bluuebunny/crossref_metadata_2025 huggingface dataset:
Pethidine binding in plasma: effects of methodological variables.
Authors: La Rosa C , Mather LE , Morgan DJ
Published: July 2012

Several methodological variables potentially influencing the plasma protein binding of [14C]‐pethidine in vitro were investigated using equilibrium dialysis and rigorous pH control. Ionic strength of buffer, pethidine concentration and 21 days of plasma samples frozen to −8 degrees C did not affect the outcome of the binding experiments. Unbound fraction decreased with increasing temperatures between 25 degrees C and 37 degrees C. Unbound fraction decreased with increased pH between pH 7.0 and 8.0; the mean unbound fraction at an equilibrium pH of 7.4 and at 37 degrees C was 0.58 (s.d. 0.03, n = 58). It is likely that previous reports of pethidine unbound fraction as being between 0.2 and 0.4 represent artefacts caused by inadequate pH control during dialysis.
Desipramine pharmacokinetics in Chinese and Caucasian volunteers.
Authors: Rudorfer MV , Lane EA , Chang WH , Zhang MD , Potter WZ
Published: July 2012

In order to better define the role of pharmacokinetic variation in reported cross‐ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics of the tricyclic antidepressant desipramine (DMI) were studied in 14 Chinese and 16 Caucasian healthy volunteers. DMI and 2‐OH‐DMI concentrations were assayed with h.p.l.c. in serial plasma and 24 h urine samples over 5 days following an oral 100 mg dose of DMI. Mean total clearance of DMI (CLDMI) from plasma was significantly (P less than 0.05) higher in the Caucasians (123 +/‐ 57 l/h) than in the Chinese (73.5 +/‐ 38.8 l/h). There was no significant difference in the apparent clearance of DMI by hydroxylation, fraction of dose metabolized to the hydroxy metabolite, DMI t1/2 or plasma protein binding between the two groups. Trimodal distribution of CLDMI was found, with 4/14 (29%) Chinese demonstrating slow CL (less than 33 l/h) and 4/16 (25%) Caucasians rapid CL (greater than 195 l/h). Correcting CL values for the greater mean weight of the Caucasians did not alter the pattern of distribution. CLDMI did not correlate with body weight. Although environmental factors cannot be ruled out, these results are consistent with genetically based differences in hepatic metabolism, probably affecting pathways in addition to hydroxylation, and suggest that 30% of Orientals would be at risk for toxicity from routine doses of tricyclics or similarly metabolized drugs.
Pharmacokinetics of (+)‐, (‐)‐ and (+/‐)‐verapamil after intravenous administration.
Authors: Eichelbaum M , Mikus G , Vogelgesang B
Published: July 2012

The pharmacokinetics of (+)‐, (‐)‐, and (+/‐)‐verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (‐)‐ and (+)‐isomers. The values for CL, V, Vz, and Vss of the (‐)‐isomer were substantially higher as compared to the (+)‐isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (‐)‐ and 5, 25 and 50 mg of (+)‐verapamil. Protein binding for the two isomers was also different. The fu of (‐)‐ (0.11) was almost twice as much as that of (+)‐verapamil (0.064). Pharmacokinetic parameters of (+/‐)‐verapamil, which was administered to three subjects who had received (+)‐ and (‐)‐ verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (‐)‐verapamil the extraction ratio of the (‐)‐isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (‐)‐verapamil will be substantially less. Since the (‐)‐isomer is more potent than the (+)‐isomer, the present findings could explain the reported differences in the concentration‐effect relationship after i.v. and oral administration of racemic verapamil.
Interaction between warfarin and propranolol.
Authors: Scott AK , Park BK , Breckenridge AM
Published: July 2012

The interaction between propranolol and warfarin was investigated in six healthy volunteers using a low dose warfarin protocol and in New Zealand white rabbits. Warfarin concentration (Cmin) in the volunteers increased by 14.7% on addition of propranolol (P less than 0.02). There was no significant change in prothrombin time. In the rabbit study, elimination half‐life was shorter in the propranolol treated animals (8.20 +/‐ 0.44 h) than in controls (10.89 +/‐ 0.62 h). This was due to a fall in its volume of distribution from 1.13 +/‐ 0.10 1 kg‐1 in controls to 0.81 +/‐ 0.08 1 kg‐1 in the propranolol treated group. Clearance was not significantly altered. The small change in warfarin concentration could be of clinical importance in some patients because warfarin has a low therapeutic index. This requires further investigation.
The effect of single doses of penbutolol and propranolol L.A. on psychomotor performance.
Authors: Broadhurst AD , Monaghan AT
Published: July 2012

The effect of single oral doses of penbutolol (40 mg) and propranolol L.A. (160 mg) on psychomotor performance of 12 normal individuals has been investigated. Subjects were randomly administered penbutolol, propranolol L.A. and placebo according to a double‐blind, three‐part cross‐over design. At 3 h post‐dosing both penbutolol and propranolol L.A. significantly increased (P less than 0.001) complex reaction times when compared to placebo. By 24 h post‐dosing the mean complex reaction times for penbutolol and propranolol L.A. were not significantly different from placebo.
The influence of naloxone on the circulatory effects of captopril.
Authors: Rubin PC , Millar JA , Sturani S , Lawrie C , Reid JL
Published: July 2012

