bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterisation of theophylline metabolism in human liver microsomes.
Authors: Robson RA , Matthews AP , Miners JO , McManus ME , Meyer UA , Hall PM , Birkett DJ
Published: July 2012

1. A radiometric high performance liquid chromatographic method is described for the assay of theophylline metabolism in vitro by the microsomal fraction of human liver. 2. Formation of the three metabolites of theophylline (3‐methylxanthine, 1‐methylxanthine and 1,3‐ dimethyluric acid) were linear with protein concentrations to 4 mg ml‐1 and with incubation times up to 180 min. 3. The coefficients of variation for the formation of 3‐methylxanthine, 1‐methylxanthine and 1,3‐dimethyluric acid were 1.2%, 1% and 1.6%, respectively. 4. Theophylline is metabolised by microsomal enzymes with a requirement for NADPH. 5. The mean (n = 7) Km values for 1‐demethylation, 3‐ demethylation and 8‐hydroxylation were 545, 630 and 788 microM, respectively, and the mean Vmax values were 2.65, 2.84 and 11.23 pmol min‐1 mg‐1, respectively. 6. There was a high correlation between the Km and Vmax values for the two demethylation pathways suggesting that the demethylations are performed by the same enzyme. 7. Overall the in vitro studies are consistent with the in vivo results which suggest the involvement of two cytochrome P‐450 isozymes in the metabolism of theophylline.
A modified trans‐membrane migration method for measuring the effect of drugs on sperm motility.
Authors: Raoof NT , Pearson RM , Turner P
Published: July 2012

1. The trans‐membrane migration ratio (TMMR) technique is a simple method for quantitating and comparing the effect of drugs on sperm motility. 2. The ultrafilter membrane (Nucleopore) used allows mixing between the solutions on either side resulting in 21‐fold dilution of a drug initially mixed with semen. 3. The concentration of drug originally mixed with semen does not remain constant over the incubation time. 4. The phosphate buffer saline (PBS) in the lower chamber should be replaced by PBS containing the same concentration of drug as in the upper chamber so that a homogenous system is established throughout the incubation. 5. Reports of previous studies using this technique may have underestimated the effect of drugs on sperm motility.
Cyclosporin‐phenytoin interaction: re‐evaluation using metabolite data.
Authors: Rowland M , Gupta SK
Published: July 2012

1 Freeman et al. (1984) evoked enzyme induction to explain the lower plasma concentration of cyclosporin following phenytoin co‐ administration in man. 2 We have examined the whole blood concentration data of two metabolites of cyclosporin, as well as unchanged drug, all measured by h.p.l.c., associated with the above mentioned study. 3 Phenytoin produced no significant effect on either the terminal half‐ life of both metabolites or the ratio of area under the concentration‐ time curve of metabolite to parent drug. 4 These data strongly suggest that phenytoin reduces the absorption of cyclosporin; they do not generally support the idea that phenytoin induces cyclosporin metabolism.
Peripheral vascular effects of beta‐adrenoceptor blockade: comparison of two agents.
Authors: Cooke ED , Maltz MB , Smith RE , Bowcock SA , Watkins CJ , Camm AJ
Published: July 2012

1. The effects of atenolol (100 mg), a beta 1‐adrenoceptor blocker, and bevantolol (200 mg) were compared on heart rate, blood pressure, lung function and on the peripheral circulation in normal volunteers before and after isoprenaline infusion. Recordings were obtained 2 and 24 h following a single dose and 24 h after continuous dosage for 7 days. 2. The effect of atenolol on the blockade of beta‐adrenergic stimuli, as measured by the ability to reduce isoprenaline‐induced tachycardia, was greater than that of bevantolol. Though both drugs achieved a similar reduction in systolic pressure there was a significantly greater reduction in diastolic pressure with bevantolol. The lung function tests gave similar results to those with other beta‐adrenoceptor blockers. 3. Atenolol produced a fall in peripheral blood flow consistent with unopposed peripheral alpha‐adrenoceptor stimulation. The effect of bevantolol differs from that of atenolol, an initial fall in peripheral blood flow being followed by a rapid recovery to baseline or greater. This effect may be due to partial alpha‐adrenoceptor agonist activity.
Propranolol disposition in patients with hepatosplenic schistosomiasis.
Authors: Homeida MM , Ali HM , Arbab BM , Harron DW
Published: July 2012

Eight Sudanese patients with hepatosplenic schistosomiasis and seven Sudanese controls were administered a single oral dose of long acting (LA), propranolol 160 mg; blood propranolol levels were measured at regular intervals for 12 h using g.l.c. In patients with hepatosplenic schistosomiasis, propranolol blood concentrations were greater (P less than 0.05) at all time intervals, Cmax 63.5 (29‐143) ng ml‐1 (median and range) than controls Cmax 23 (12‐37) ng ml‐1. Median AUC0‐12 was also greater (P less than 0.05) (533 and 218 ng ml‐1 h respectively), tmax were not significantly different. In patients and controls prior to treatment, standing heart rate (77.5 (60‐110), 72 (68‐74) beats min‐ 1) systolic (120 (105‐150), 110 (100‐120) mm Hg) and diastolic blood pressure (75 (60‐90), 70 (60‐80) mm Hg) were not significantly different. However following propranolol administration a reduction (P less than 0.05) occurred in both systolic (median 20 mm Hg) and diastolic (median 12.5 mm Hg) blood pressure in the patients compared with controls. Heart rate was reduced by a median of 10 beats min‐1 in both groups. These observations indicate that propranolol bioavailability in patients with hepatosplenic schistosomiasis is increased possibly due to reduced presystemic extraction.
Early cardiovascular changes with ibopamine: evidence for a biphasic haemodynamic action.
Authors: Hogg KJ , Hornung RS , Howie CA , Hillis WS
Published: July 2012

