sulphinpyrazone (50‐500 mg l‐1) or cimetidine (0.5‐5 mg l‐1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/‐)‐verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of captopril, the nitrates and propranolol on apparent liver blood flow.
Authors: Shepherd AN , Hayes PC , Jacyna M , Morrison L , Bouchier IA
Published: July 2012

Indocyanine green estimated apparent liver blood flow was measured in normal volunteers following glyceryl trinitrate, propranolol, isosorbide mononitrate and captopril. Glyceryl trinitrate and propranolol significantly reduced apparent liver blood flow. Isosorbide mononitrate did not alter apparent liver blood flow or produce an additional reduction in apparent liver blood flow when combined with propranolol. Captopril did not alter apparent liver blood flow despite a significant fall in mean arterial pressure and rise in plasma renin activity. Captopril and isosorbide mononitrate if shown to reduce portal pressure, do so without a fall in apparent liver blood flow.
The effects of propranolol and digoxin on the acute vascular responses to frusemide in normal man.
Authors: Johnston GD , O'Connor PC , Nicholls DP , Leahey WJ , Finch MB
Published: July 2012

To examine the importance of acute frusemide‐induced renin release in the production of the acute peripheral venous and arterial responses to frusemide in man, the effects of two drugs, previously described as inhibitors of acute frusemide‐induced renin release, propranolol and digoxin, were examined. Propranolol abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by frusemide. The acute increases in plasma renin activity and plasma aldosterone concentrations were also abolished. Pre‐treatment with digoxin had no effect on the acute peripheral vascular responses to frusemide and failed to inhibit the acute increases in plasma renin activity and plasma aldosterone produced by frusemide. The study provides further evidence of a relationship between acute frusemide‐induced renin release and the acute peripheral vascular effects of frusemide in man.
Genetic polymorphism of mephenytoin p(4′)‐hydroxylation: difference between Orientals and Caucasians.
Authors: Jurima M , Inaba T , Kadar D , Kalow W
Published: July 2012

The genetically controlled mephenytoin p(4′)‐hydroxylation capacity was determined in 118 Caucasians and 70 Orientals. After an oral dose of 50 or 100 mg of racemic mephenytoin, the amount of p(4′)‐ hydroxymephenytoin in 24 h urine was measured by gas chromatography. Bimodal distribution was found with 9/70 (13%) Orientals and 5/118 (4%) Caucasians demonstrating deficient p(4′)‐hydroxylation. The statistically significant difference between Orientals and Caucasians (P less than 0.05) was accounted for by the high incidence of poor metabolizers among the Japanese subjects, 7/31 (23%). The frequency among Chinese subjects, 2/39 (5%), was similar to the frequency among Caucasians.
Penbutolol and propranolol: a comparison of their effects on antipyrine clearance in man.
Authors: Bax ND , Jones RW , Lennard MS , Tucker GT , Woods HF
Published: July 2012

The effects of two beta‐adrenoceptor antagonists, penbutolol (administered on separate occasions as (+/‐)‐ and (‐)‐forms) and propranolol, on the kinetics of antipyrine were studied in eight normal subjects. At the same degree of beta‐adrenoceptor blockade, as assessed by the lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 31 +/‐ 11 s.d.% (P less than 0.001) whereas neither of the two penbutolol formulations had a significant effect. The volume of distribution of antipyrine was unchanged following any of the beta‐adrenoceptor antagonist treatments. The lack of effect of penbutolol on oxidative drug metabolism is not consistent with in vitro data suggesting a relationship between the lipid solubility of beta‐ adrenoceptor antagonists and inhibition of metabolism.
The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.
Authors: Bax ND , Tucker GT , Lennard MS , Woods HF
Published: July 2012

To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100‐ 140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre‐treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/‐ 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/‐ 50 s.d.% (P less than 0.025) and it prolonged the elimination half‐life of lignocaine by 20 +/‐ 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/‐ 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.
Effective dose range of enalapril in mild to moderate essential hypertension.
Authors: Bergstrand R , Herlitz H , Johansson S , Berglund G , Vedin A , Wilhelmsson C , Gomez HJ , Cirillo VJ , Bolognese JA
Published: July 2012

The dose‐response relationship of enalapril was evaluated in a double‐ blind, balanced, two‐period, incomplete‐block study in 91 patients with mild to moderate essential hypertension. Patients were randomly assigned to two of six treatments: placebo, 2.5, 5, 10, 20 and 40 mg/day of enalapril maleate. There were two 3‐week treatment periods, each preceded by a 4‐week, single‐blind placebo washout. Each dose of enalapril produced significant decreases in standing and supine systolic and diastolic blood pressure after 2 and 3 weeks of treatment. There were no significant changes on placebo. There was a significant linear dose response relationship for both mean blood pressure and mean change from baseline in blood pressure (P less than 0.01 for systolic and mean arterial pressure, and P less than 0.05 for diastolic pressure). Enalapril was associated with an increasing dose‐response relationship across the 2.5‐40 mg/day range. The 2.5 mg/dose is effective in some patients; however, doses greater than or equal to 10 mg/day may be necessary to achieve satisfactory blood pressure control.
Effects of the beta 2‐adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline‐induced beta‐adrenoceptor responses in man.
Authors: Arnold JM , O'Connor PC , Riddell JG , Harron DW , Shanks RG , McDevitt DG
Published: July 2012

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline‐induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2‐adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2‐adrenoceptors in man.
Comparative pharmacodynamics and clinical pharmacokinetics of phenoxymethylpenicillin and pheneticillin.
Authors: Overbosch D , Mattie H , van Furth R
Published: July 2012

In this study the antimicrobial effects of phenoxymethylpenicillin (PM) and pheneticillin (PE) in vitro and in an experimental animal infection model were compared as well as the pharmacokinetic properties of both drugs in patients. For the inhibitory effect of PM on short‐term (3 h) growth of S. aureus in vitro, this drug was 2.13 times more potent than PE. The protein binding of both drugs was similar (78‐80%). The potency ratio of PM to PE against S. aureus in an experimental mouse‐thigh infection was only 1.25 to 1. This is explained by the difference in the AUC after subcutaneous administration of PM (0.47 mg 1(‐1) h) and PE (0.92 mg 1(‐1) h). The plasma clearance after intravenous administration of PM was 476.4 ml/min and that of PE was 295.1 ml/min; the plasma clearance of both drugs was strongly correlated with the creatinine clearance. The volume of distribution in the steady state of PM was 35.41 and that of PE 22.51. In 10 patients, the absorption after oral administration of PM as the acid was 48% and that of the potassium salt of PE was 86% of the dose. From the present results it can be concluded that a difference in effectiveness of different formulations of PM and PE would depend entirely on differences in absorption.
The effects of age and sex on the disposition of acetylsalicylic acid and its metabolites.
Authors: Ho PC , Triggs EJ , Bourne DW , Heazlewood VJ
Published: July 2012

The disposition of a low dose (600 mg) of acetylsalicylic acid (ASA) and its metabolites (salicylate, salicyluric acid and salicyl glucuronides) was studied in 25 male and female patients of different ages. Plasma levels of ASA and salicylate were found to be significantly higher in the females (young and elderly), whereas plasma levels of salicyluric acid were found to be significantly higher in the elderly (male and female) groups. The higher plasma levels of ASA and salicylate in the females appear to be due to an intrinsically lower metabolic activity in that sex, while the lower clearance of salicyluric acid leads to the accumulation of that compound in the aged. No age and sex effects were found to influence the volumes of distribution of ASA, salicylate and salicyluric acid.