The fall in blood pressure produced by captopril is not accompanied by a compensatory tachycardia. Angiotensin converting enzyme may participate in the metabolism of endogenous opioids and these substances can lower blood pressure without reflex tachycardia. It is therefore possible that the hypotensive effect of captopril involves an action on endogenous opioid metabolism. The influence of naloxone, an opiate receptor antagonist, on the cardiovascular effects of captopril has been studied in nine normal volunteers. Mean blood pressure following a 70 degrees head up tilt 1.5 h after captopril was significantly lower than following placebo, but the blood pressure following the combination of captopril and naloxone differed from neither the placebo nor the captopril values. Blood pressures (mm Hg) were: placebo 97.7 +/‐ 5.9; captopril 83.3 +/‐ 14.2; captopril + naloxone 89.6 +/‐ 11.8. Heart rate (beats/min) following a 70 degrees head up tilt at 1.5 h was the same on all three treatments: placebo 83.4 +/‐ 21.1; captopril 83.3 +/‐ 16.5; captopril + naloxone 83.6 +/‐ 11.8. Maximum systolic blood pressure achieved during isometric exercise following captopril + naloxone was intermediate between, and did not differ significantly from, pressures obtained on the other two treatment days. We conclude that co‐administration of naloxone may attenuate the effect of captopril on blood pressure and that endogenous opioids could be involved in the actions of this drug.
The relaxant action of hymecromone and lignocaine on induced spasm of the bile duct sphincter.
Authors: McFarland RJ , Corbett CR , Taylor P , Nash AG
Published: July 2012

The retained stone in the common bile duct remains a problem for the surgeon. Although more effective methods are available, mechanical flushing of the bile duct is, when successful, a simple solution. Pharmacological dilatation of the sphincter of Oddi is a logical adjunct to flushing. Pressure changes in the bile duct during flushing were studied in 20 postoperative patients with T‐tube drains and the effectiveness of two drugs in reducing Omnopon induced spasm of the sphincter was compared. Hymecromone intravenously and lignocaine via the T‐tube were equally effective, reducing sphincter activity in the majority of patients, but there was considerable individual variation.
Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol.
Authors: Gangji D , Juvent M , Niset G , Wathieu M , Degreve M , Bellens R , Poortmans J , Degre S , Fitzsimons TJ , Herchuelz A
Published: July 2012

The influence of chronic therapy with nifedipine on the pharmacokinetics of propranolol 80 mg twice daily, metoprolol 100 mg twice daily and atenolol 100 mg once daily was investigated in eight healthy volunteers. Nifedipine 10 mg three times daily did not affect the pharmacokinetics of metoprolol and atenolol whereas nifedipine shortened the time to peak plasma concentration for propranolol by about 1 h. Propranolol, metoprolol and atenolol provoked comparable decreases in heart rate measured at rest and during exercise. The beta‐ adrenoceptor blocking properties of propranolol, metoprolol and atenolol were not affected by concomitant therapy with nifedipine. The present study did not show significant pharmacokinetic and pharmacodynamic interactions between nifedipine and lipophilic beta‐ adrenoceptor blockers.
Comparison of the effects of ranitidine, cimetidine and thioridazine on psychomotor functions in healthy volunteers.
Authors: Theofilopoulos N , Szabadi E , Bradshaw CM
Published: July 2012

Eight healthy male volunteers participated in four experimental sessions in which they ingested one of the following drugs: ranitidine hydrochloride (150 mg), cimetidine hydrochloride (400 mg), thioridazine hydrochloride (50 mg), placebo (lactose). Drugs were allocated to subjects and sessions in a double‐blind fashion, according to a balanced cross‐over design. The subjects' mood state and psychomotor performance were assessed 1 and 3 h after drug taking. Mood state was measured using a battery of visual analogue scales, and psychomotor performance using pencil‐and‐paper tests, critical flicker fusion frequency, wire‐maze tracing and tapping. Ranitidine and cimetidine had no significant effect on subjectively rated alertness, whereas thioridazine caused a significant decrease in alertness. Ranitidine and cimetidine had no significant effect on performance on the pencil‐and‐ paper tests (digit cancellation, digit symbol substitution, symbol copying), whereas thioridazine caused a significant decrement on these tests. Ranitidine and cimetidine had no significant effect on critical flicker fusion frequency, wire‐maze tracing, and tapping rate. Thioridazine caused a significant impairment of psychomotor performance as evidenced by all the instrumental tests. It is concluded that, in contrast to thioridazine and similarly to cimetidine, ranitidine has little effect on subjectively rated alertness and psychomotor performance in healthy volunteers.
The effects of cyclosidimine, a peripheral vasodilator drug, on blood pressure and heart rate in healthy subjects.
Authors: Shanks RG , Balnave K , Russell C
Published: July 2012

Cyclosidimine is a new vasodilator drug with a direct action on vascular smooth muscle. Oral administration of 2.5, 5.0 and 7.5 mg in five normal volunteers had no effect on blood pressure in the supine position but reduced systolic and diastolic pressure in the erect position. In both positions heart rate was significantly greater after cyclosidimine than after placebo. Propranolol prevented the increases in heart rate produced by cyclosidimine which then produced greater reductions in blood pressure.
Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion.
Authors: Karhunen M
Published: July 2012