1. The haemodynamic effects of ibopamine, an oral dopamine derivative, were studied in eight patients with left ventricular dysfunction using invasive catheterisation techniques. 2. An early rise was seen in the mean right atrial pressure (P less than 0.05), the mean capillary wedge pressure (P less than 0.01) and the mean pulmonary arterial pressure (P less than 0.001) which occurred at 15 min and persisted for 30 min. 3. A second, later, positive chronotropic effect was seen as an increase in the heart rate (P less than 0.05) at 45 min with an increased cardiac output (P less than 0.05) persisting above baseline values at 1 h, but with no change in stroke volume. 4. These results support a biphasic mode of action for ibopamine which may be explained by a time phase difference in alpha‐ and beta‐adrenoceptor stimulatory effects.
The trans‐hepatic extraction of nifedipine.
Authors: Challenor VF , Waller DG , Renwick AG , Gruchy BS , George CF
Published: July 2012

1. The trans‐hepatic extraction of nifedipine during steady state infusion was studied in six patients undergoing cardiac catheterisation for suspected coronary disease. 2. Mean extraction ratio across the liver was 0.64 but hepatic clearance accounted for a mean of only 65% of total body clearance. 3. These results are consistent with the liver as the major site of metabolism of nifedipine, but also suggest that significant metabolism occurs outside the liver.
Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.
Authors: Gupta SK , Legg B , Solomon LR , Johnson RW , Rowland M
Published: July 2012

1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg‐1 day‐1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg‐1 day‐1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h‐1 kg‐ 1. 5 Clearance associated with the 10 mg kg‐1 day‐1 infusion rate (0.43 l h‐1 kg‐1) was estimated to be lower than that following the 4 and 7 mg kg‐1 day‐1 rates (0.52 and 0.54 l h‐1 kg‐1 respectively) but the difference is unlikely to be of clinical significance.
A comparative pharmacokinetic study of conventional propranolol and long acting preparation of propranolol in patients with cirrhosis and normal controls.
Authors: Watson RG , Bastain W , Larkin KA , Hayes JR , McAinsh JA , Shanks RG
Published: July 2012

1 Six male patients with alcoholic cirrhosis and seven normal control subjects were each given 80 mg twice daily of conventional propranolol for 1 week and 160 mg once daily of a long acting preparation (LA) of propranolol for 1 week. 2 Plasma propranolol levels were measured at regular intervals on the first and seventh days of both weeks and also following an acute intravenous infusion of 10 mg propranolol on a separate occasion. 3 After the single intravenous dose the elimination half‐life tended to be prolonged in the cirrhotic group (median 7.15 h) compared with controls (median 2.92 h) (P = 0.055). 4 After multiple oral dosing with 80 mg twice daily of conventional propranolol the steady‐state plasma concentration (Css), area under the curve (AUC tau), peak concentration (Cmax) and trough concentration (Cmin) were significantly higher in cirrhotic patients and the peak: trough ratio (Cmax/Cmin) was significantly lower than controls. 5 After multiple oral dosing with 160 mg LA once daily Cmin was significantly higher than Cmax/min significantly lower in cirrhotic patients; Css, AUC and Cmax were higher than controls but not statistically different. 6 Within both subject groups the bioavailability of 80 mg twice daily of conventional propranolol tended to be greater than 160 mg LA once daily. Cmax was significantly higher in both groups and Css higher in the cirrhotic group with conventional propranolol. 7 In the cirrhotic group the mean reduction in supine heart rate in the steady state was 31.8% with conventional 80 mg twice daily propranolol and 23.75% with 160 mg LA once daily.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral phenytoin pharmacokinetics during omeprazole therapy.
Authors: Prichard PJ , Walt RP , Kitchingman GK , Somerville KW , Langman MJ , Williams J , Richens A
Published: July 2012

1. In a double‐blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day‐1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/‐ s.e. mean) from 121.6 +/‐ 14.0 to 151.4 +/‐ 13.6 micrograms ml‐1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half‐life of phenytoin also tended to be increased though not significantly. 4. The omeprazole‐phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.
Effects of antacids and food on absorption of famotidine.
Authors: Lin JH , Chremos AN , Kanovsky SM , Schwartz S , Yeh KC , Kann J
Published: July 2012

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three‐way cross‐over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Coadministration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 +/‐ 54.2 to 60.8 +/‐ 21.6 ng ml‐1 (P less than 0.05) and a small decrease in the area under plasma concentration‐time curve [AUC] from 443.3 +/‐ 249.2 to 355.0 +/‐ 125.1 ng ml‐1 h (P greater than 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 +/‐ 29.6 ng ml‐1 and 434.8 +/‐ 145.9 ng ml‐ 1 h, respectively.
Temelastine does not affect theophylline pharmacokinetics in normal subjects.
Authors: Charles BG , Schneider JJ , Norris RL , Ravenscroft PJ
Published: July 2012