Concentrations of metronidazole and tinidazole were analysed in mother's serum, placental tissue and foetal tissue after a single intravenous infusion of 500 mg of either drug in 21 patients who underwent a first trimester legal abortion. At the time of the evacuation (60 min from the start of the infusion) the concentrations of metronidazole and tinidazole in serum were 13.6 +/‐ 0.6 micrograms/ml and 13.2 +/‐ 0.4 micrograms/ml, respectively. In foetal tissue the concentrations of metronidazole and tinidazole reached 66% and 58%, and in placental tissue 26% and 37%, of the respective serum values.
Lack of a pharmacokinetic interaction between nifedipine and the beta‐ adrenoceptor blockers metoprolol and atenolol.
Authors: Kendall MJ , Jack DB , Laugher SJ , Lobo J , Smith S Rolf
Published: July 2012

Nifedipine, metoprolol and atenolol were administered orally to young, healthy volunteers. Each drug was given alone and nifedipine was also given with both beta‐adrenoceptor blockers. Each drug was given for 3 days immediately before the study days. Plasma and urine drug concentrations were measured and the relevant pharmacokinetic parameters calculated. No pharmacokinetic interaction between nifedipine and the beta‐adrenoceptor blockers was revealed.
Assessment of beta‐adrenoceptor selectivity of a new beta‐adrenoceptor antagonist, bisoprolol, in man.
Authors: Tattersfield AE , Cragg DJ , Bacon RJ
Published: July 2012

Bisoprolol is a new beta‐adrenoceptor antagonist which has shown beta‐ adrenoceptor selectivity in studies in isolated tissues. Bronchial and cardiac beta‐adrenoceptor blockade were assessed in eight normal subjects before and after oral ingestion of placebo, bisoprolol 20 and 40 mg, metoprolol 200 mg and propranolol 80 mg in random order. Bronchial beta‐adrenoceptor blockade was assessed as the displacement of the bronchodilator dose‐response curve to inhaled isoprenaline after each beta‐adrenoceptor blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta‐ adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the fifth minute of exercise at 70% of the subject's maximum work rate. Bisoprolol 20 and 40 mg caused a 24 and 25% reduction in exercise heart rate respectively, compared to 26% with metoprolol 200 mg and 20% with propranolol 80 mg. The dose ratios for the airway dose‐response curves for the four beta‐adrenoceptor blocking drugs were 1.04 and 3.4 for bisoprolol 20 and 40 mg, 1.4 for metoprolol 200 mg and 30 for propranolol 80 mg. Both doses of bisoprolol produced considerably less bronchial beta‐adrenoceptor blockade than propranolol 80 mg despite causing a greater reduction in exercise heart rate. Bisoprolol 20 mg caused a similar amount of bronchial beta‐adrenoceptor blockade and a similar reduction in exercise heart rate as metoprolol 200 mg, confirming that it is cardio‐selective in man.
Effects of cimetidine on carbamazepine auto‐ and hetero‐induction in man.
Authors: Macphee GJ , Thompson GG , Scobie G , Agnew E , Park BK , Murray T , McColl KE , Brodie MJ
Published: July 2012

The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme‐inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. CMT alone had no significant effect on antipyrine kinetics, urinary 6 beta‐ hydroxycortisol excretion or leucocyte delta‐aminolaevulinic acid synthase (ALA.S) activity. CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P less than 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. Antipyrine clearance and urinary 6 beta‐hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P less than 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 beta‐hydroxycortisol excretion was unaffected. Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P less than 0.05). CBZ half‐life fell by 36% and clearance rose by 29% (both P less than 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. CMT inhibits CBZ auto‐ and hetero‐induction in man. Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.
The influence of cimetidine on the pharmacokinetics of 5‐fluorouracil.
Authors: Harvey VJ , Slevin ML , Dilloway MR , Clark PI , Johnston A , Lant AF
Published: July 2012

The influence of cimetidine pretreatment on the pharmacokinetics of 5‐ fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration‐time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/‐ 4.5 micrograms/ml (mean +/‐ s.e. mean) to 32.6 +/‐ 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/‐ 133 micrograms/ml‐1 min (mean +/‐ s.e. mean) to 911 +/‐ 152 micrograms ml‐1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/‐ 96 micrograms ml‐1 min (mean +/‐ s.e. mean) to 1353 +/‐ 124 micrograms ml‐1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/‐ 116 ml/min (mean +/‐ s.e. mean) to 711 +/‐ 87 ml/min (P less than 0.01). The elimination half‐life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.
Atenolol pharmacokinetics in patients on continuous ambulatory peritoneal dialysis.
Authors: Salahudeen AK , Wilkinson R , McAinsh J , Bateman DN
Published: July 2012