The pharmacokinetics of theophylline (i.v. aminophylline 250 mg) were studied in a balanced, double‐blind crossover following the administration of oral temelastine (100 mg) or placebo, twice daily for 7 days, to 10 normal volunteers. Comparison of volumes of distribution, elimination rate constants, elimination half‐lives and areas under the plasma concentration‐time curve indicated that temelastine had no significant effect on theophylline pharmacokinetics.
Differences in the binding of quinine and quinidine to plasma proteins.
Authors: Mihaly GW , Ching MS , Klejn MB , Paull J , Smallwood RA
Published: July 2012

1. Little is known about the comparative plasma protein binding of the antimalarial agents quinine (QN) and its isomer quinidine (QD). We have examined the in vitro binding of QN and QD to albumin, alpha 1‐acid glycoprotein, normal human plasma, and maternal and foetal umbilical cord plasma. 2. QN was more avidly bound than QD, and binding of both drugs was substantially higher to alpha 1‐acid glycoprotein than to albumin, indicating that alpha 1‐acid glycoprotein is the more important binding protein. 3. Protein and drug concentration dependent binding was evident for both QN and QD. The unbound fraction of both drugs fell with increasing albumin (10 to 60 g l‐1) and alpha 1‐acid glycoprotein (0.5 to 2.0 g l‐1) concentration, and there was a marked increase in unbound fraction of QN (6 to 19%) and QD (13 to 36%) in human plasma when drug concentrations were increased over the antimalarial therapeutic range (0.5 to 10 mg l‐1). 4. In human volunteer plasma, the unbound fractions of QN and QD were 7.5 +/‐ 2.2% and 12.3 +/‐ 2.3% respectively, whilst the unbound fractions for both drugs were significantly higher in maternal plasma (QN = 13.0 +/‐ 5.4%, QD = 18.3 +/‐ 2.5%) and significantly higher still in foetal umbilical cord plasma (QN = 25.7 +/‐ 10%, QD = 35 +/‐ 5.3%).
Determination of debrisoquine metabolic ratio from hourly urine collections in healthy volunteers.
Authors: Philip PA , James CA , Rogers HJ
Published: July 2012

The possibility of simplifying the regimen for the collection of urine samples in the determination of the debrisoquine metabolic ratio (DMR) was explored in 15 normal subjects. In the extensive metaboliser subgroup (EM; n = 11), there was a close correlation between the DMR as determined by an 8 h urine collection and the debrisoquine/4‐ hydroxydebrisoquine ratio (D/4‐OHD) in the hourly samples (excluding the first hour). In the poor metabolisers (PM; n = 4) the phenotype could be identified, but it was not possible to estimate the DMR reliably.
The effect of charcoal on mefenamic acid elimination.
Authors: Allen EM , Buss DC , Williams J , Routledge PA
Published: July 2012

Mefenamic acid suppository 500 mg was administered by rectum to eight healthy adult volunteers followed by either activated charcoal 5 g orally at hourly intervals for 7 h or an equal volume of water on two separate occasions 7 days apart. Administration of charcoal did not significantly affect the pharmacokinetic variables of mefenamic acid. Thus the beneficial effects of charcoal in the treatment of mefenamic acid overdose are largely due to interference with absorption, rather than enhancement of elimination of the drug.
Disposition of fosinopril sodium in healthy subjects.
Authors: Singhvi SM , Duchin KL , Morrison RA , Willard DA , Everett DW , Frantz M
Published: July 2012

1 Fosinopril sodium is the first phosphorus‐containing angiotensin‐ converting enzyme (ACE) inhibitor to be studied clinically as an antihypertensive agent. It is an ester prodrug that is hydrolysed in vivo to the active diacid ACE inhibitor, SQ 27, 519. 2 In a three‐way crossover study, nine healthy male subjects (age range 20‐34 years) each received an intravenous 7.5 mg dose of SQ 27, 519‐[14C] and two oral 10 mg doses of [14C]‐fosinopril sodium, administered as a capsule and in solution. 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a beta‐ glucuronide conjugate of SQ 27, 519 (15‐20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min‐1), renal clearance (17 ml min‐1), Vss (10 1), and plasma protein binding (approximately 95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites.
Psychotropic effects of repeated doses of enalapril, propranolol and atenolol in normal subjects.
Authors: Frcka G , Lader M
Published: July 2012

1 Enalapril 20 mg, propranolol 160 mg, atenolol 50 mg and placebo each were given once a day for 8 days to 12 normal volunteers, using a Latin‐ square design and double‐blind procedures. A battery of tests was applied before, 2 and 4 h after the dose on day 1 and 8. 2 EEG effects were detected on day 8 with propranolol but not consistently after atenolol or enalapril. 3 Reaction‐time, symbol copying and memory were impaired with propranolol; only memory was marginally affected by atenolol. Enalapril impaired memory but improved tapping ability. 4 Subjectively, propranolol was associated with drowsiness, enalapril with calmness and perhaps contentedness. Ratings of headache were increased with enalapril. 5 It is concluded that the apparent beneficial subjective effects of enalapril in clinical practice are attributable partly to intrinsic central effects but mainly to the contrast with beta‐adrenoceptor blockers such as propranolol.
Exercise haemodynamics and maximal exercise capacity during beta‐ adrenoceptor blockade in normotensive and hypertensive subjects.
Authors: Van Baak MA , Koene FM , Verstappen FT
Published: July 2012

1. The effects of atenolol administration on maximal exercise capacity and exercise haemodynamics have been compared in eight normotensive and eight mildly hypertensive subjects, matched for sex, age, body weight, and maximal oxygen uptake, and familiar with maximal exercise testing. 2. Supine and exercise blood pressure, and exercise total peripheral resistance were significantly higher, and exercise cardiac output was significantly lower in the hypertensive than in the normotensive subjects. 3. Administration of atenolol (1 × 100 mg day‐1) for 3 days reduced supine and exercise systolic blood pressure, heart rate, and cardiac output, and increased exercise stroke volume. Supine and exercise diastolic blood pressure and exercise total peripheral resistance were unaffected by atenolol. The effects of atenolol did not differ in the normotensive and the hypertensive subjects. 4. Maximal work load, maximal oxygen uptake, and maximal heart rate were reduced to a similar extent in normotensive and hypertensive subjects during atenolol treatment. 5. It is concluded that there is no difference in the effects of short‐term atenolol administration on exercise haemodynamics and maximal exercise capacity in normotensive and mildly hypertensive subjects.
Pimobendane (UD‐CG 115 BS) in the treatment of severe congestive heart failure. An acute haemodynamic cross‐over and double‐blind study with two different doses.
Authors: Walter M , Liebens I , Goethals H , Renard M , Dresse A , Bernard R
Published: July 2012

1. We compared the effects of two doses (5 and 10 mg) of oral pimobendane (UD‐CG 115) on haemodynamics in eight patients suffering from chronic congestive heart failure. The two doses were given according to a randomized cross‐over double‐blind protocol; haemodynamics and plasma levels of pimobendane and its main metabolite UD‐CG 212, were determined 1, 2, 3, 5, 7, 9, 11 and 12 h after each dose. 2. Both doses significantly improved the left and right ventricular functions of these patients, with a peak action 3 h after drug intake and long duration (more than 12 h). A significant dose‐ effect relationship was observed only for pulmonary wedge pressure and right atrial pressure. Significant correlations were found between UD‐ CG 212 plasma levels and cardiac index (r = 0.54, P less than 0.05), and pulmonary wedge pressure (r = 0.74, P less than 0.001); no correlation was found between these haemodynamic variables and pimobendane plasma levels. 3. One patient developed a transient drop in blood platelets together with a cutaneous rash, while three others had a transient and mild decrease of thrombocytes. 4. In conclusion, pimobendane improved right and left ventricular functions in severe heart failure. Both doses (5 and 10 mg) were effective. The higher dose induced marked improvement of the haemodynamic variables but the difference between doses was only significant for right atrial and pulmonary wedge pressures.
Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.
Authors: Partanen J , Heikkila J , Pellinen T , Nieminen MS
Published: July 2012

1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/‐ s. d.) were 0.4 +/‐ 0.2, 0.6 +/‐ 0.3 and 1.4 +/‐ 0.5 nmol l‐1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/‐ 10 to 53 +/‐ 6 beats min‐1, and fractional shortening rose from 28 +/‐ 6 to 33 +/‐ 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose‐related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/‐ 6 to 86 +/‐ 6 beats min‐1 (0.25 mg) and to 83 +/‐ 6 beats min‐1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long‐term digoxin on heart rate is partly direct without autonomic mediation. The effect of digoxin is dose‐dependent.
Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.
Authors: Robson RA , Miners JO , Birkett DJ
Published: July 2012

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1‐ and 3‐ demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1‐ and 3‐ demethylation and 8‐hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.
Absence of excess peripheral muscle fatigue during beta‐adrenoceptor blockade.
Authors: Cooper RG , Stokes MJ , Edwards RH , Stark RD
Published: July 2012