The elimination of atenolol (20 mg i.v.) has been studied in seven patients with renal failure on continuous ambulatory peritoneal dialysis (CAPD). Although atenolol was eliminated in the peritoneal fluid, the amount recovered in 24 h was relatively low (1.2 +/‐ 0.15 mg). The calculated urinary (n = 4) and peritoneal (n = 7) clearance was 0.289 +/‐ 0.058 l/h and 0.152 +/‐ 0.018 l/h respectively. This was considerably less than calculated total body clearance (1.21 +/‐ 0.086 l/h). The kinetics of atenolol in CAPD are worthy of further study.
The effect of acetylator phenotype on the disposition of aminoglutethimide.
Authors: Adam AM , Rogers HJ , Amiel SA , Rubens RD
Published: July 2012

Aminoglutethimide (AG) 500 mg was administered orally to four normal volunteers and eight patients undergoing treatment for metastatic breast cancer. In each subject the acetylator phenotype was established from the monoacetyldapsone (MADDS)/dapsone (DDS) ratio. Acetylaminoglutethimide (acetylAG) rapidly appeared in the plasma and its disposition paralleled that of AG. A close relationship (P less than 0.01) was observed between the acetyl AG/AG and MADDS/DDS ratio suggesting that AG may undergo polymorphic acetylation like DDS. AG half‐life was 19.5 +/‐ 7.7 h in seven fast acetylators of DDS and 12.6 +/‐ 2.3 h in five slow acetylators and its apparent metabolic clearance was significantly (P less than 0.01) related to the acetylAG/AG ratio. Over 48 h the fast acetylators excreted 7.7 +/‐ 4.4% of the administered AG dose in the urine as unchanged AG as compared to 12.4 +/‐ 2.8% in slow acetylators. A much smaller fraction of the dose was excreted as acetylAG: 3.6 +/‐ 1.5% by fast and 1.9 +/‐ 1.0% by slow acetylators respectively. After 7 days treatment with AG at an accepted clinical dose regimen to the eight patients there were significant reductions in the half‐lives of AG (P less than 0.01) and acetylAG (P less than 0.01) and a trend (0.1 greater than P greater than 0.05) towards reduction of the acetylAG/AG ratio which became significant (P less than 0.05) if the one patient on a known enzyme inducer was omitted. The mean apparent volume of distribution was not significantly (P greater than 0.1) altered but the mean apparent systemic clearance of AG was increased (P less than 0.05). These changes are attributed to auto‐induction of oxidative enzymes involved in AG metabolism.
Genetic aspects of the polymodally distributed sulphoxidation of S‐ carboxymethyl‐L‐cysteine in man.
Authors: Mitchell SC , Waring RH , Haley CS , Idle JR , Smith RL
Published: July 2012

Interindividual variation in the sulphoxidation of S‐carboxymethyl‐L‐ cysteine (750 mg p.o.) was investigated in 200 healthy volunteers. Nearly a 100‐fold difference was observed between individuals with respect to the amount of sulphoxide metabolites detected in their 0‐8 h urine (0.6 to 59.1% recovery). Such a difference was shown to be reproducible over several months in 40 subjects who spanned the entire range of capacities. Cumulative plots and maximum likelihood analysis of the distribution indicated that a bimodal model was most probable. Analysis of pedigree data obtained from 12 families suggested a genetic effect with overlying environmental influences.
Comparative bioavailability of tetracycline and lymecycline.
Authors: Sjolin‐Forsberg G , Hermansson J
Published: July 2012

The relative bioavailability of lymecycline and tetracycline hydrochloride was compared in 12 healthy volunteers in a double‐blind cross‐over study using a high performance liquid chromatographic method for plasma and urine analyses. A statistical significant difference in favour of tetracycline hydrochloride was found concerning the mean AUC and the mean lag time. The relative bioavailability of lymecycline was only 70% compared with tetracycline in multiple dosing (19.13 +/‐ 5.39 micrograms ml‐1 h and 27.22 +/‐ 6.26 micrograms ml‐1 h respectively) and 80% in a single dose (21.88 +/‐ 4.23 micrograms ml‐1 h and 26.91 +/‐ 6.01 respectively) and the mean lag time of tetracycline was only 60% compared with lymecycline.
Accuracy and clinical utility of simplified tests of antipyrine metabolism.
Authors: Farrell GC , Zaluzny L
Published: July 2012

High‐performance liquid chromatography (h.p.l.c.) was used to measure plasma antipyrine concentrations in sixteen healthy subjects; five males, six females taking oral contraceptive steroids (OCS) and five age‐matched females not taking OCS. Following oral administration of the drug, antipyrine clearance could be determined with similar precision and accuracy from plasma concentrations at two selected times (4 h and 24 h) (‘two‐sample antipyrine clearance test’) as from six samples taken over two to three elimination half‐lives (t1/2) of the drug (‘conventional antipyrine clearance test’). Provided times for plasma sampling were modified appropriately, the two‐sample antipyrine clearance test also gave reliable results in four patients taking phenytoin (sampling times 4 h and 8 h) who had significantly enhanced antipyrine clearance, and in nine patients with severe liver disease (using 4 h and 48 h) in whom antipyrine clearance was impaired. Urinary excretion of antipyrine metabolites (from 0‐24 h) was determined in the above groups. Antipyrine systemic clearance correlated best with the percentage of administered dose excreted as 4‐hydroxyantipyrine (r = 0.66, P less than 0.001) but also with 3‐hydroxymethylantipyrine (r = 0.54, P less than 0.001) and with total metabolites excreted (r = 0.60, P less than 0.001). Total antipyrine metabolites excreted in urine in 24 h were significantly different from controls only in patients with liver disease (14 +/‐ 7.6% of administered dose vs 62 +/‐ 14%, P less than 0.001). The relative proportion of antipyrine metabolites did not appear to be altered when hepatic mixed function oxidation was induced by phenytoin or inhibited by OCS or by severe liver disease.
Effects of ethanol ingestion on alpha‐adrenoceptor‐mediated circulatory responses in man.
Authors: Eisenhofer G , Lambie DG , Johnson RH
Published: July 2012