1. In eight normal volunteers, the adductor pollicis (AP) was fatigued using intermittent trains of programmed, supramaximal stimulation at 1, 10, 20, 50, 100 and 1 Hz. Activity protocols were performed both with and without circulatory occlusion, both without and during propranolol 80 mg thrice daily in order to investigate the effects of beta‐ adrenoceptor blockade on ‘peripheral’ fatigue mechanisms. 2. The degree of beta‐adrenoceptor blockade was assessed by the reduction of exercise tachycardia during cycle ergometry, e.g. pulse rates at 210 watts were reduced from 190 +/‐ 15 to 127 +/‐ 5 beats min‐1 (mean +/‐ 1 s.d.) indicating that beta‐adrenoceptor blockade was substantial and highly significant (P less than 0.001). 3. Before, during and following fatiguing activity with circulatory occlusion force declines were identical during and without beta‐adrenoceptor blockade. During and following activity without occlusion, there were slight declines in force which were questionably significantly different at 20 Hz (P less than 0.05). 4. The compound muscle action potential (CMAP) amplitude, measured from the skin surface over the muscle, was unaltered by beta‐ adrenoceptor blockade before, during or after activity whether with or without circulatory occlusion. 5. The maximal relaxation rate (MRR) was not significantly reduced in previously unfatigued muscle during beta‐ adrenoceptor blockade. During activity, both with and without circulatory occlusion, there was no evidence that MRR was reduced significantly more during beta‐adrenoceptor blockade. 6. The absence of a convincing effect of beta‐adrenoceptor blockade on peripheral fatigue mechanisms may indicate that central mechanisms are involved or that impairments of peripheral force production, of a specific nature or as a result of exacerbation of limitations of circulatory oxygen transport, though small are detected during voluntary exercise and give rise to increases in motor unit recruitment and/or firing rates, and hence increased perception of fatigue.
Effects of the beta 2‐adrenoceptor antagonist ICI 118,551 on blood pressure in hypertensive patients known to respond to beta 1‐ adrenoceptor antagonists.
Authors: Robb OJ , Webster J , Petrie JC , Harry JD , Young J
Published: July 2012

1. The selective beta 2‐adrenoceptor antagonist ICI 118,551, 50 mg orally given thrice daily, did not lower blood pressure in hypertensive patients known to respond to therapy with atenolol or propranolol. 2. This dosage regimen resulted in a small decrease in supine heart rate which might represent partial beta 1‐adrenoceptor antagonism by ICI 118,551. 3. The results suggest that beta 2‐selective antagonism does not play a role in the hypotensive action of beta‐adrenoceptor antagonists.
The influence of aprotinin on regional absorption of soluble human insulin.
Authors: Owens DR , Vora JP , Birtwell J , Luzio S , Hayes TM
Published: July 2012

1. The absorption of 6U of soluble human insulin following subcutaneous injection into the anterior abdominal wall, thigh and into the thigh following admixture with aprotinin was assessed in normal subjects. The plasma immunoreactive insulin profiles were determined during a 6 h post injection period in subjects receiving concomitantly somatostatin to suppress endogenous insulin secretion. 2. Subcutaneous injection of human insulin into the anterior abdominal wall compared with the thigh led to significantly higher incremental insulin levels between 30 and 50 min (P less than 0.05) followed by lower values at 240‐300 min (P less than 0.05). The absorption of soluble human insulin from a subcutaneous depot is faster from the anterior abdominal wall compared with the thigh associated with a faster clearance from plasma. 3. Injection into the thigh of insulin admixed with aprotinin resulted in higher plasma insulin levels at 10 min (P less than 0.001) and 20 min (P less than 0.05) compared with insulin given alone. Similarly, the insulin level was significantly higher with the admixture between 10 and 20 min (P less than 0.05) compared with insulin into the anterior abdominal wall. 4. Admixture of insulin with aprotinin therefore leads to an acceleration of the early phase of absorption from subcutaneous tissue due to a local hyperaemic effect.
The immunocytochemical localisation and distribution of cytochrome P‐ 450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P‐450.
Authors: Murray GI , Barnes TS , Sewell HF , Ewen SW , Melvin WT , Burke MD
Published: July 2012

1. The localisation and distribution of cytochrome P‐450 in human tissues has been studied by immunocytochemistry using a monoclonal antibody to a major form of human hepatic cytochrome P‐450, P‐450hA7, which is closely related to cytochromes P‐450 HLp and P‐450NF. 2. Strong immunoreactivity was identified in hepatocytes, columnar absorptive epithelial cells of the small intestine, polymorphonuclear leucocytes and their precursors in the bone marrow, and in mast cells. 3. Weak immunoreactivity was present in the proximal tubules of the kidney, pancreatic acini, gall bladder epithelium, squamous epithelium and sebaceous glands of the skin, interstitial cells of the testis and luteal cells of the ovary. 4. Immunoreactivity could not be demonstrated in the adrenal gland, placenta, colonic epithelium and alveolar type II cells and Clara cells of the lung.
Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline.
Authors: Whyte KF , Reid C , Addis GJ , Whitesmith R , Reid JL
Published: July 2012

1. We have previously shown that salbutamol induced hypokalaemia, like adrenaline induced hypokalaemia, is the result of stimulation of a membrane bound beta 2‐adrenoreceptor linked to Na+/K+ ATPase. We have also demonstrated that adrenaline induced hypokalaemia is potentiated by therapeutic concentrations of theophylline. 2. In a single‐blind study of 14 normal volunteers, we infused salbutamol in doses used in clinical practice and examined the effects of the addition of theophylline alone or combined with (‐)‐adrenaline on plasma potassium levels, heart rate and blood pressure. The combinations studied were (i) salbutamol + vehicle control adrenaline infusion + placebo theophylline; (ii) salbutamol + vehicle control adrenaline infusion + theophylline; (iii) salbutamol + adrenaline + theophylline. 3. In a randomised, balanced placebo controlled design oral slow release theophylline or placebo was given for 9 days. Subjects were studied twice on the active limb (days 7 and 9) and once on the placebo limb (day 9) and the procedure was identical on each of the 3 study days except for the solutions administered. 4. Theophylline increased salbutamol induced hypokalaemia and in some individuals profound hypokalaemia (less than 2.5 mmol l‐1) was observed with these relatively low doses of salbutamol and theophylline. Adrenaline did not further increase the magnitude of the fall in potassium observed. Combining theophylline with salbutamol increased the tachycardia resulting from the salbutamol infusion. Salbutamol infusion caused a fall in diastolic and rise in systolic blood pressure on all 3 study days and this was not altered by either theophylline or adrenaline alone or together.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of bile on cyclosporin absorption in liver transplant patients.
Authors: Mehta MU , Venkataramanan R , Burckart GJ , Ptachcinski RJ , Delamos B , Stachak S , Van Thiel DH , Iwatsuki S , Starzl TE
Published: July 2012

1. We quantitated the effect of biliary diversion on cyclosporin (CyA) absorption in liver transplant patients. Multiple blood samples were obtained over one dosing interval following oral CyA administration in eight liver transplant patients before and after T‐tube clamping. 2. Cyclosporin concentrations were measured by a high pressure liquid chromatographic method. 3. The mean (+/‐ s.d.) dose‐normalized area under the blood concentration vs time curve (AUC) over a dosing interval was 5.23 (+/‐ 3.22) ng ml‐1 h during the pre clamping period and 15.79 +/‐ 7.92 ng ml‐1 h during the post clamping period. A significant (P less than 0.05) increase (276%) in the dose normalized AUC was observed following the T‐tube clamping. 4. Analysis of bile revealed less than 1 mg (less than 1% of dose) of unchanged CyA to be eliminated in bile over 12 h. Therefore the increased CyA AUC/dose following T‐tube ligation cannot be explained by enterohepatic recirculation. 5. Increased bile flow secondary to clamping of the T‐ tube most likely increased the absorption of CyA. Increase in CyA absorption may be due to a bile mediated increase in CyA solubility or gastrointestinal membrane permeability, or increased residence time at the site of absorption. 6. Independent of the mechanism involved, our results indicate that adjustments in CyA dosage must be made whenever external bile diversion is instituted or discontinued.
Stereospecific assay of nicoumalone: application to pharmacokinetic studies in man.
Authors: Gill TS , Hopkins KJ , Rowland M
Published: July 2012

1. A stereospecific h.p.l.c. assay of nicoumalone in plasma has been developed. 2. The assay was applied to a study in which 20 mg racemic nicoumalone was given orally to three volunteers and blood samples taken for 168 h. 3. The mean pharmacokinetic parameters of the individual enantiomers were: clearance/bioavailability 1.28 1 h‐1, R‐ enantiomer; 17.5 1 h‐1, S‐enantiomer: volume of distribution/bioavailability 12.5 1, R‐enantiomer; 22.6 1, S‐ enantiomer: terminal half‐life 6.8 h, R‐enantiomer; 0.91 h, S‐ enantiomer. 4. The data are consistent with a substantial first‐pass hepatic loss of S‐nicoumalone.
Warfarin dosage requirements: prospective clinical trial of a method for prediction from the response to a single dose.
Authors: Jupe DM , Peterson GM , Coleman RL , McLean S
Published: July 2012

We have previously described a model for predicting individual daily maintenance dosage (MD) requirements of warfarin 24 h after the administration of a single dose. This model relies on measurement of the initial anticoagulant response as the 24 h percentage fall in plasma clotting factor VII activity. It permits prediction of the individual MD given the size of the initial dose, a baseline and desired maintenance value of the prothrombin ratio, and a baseline and 24 h plasma level of factor VII activity. We now present the results of a prospective clinical trial of the method. Data from 65 patients were suitable for analysis. The mean daily MD of warfarin was 4.0 mg (range 1‐10 mg). There was a moderately strong linear relationship between predicted and actual MDs of warfarin (r = 0.66, P less than 0.001). Actual vs predicted MDs in individual patients were not significantly different. The mean difference was 0.39 mg. The results of this prospective trial suggest that our model predicts warfarin MD requirements with reasonable accuracy. Nevertheless, the accuracy of the model is not sufficient to replace careful clinical and haematological monitoring of each patient commencing warfarin therapy.
Effect of valpromide on the pharmacokinetics of carbamazepine‐10, 11‐ epoxide.
Authors: Pisani F , Fazio A , Oteri G , Spina E , Perucca E , Bertilsson L
Published: July 2012

The single oral dose pharmacokinetics of carbamazepine‐10, 11‐epoxide (CBZ‐E) were investigated in six normal volunteers during a control session and during concurrent treatment with valpromide (VPM) (300 mg twice daily for 8 days). VPM caused a prolongation of the CBZ‐E half‐ life from 6.4 +/‐ 1.4 to 20.5 +/‐ 6.3 h and decreased CBZ‐E clearance from 73.5 +/‐ 20.0 to 23.5 +/‐ 4.0 ml h‐1 kg‐1 (P less than 0.01). These results suggest that the elevation of plasma CBZ‐E levels in patients receiving carbamazepine and VPM in combination is due to inhibition of epoxide hydrolase in the liver.
Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.
Authors: Loewen GR , Herman RJ , Ross SG , Verbeeck RK
Published: July 2012