The acute effects of ethanol on pressor responses to graded intravenous infusions of noradrenaline (24, 48, 90 ng kg‐1 min‐1) and methoxamine (0.2, 0.4, 0.8, 1.6, 2.0 mg/min, 1 min each) were each investigated in eight normal male subjects. The effects of ethanol on blood pressure, heart rate and plasma catecholamine responses to lower body negative pressure were also examined in six normal male subjects. Each subject acted as his own control by participating twice, once after consumption of ethanol (1.0 ml/kg, 20% v/v, in orange juice) and once after an equivalent volume of orange juice. Ethanol consumption significantly reduced the diastolic blood pressure response to infusion of noradrenaline. This occurred despite a significantly greater increase in plasma noradrenaline concentrations during infusion after ethanol. The systolic and diastolic blood pressure responses to infusion of methoxamine were both significantly reduced after ethanol. During lower body negative pressure, prior consumption of ethanol resulted in a greater fall in systolic blood pressure and a smaller rise in diastolic blood pressure. Plasma noradrenaline responses to lower body negative pressure were significantly increased after ethanol. It is concluded that acute ethanol ingestion depresses alpha‐adrenoceptor‐mediated vasoconstriction, with resulting impairment of blood pressure control.
Maximally effective plasma concentrations of enprofylline and theophylline during constant infusion.
Authors: Laursen LC , Johannesson N , Sondergaard I , Weeke B
Published: July 2012

Bronchodilating effects produced by increasing intravenously administered doses of enprofylline and theophylline compared to placebo were evaluated in 20 asthmatic outpatients. Three mean plasma plateaux of enprofylline of 1.5, 2.9 and 4.0 micrograms/ml produced a mean increase in forced expiratory volume in the first second (FEV1.0) as a percentage of baseline, of 12.8%, 18.8% and 30.1%, respectively. Comparable plasma plateaux of theophylline i.e. 5.5, 10.8 and 15.2 micrograms/ml produced a mean increase of FEV1.0 in percent of basal values of 12.4%, 21.6% and 28.2%, respectively. Enprofylline at plasma concentrations above 2.9 micrograms/ml induced more headache and slightly more nausea than theophylline and placebo. Theophylline infusion produced more tremor (finger oscillation) than enprofylline and placebo. Intravenously administered enprofylline produces bronchodilation comparable to theophylline in a mean dose ratio of 3.8.
The effects of ranitidine on pituitary‐thyroid function.
Authors: Hine KR , Harrop JS , Hopton MR , Holmes GK , Matthews HL
Published: July 2012

Although several studies have examined the effects of cimetidine on pituitary‐thyroid function, few have investigated ranitidine in this respect. We found no changes in thyroid‐stimulating‐hormone (TSH) or prolactin responses to TSH‐releasing‐hormone (TRH) in 10 patients with peptic ulcer disease given oral ranitidine. Serum total and free thyroxine (TT4 and FT4) concentrations declined slightly, whereas total and free triiodothyronine (TT3 and FT3) increased slightly following ranitidine. None of these changes achieved statistical significance. Both the ratio of TT4/TT3 and FT4/FT3, however, declined (P less than 0.05) following ranitidine. Thus ranitidine may have a minor influence on peripheral deiodination of thyroxine but has little effect on hormone production from the thyroid gland. The diagnostic value of biochemical tests of thyroid function is not seriously compromised in patients receiving ranitidine.
A study of the potential interactions between azapropazone and frusemide in man.
Authors: Williamson PJ , Ene MD , Roberts CJ
Published: July 2012

Ten healthy individuals received frusemide 40 mg orally for 7 days. Following a drug free period of 7 days they received azapropazone 600 mg twice daily for 7 days and then both treatments for a further 7 days. Sodium excretion fell from 141 +/‐ 16.8 mmol/day to 84.3 +/‐ 6.8 mmol/day (P less than 0.01) on initiation of azapropazone treatment. The natriuretic response to frusemide was unchanged by premedication with azapropazone. Urate excretion rose from 3.35 +/‐ 0.249 mmol/day to 4.98 +/‐ 0.365 mmol/day on initiation of azapropazone therapy but subsequently returned to baseline values. Plasma uric acid fell from 0.289 +/‐ 0.024 mmol/l to 0.167 +/‐ 0.0125 mmol/l (P less than 0.001) on azapropazone but rose to 0.186 +/‐ 0.0116 mmol/l (P less than 0.001) with the addition of frusemide. Azapropazone may cause sodium retention but after repeated administration frusemide still has a marked diuretic action. The hypouricaemic effect of azapropazone is only slightly antagonised by frusemide at the doses studied.
Study of the bioavailability of pindolol in malabsorption syndromes.
Authors: Evard D , Aubry JP , Le Quintrec Y , Cheymol G , Cheymol A
Published: July 2012

Pindolol kinetics and bioavailability were studied after a single dose (oral 5 mg; intravenous 3 mg) in nine patients with malabsorption (two with villous atrophies, seven with short bowel syndromes) and in six healthy volunteers. After oral administration no significant differences were observed in bioavailability (59.4 +/‐ 6.2% in patients vs 79.5 +/‐ 8.6% in controls) and for most plasma and urinary pharmacokinetic parameters between the experimental and control groups as a whole. However, detailed analysis revealed decreased absorption for pindolol in two out of nine patients. After i.v. administration, apparent distribution volume was smaller (V: 2.10 +/‐ 0.25 l kg‐1 vs 3.05 +/‐ 0.31 l kg‐1) and global elimination constant was larger (ke: 1.43 +/‐ 0.46 h‐1 vs 0.56 +/‐ 0.10 h‐1), in patients with malabsorption than in controls (P less than 0.05). The smaller weight of patients and pharmacokinetic modifications due to the pathology could account for this.
Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects.
Authors: Smith SR , Ryder C , Kendall MJ , Holder R
Published: July 2012

When conventional therapeutic doses of nebulised salbutamol were given to normal volunteers, there was a significant rise in pulse rate, systolic blood pressure and plasma glucose and a significant fall in diastolic blood pressure and serum potassium in comparison with placebo. Such changes may be potentially hazardous in certain situations. Patients with airways obstruction due to chronic bronchitis who have coexistent ischaemic heart disease or diuretic induced hypokalaemia may be at particular risk from the unwanted cardiovascular and biochemical responses to nebulised salbutamol.
Estimation of gentamicin clearance and volume of distribution in neonates and young children.
Authors: Kelman AW , Thomson AH , Whiting B , Bryson SM , Steedman DA , Mawer GE , Samba‐ Donga LA
Published: July 2012

Gentamicin therapy should be guided by serum level monitoring in all age groups, dosage adjustments depending on age related changes in pharmacokinetics. Population data analysed from two centres (43 infants from Glasgow and 100 infants and children from Manchester) by the computer program NONMEM showed that volume of distribution was related to body weight by a proportionality factor that decreased from the region of 0.41‐0.46 l/kg in children less than 3 months to 0.25‐0.32 l/kg in older children, a value which merges with that accepted for adults (0.25 l/kg). In both young and older children, clearance was also found to be dependent on body weight. Renal function (creatinine concentrations) provided no further explanatory power. When these results were used prospectively to forecast gentamicin concentrations with a Bayesian kinetic parameter estimation program, trough concentrations were more precisely predicted than peaks when a single concentration measurement was used. In clinical practice, however, two concentration measurements are usually routinely available and these should lead to greater precision of both peak and trough predictions. These results have been incorporated into a simple nomogram which can be used to determine a dose of gentamicin which will achieve target peak concentrations in infants, assuming that troughs should not exceed 2 micrograms/ml.
Azathioprine metabolism in kidney transplant recipients.
Authors: Lennard L , Brown CB , Fox M , Maddocks JL
Published: July 2012

Azathioprine metabolite concentrations were studied in 54 kidney transplant recipients. Thirty‐seven of these patients were studied over a 6 month period to investigate the intrapatient variation in metabolite concentrations. All patients had stable functioning grafts and normal peripheral white blood cell counts. The metabolites measured were plasma 6‐mercaptopurine and red blood cell 6‐thioguanine nucleotide. There was no correlation between azathioprine dose and plasma 6‐mercaptopurine concentration but there was a significant correlation between dose and red blood cell 6‐thioguanine nucleotide concentration (rs = 0.41, P less than 0.005). The individual transplant recipient showed little variation in metabolite concentrations over several months. Using this group as a control we studied metabolite concentrations in patients with kidney transplants who developed leucopenia. Our preliminary findings indicate that elevated red cell 6‐ thioguanine nucleotide concentrations, above the control range, can be associated with bone marrow depression.
Stereoselective ring oxidation of propranolol in man.
Authors: Walle T , Walle UK , Wilson MJ , Fagan TC , Gaffney TE
Published: July 2012

The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium‐labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. The (‐)/(+)‐ enantiomer ratios for unchanged propranolol, 1.50 +/‐ 0.10 (mean +/‐ s.e. mean), and propranolol glucuronide, 1.76 +/‐ 0.10, were similar to previous findings in plasma. All products of side‐chain oxidation also consisted mainly of the (‐)‐enantiomer, with an overall (‐)/(+) ratio of 1.61 +/‐ 0.11. A (‐)/(+) ratio of 1.04 +/‐ 0.17 for 4‐ hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 +/‐ 0.19 and for its sulphate conjugate of 0.27 +/‐ 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4‐ hydroxypropranolol, or both. When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)‐propranolol with a (‐)/(+)‐enantiomer ratio of 0.59 +/‐ 0.09. The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)‐propranolol, leading to a greater bioavailability of the pharmacologically more active (‐)‐propranolol and subsequent preferential side‐chain oxidation and glucuronidation of this enantiomer.
Relationship between alpha 1‐acid glycoprotein and plasma binding of disopyramide and mono‐N‐dealkyldisopyramide.
Authors: Bredesen JE , Kierulf P
Published: July 2012