1. The effect of dose (100 mg, 250 mg, 500 mg, 750 mg and 1000 mg) on the glucuronidation and sulphation of diflunisal was studied in six healthy volunteers. 2. Total urinary recovery ranged from 78.9 +/‐ 11.9% to 91.5 +/‐ 18.7% of the administered dose. Urinary recovery (normalized for total urinary recovery) of diflunisal sulphate (DS) significantly increased with dose from 9.3 +/‐ 3.7% to 18.1 +/‐ 4.8%. 3. Normalized urinary recovery for diflunisal phenolic glucuronide (DPG) was unaffected by dose (range: 30.6 +/‐ 3.8% to 40.6 +/‐ 6.6%). Normalized urinary recovery for the acyl glucuronide (DAG) significantly decreased from 52.3 +/‐ 4.6% to 40.2 +/‐ 3.4% as the dose increased. 4. Total plasma clearance of diflunisal significantly decreased from 14.4 +/‐ 1.4 ml min‐1 to 8.7 +/‐ 1.4 ml min‐1 as the dose increased from 100 mg to 750 mg. A further increase in dose to 1000 mg resulted in an unexplained increase in total plasma clearance to 10.3 +/‐ 1.8 ml min‐1. 5. Dose‐dependent plasma clearance of diflunisal was caused mainly by saturation of the formation of DAG, whereas the formation of DS and DPG were relatively unaffected by dose.
A comparison of bisoprolol and atenolol in the treatment of mild to moderate hypertension.
Authors: Lewis R , Maclean D , Ioannides C , Johnston A , McDevitt DG
Published: July 2012

1. Fourteen patients (mean age 56.0, range 37‐61 years; eight females) with mild essential hypertension (DBP greater than 90 mm Hg on placebo) completed a randomised, double‐blind placebo controlled crossover study comparing the hypotensive effects of bisoprolol (10‐20 mg) and atenolol (50‐100 mg) each taken once daily. 2. Bisoprolol had a significantly greater antihypertensive effect than atenolol, reducing sitting blood pressures by 15.9 mm Hg (diastolic) and 21.9 mm Hg (systolic) compared with placebo. Corresponding figures for atenolol were 10.7 and 5.7 mm Hg respectively. Bisoprolol reduced standing blood pressures by 15.9 mm Hg (diastolic) and 22.8 mm Hg (systolic) compared with 7.3 and 8.6 mm Hg respectively for atenolol. 3. Examination of the pharmacokinetic data showed that bisoprolol had a median elimination half‐life of 11.2 h during chronic dosing, compared with 6.4 h for atenolol. For bisoprolol, the median clearance fell from 264 ml min‐1 after a single dose to 212 ml min‐1 during chronic dosing, although clinically significant accumulation would not be expected during chronic administration. 4. Overall, the results suggest that bisoprolol may be a more effective antihypertensive agent than atenolol but larger studies are necessary to confirm these findings.
Circadian variation in theophylline absorption during chronic dosing with a slow release theophylline preparation and the effect of clock time of dosing.
Authors: Jackson SH , Johnston A , Woollard R , Abrams SM , Turner P
Published: July 2012

1. Eight volunteers were given seven doses of 200 mg of slow release theophylline at either 11.00 h and 23.00 h (regimen 1) or 17.00 h and 05.00 h (regimen 2). At the time of the sixth dose (60 h) hourly blood sampling was started and continued for 24 h. After at least 1 week volunteers crossed over to the other regimen. 2. Volunteers retired to bed at 23.00 h and arose after the 07.00 h sample during both regimens. 3. During regimen 1 there was a marked rise in mean tmax from 3.3 h after dosing at 11.00 h to 9.3 h after dosing at 23.00 h (P less than 0.001). There was also a fall in AUC(0,12) from 89.9 mg l‐1 h after dosing at 11.00 h to 79.0 mg l‐1 h after dosing at 23.00 h. There was no difference in mean Cmax values. 4. During regimen 2 these circadian changes were abolished with mean values after both dosing times lying between those observed during regimen 1. 5. A marked delay in absorption occurs at night and cannot be explained by food intake.
Penetration of nadolol into aqueous humour after a single oral dose.
Authors: Tiong TH , Hung SO , Perelman MS
Published: July 2012

Nadolol 20 mg was administered orally as a single‐blind, single dose to nine patients about to undergo cataract extraction. Intraocular pressures fell by a mean of 24% 3 h after administration. During the operation, aqueous humour and serum samples were taken for measurement of nadolol concentrations. Aqueous nadolol concentrations ranged from 3.8 to 13.4 ng ml‐1, and correlated with the serum drug concentrations (r = 0.84). The fall in intraocular pressure did not correlate with either the aqueous humour or plasma concentrations of nadolol.
LTD4‐induced bronchoconstriction in patients with asthma: lack of a vagal reflex.
Authors: Ayala LE , Choudry NB , Fuller RW
Published: July 2012