Highly purified serum albumin did not bind either disopyramide (DP) or mono‐N‐dealkyldisopyramide (MND). The unbound fraction of DP and MND in highly purified serum alpha 1‐acid glycoprotein (AAG) at 0.5 g/l was 57 and 62 and at 2.0 g/l 19 and 30% respectively. Unbound DP and MND were measured in spiked plasma (10 mumol/l of DP or MND), from 60 patients, having AAG concentrations varying from 0.4 to 3.0 g/l. Unbound drug varied from 13 to 58 and from 24 to 62% for DP and MND, respectively, and was inversely related to the plasma concentration of AAG (r = ‐ 0.9016, r = ‐0.9157). A linear relationship was found between the binding ratio (moles bound divided by moles unbound) and the plasma concentration of AAG for both DP (r = 0.9199) and MND (r = 0.9270), whereas no relationship was found between the binding ratios of DP or MND and the plasma concentrations of total protein, albumin, haptoglobin, alpha 1‐antitrypsin or the immunoglobulins IgG, IgA or IgM. In patients on DP maintenance therapy, a linear relationship was found between percent unbound DP and the plasma concentration of DP in samples with similar AAG concentrations. Furthermore, a linear relationship was found between the binding ratio of DP and the plasma concentration of AAG in samples with similar DP concentrations. The present findings support the concept that AAG is the major serum protein responsible for the binding of DP and MND.
Effects of beta‐adrenoceptor blockade on exercise performance and respiratory response in healthy, physically untrained humans.
Authors: Violante B , Buccheri G , Brusasco V
Published: July 2012

The effects of propranolol 80 mg orally were compared with those of placebo on the response to a stepwise increasing exercise test in 17 healthy and physically untrained volunteers, of whom eight were female. Propranolol showed no significant effects on maximum work rate or perceived exertion rate. However, submaximal O2 uptake, CO2 output and minute ventilation tended to be lower after propranolol than after placebo. It is concluded that in subjects with a low work capacity, beta‐adrenoceptor blockade does not impair maximal exercise capacity. The mechanisms underlying changes in respiratory response to exercise after propranolol are not fully explained. However, changes in substrate utilisation, the reduction in cardiac output and an alteration in respiratory drive may all be involved.
Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients.
Authors: Jawad S , Richens A , Oxley J
Published: July 2012

The pharmacokinetics of clobazam were studied in six healthy volunteers and six age and sex matched enzyme‐induced epileptic patients. In the epileptic patients the area under the plasma concentration‐time curve for clobazam was significantly smaller and the area under the plasma concentration‐time curve for N‐desmethylclobazam was significantly greater than in the healthy volunteers. Plasma N‐desmethylclobazam concentrations were found to be much higher than those of clobazam in the epileptic patients, raising the possibility that the antiepileptic properties of clobazam are to be attributed more to its metabolite than the parent drug.
Histamine released locally after intradermal antigen challenge in man.
Authors: Heavey DJ , Ind PW , Miyatake A , Brown MJ , Macdermot J , Dollery CT
Published: July 2012

Plasma histamine concentration was measured in venous blood draining the site of antigen‐induced wheal and flare responses in the forearm skin of seven atopic volunteers. Concentrations were measured using a double isotope radioenzymatic method. The mean +/‐ s.e. mean resting plasma concentration was 0.18 +/‐ 0.01 ng/ml. In all subjects an increase was detected in local plasma histamine concentration after intradermal antigen challenge. The peak histamine concentration occurred between 2 and 15 min after challenge, and represented an increase of three‐ to 20‐fold above the resting concentration. Plasma histamine concentration remained significantly elevated for at least 60 min after challenge. A 30 min incubation at 37 degrees C of blood taken at the time of peak plasma concentration caused a fall in histamine concentration. This suggests that histamine release from basophils during the sampling procedure was not a significant problem. This method is less invasive than skin chamber or blister techniques for the demonstration of mediator release in cutaneous inflammation and allows a simultaneous assessment of tissue response.
Performance and its measurement.
Authors: Broadbent DE
Published: July 2012

Performance involves numerous sub‐functions, and cannot be treated as a unit. Several attempts have been made to separate functions impaired by different classes of drug: for example, high (monitoring) vs lower (performing) levels of function, early (perceptual) vs later (motor) functions, and strategic vs executive functions. The practical implications are that one cannot predict effects of a drug from a single performance test. One must either simulate the practical situation exactly, or use a battery of analytical tests to form a profile of effects. The latter is the policy urged in this paper.
Pencil and paper tests‐sensitivity to psychotropic drugs.
Authors: Stone BM
Published: July 2012

The literature on pencil and paper tests and the effects of psychotropic drugs is reviewed. Performance at digit symbol substitution, symbol copying, letter cancellation, arithmetic, logic and cognitive processing with a relatively constant level of triazolam was compared with placebo. Analysis of variance, covariance analysis and principal component analysis were applied to the data. Pencil and paper tests which measure various skills are useful for detecting drug effects. Letter cancellation, arithmetic and DSST appear to be most sensitive, although logic and symbol copying may be useful.
Interactions of benzodiazepines on psychomotor skills.
Authors: Mattila MJ
Published: July 2012