The mechanism by which leukotriene D4 (LTD4) induces bronchoconstriction in man is unclear. We have investigated this mechanism by examining the effect of nedocromil sodium and ipratropium bromide on LTD4‐induced bronchoconstriction in six mild asthmatic patients. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.08 to 100 nmol) was assessed by measuring changes in respiratory resistance (Rrs) at 6 Hz by the forced oscillation method. Results were expressed as the provocative dose causing 100% increase in Rrs (PD100). Neither nedocromil (4 mg) nor ipratropium (0.8 mg) showed significant effect on LTD4‐induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatics LTD4‐induced bronchoconstriction is unlikely to involve vagal reflexes.
Delayed‐release mesalazine (5‐aminosalicylic acid): coat dissolution and excretion in ileostomy subjects.
Authors: Riley SA , Tavares IA , Bennett A , Mani V
Published: July 2012

1. Delayed‐release mesalazine has been formulated to deliver 5‐ aminosalicylic acid to the colon. We have therefore studied the ileostomy excretion and coat dissolution of this preparation. 2. Following ingestion of a single tablet 88% (range 69‐114%) of the 400 mg dose appeared unchanged in the ileosomy effluent over the subsequent 12 h. 3. Ileostomy effluent pH appeared to be a major determinant of 5‐ aminosalicylic acid release. 4. In vitro studies revealed rapid coat dissolution above pH 7.0, slow dissolution between pH 6.0 and 7.0 and non‐dissolution at pH 2.0 and 4.0.
A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O‐deethylation of phenacetin and is inducible by cigarette smoking.
Authors: Sesardic D , Boobis AR , Edwards RJ , Davies DS
Published: July 2012

1. In previous studies (Boobis et al., 1985b) it was shown that a monoclonal antibody (MAb 3/4/2), raised against rat cytochrome P450 form c, reacts with an isoenzyme(s) of cytochrome P450 in human liver. It was predicted that the epitope with which this antibody reacts should be present on both isoenzymes of the P450IA gene sub‐family (the orthologues of forms c and d) in man (Edwards et al., 1987). 2. This antibody was used to probe 45 different samples of human liver, by the technique of Western blotting. With one exception, all of the samples contained immunoreactive protein, a single band at Mr 54,000 (orthologous to rat form d), which ranged in content from less than 0.5 to 33.5 pmol mg‐1 microsomal protein. The content of the human orthologue of form c was below 0.5 pmol mg‐1, the limit of detection of the assay. 3. Thirteen of the samples were from patients of known smoking status. Immunoreactive P450 content was 3.5‐fold higher, and phenacetin O‐deethylase activity was four‐fold higher, in the smokers than in the non‐smokers. 4. There was a highly significant correlation between the amount of immunoreactive cytochrome P450 and the high affinity component of phenacetin O‐deethylase activity in both smokers and non‐smokers. 5. It is concluded that the high affinity component of phenacetin O‐deethylase activity in man is catalysed by the orthologue of rat cytochrome P450d, and that this isoenzyme is inducible by cigarette smoking. 6. In a number of previous publications it has been suggested that there is an association between the poor metaboliser (PM) phenotype for debrisoquine and impaired phenacetin O‐deethylation. In the present study it was shown that not all subjects PM for debrisoquine are poor metabolisers of phenacetin.
Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a ‘cocktail’ approach.
Authors: Schellens JH , van der Wart JH , Danhof M , van der Velde EA , Breimer DD
Published: July 2012

1. Three model substrates for the characterization of drug oxidation activity, antipyrine (AP), hexobarbitone (HB) and theophylline (TH), were administered to 26 healthy volunteers on two different occasions: in the first experiment a combination of AP (250 mg) and HB (250 mg) was given and in the second experiment TH (150 mg) was added to the former combination. 2. Plasma concentrations of AP, HB and TH and urinary excretion of TH and the three main metabolites of AP (3‐ hydroxymethylantipyrine: HMA, norantipyrine: NORA and 4‐ hydroxyantipyrine: OHA) were determined and the intrinsic clearance (CLint) of the three substrates and the clearance to the formation of AP metabolites were calculated. 3. The correlation coefficients between CLHB and CL‐greater than metabolites of AP were highest for CL‐greater than HMA and CL‐greater than NORA (greater than 0.80) and lowest for CL‐ greater than OHA (0.63). High correlation coefficients also were found between CLTH and CL‐greater than OHA (0.89) and CL‐greater than HMA (0.80). 4. Ideal relationships, defined by a slope of the orthogonal regression line equal to unity, did exist between CLHB and CL‐greater than HMA as well as CL‐greater than NORA and between CLTH and CLAP as well as CL‐greater than OHA. 5. Based on the results of correlation and regression analysis it can be concluded that isozymes of the cytochrome P‐450 system responsible for the oxidation of HB and formation of HMA and NORA are very closely related and also that isozymes responsible for the oxidation of TH and formation of OHA show a very close relation. 6. With this strategy of simultaneous administration of substrates (‘cocktail’ approach) it seems possible to characterize and correlate activities of different P‐450 isozymes and to investigate their in vivo substrate selectivity without the disturbing influence of intra‐individual variation in drug oxidation.
Linearity of metoclopramide kinetics at doses of 5‐20 mg.
Authors: Wright MR , Axelson JE , Rurak DW , McErlane B , McMorland GH , Ongley RC , Tam YK , Price JD
Published: July 2012

The disposition of metoclopramide was studied on a four‐way crossover basis in six healthy non‐smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/‐ 0.38 (mean +/‐ s.d.) from the oral dosage forms examined in this study.