Interactions of centrally active drugs are difficult to analyse in man due to methodological and ethical problems. Alcoholic and methylxanthine beverages are the most common centrally active agents that might modify the effects of benzodiazepines on performance. In sufficiently large doses ethanol enhances the effects of benzodiazepines, even those that are not metabolized by mixed function oxidases sensitive to blockade by ethanol. Consequently, the combined effect of ethanol and benzodiazepines may occur at the receptor level and/or result from altered binding of benzodiazepines to plasma proteins. Newer benzodiazepines may differ from the older in their interactions. Caffeine and theophylline counteract benzodiazepine effects on performance, resulting perhaps from the blockade of adenosine receptors which could be linked with the GABA‐benzodiazepine receptor system. Central stimulants of the amphetamine type also counteract benzodiazepine effects in a somewhat selective way. New stimulant antidepressants rather counteract than increase benzodiazepine effects. Central antimuscarinics in combination with benzodiazepines are detrimental for memory. Specific benzodiazepine antagonists are effective also in man but without known clinical applications.
The role of digitalis in the future.
Authors: Poole‐Wilson PA
Published: July 2012

Cardiac glycosides exert an acute positive inotropic effect on the normal and failing heart. Recent evidence establishes that the positive inotropic effect is maintained over several months in many patients. The effectiveness of long‐term treatment with cardiac glycosides in relieving symptoms is less certain; only a small subset of patients benefits. An effect on mortality is not established. The use of digoxin in the treatment of mild heart failure is questionable since the drug has serious side‐effects and the efficacy in patients already taking diuretics has not been established. The use of glycosides in the treatment of severe chronic heart failure is being challenged because of the availability of powerful diuretics, new vasodilators and alternative positive inotropes.
Information, compliance and side‐effects: a study of patients on antidepressant medication.
Authors: Myers ED , Calvert EJ
Published: July 2012

A study was carried out to elucidate whether the improved compliance associated with the provision of verbal and written information about a prescribed drug is due to the specific information or to a non‐specific attention‐placebo effect. 120 depressed outpatients were prescribed dothiepin and randomly allocated to one of three groups: Group A were given verbal and written information about side‐effects; Group B were given verbal and written information about beneficial effects; Group C were told only that the drug was being given to treat their depression and received no written information. Compliance with medication was assessed at 3 weeks and 6 weeks by interrogation and by pill count. At the same time, side‐effects were enquired for and their occurrence or non‐occurrence noted. No significant differences were found between the groups in the rates of compliance at either 3 weeks or 6 weeks. When Groups A and B were combined to give a total ‘information’ group and compared with Group C‐the ‘no‐information’ group‐the rate of compliance at 3 weeks was significantly higher (P less than 0.05) in the ‘information’ group. No significant differences were found between the groups in the rates of reported side‐effects at either 3 weeks or 6 weeks. When Groups A and C were combined and compared with Group B (information about beneficial effects), side‐effects were found to be reported significantly less frequently (P less than 0.05) in the latter at 6 weeks. Of 175 compliance estimates, 97.7% gave concordant results for estimation by interrogation and by pill count.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption of lignocaine and bupivacaine from the respiratory tract during fibreoptic bronchoscopy.
Authors: McBurney A. , Jones DA , Stanley PJ , Ward JW
Published: July 2012

Absorption of lignocaine and bupivacaine from the upper and lower respiratory tract was studied in patients undergoing fibreoptic bronchoscopy. No significant differences were found between the drugs and between the routes of administration in terms of the time taken to achieve maximum plasma concentrations. The relative availability of lignocaine was greater following administration via the upper respiratory tract, but bupivacaine availability did not differ. The apparent clearance of lignocaine was not affected by the route of administration but bupivacaine clearance was higher following administration via the lower respiratory tract. Bupivacaine, previously unreported as a topical agent in man, produced adequate anaesthesia at one‐eighth of the dose of lignocaine. Plasma bupivacaine concentrations had a very wide safety margin.
Factors affecting the response to inhibition of drug metabolism by cimetidine‐dose response and sensitivity of elderly and induced subjects.
Authors: Feely J. , Pereira L. , Guy E. , Hockings N.
Published: July 2012

The effect of cimetidine on oxidative drug metabolism was characterised using antipyrine clearance in a group of healthy volunteers. In six subjects cimetidine produced a dose dependent reduction of antipyrine clearance: 400 mg/day (16.8 +/‐ 2.2%, mean +/‐ s.e. mean), 800 mg/day (26.3 +/‐ 1.5%) and 1600 mg/day (33.5 +/‐ 2.4%). The effect of cimetidine (800 mg/day) was of similar magnitude (approximately 25%) in two groups of six young (21‐26 years) and six elderly (65‐78 years) subjects. The effect of pretreatment begun just 1 h before administration of antipyrine was similar to that of 24 h pretreatment and that reported for chronic cimetidine pretreatment. The percentage reduction in antipyrine clearance produced by cimetidine 800 mg/day was greater (44 +/‐ 5 vs 24 +/‐ 3%; P less than 0.05) in six subjects who had been pretreated with the hepatic enzyme inducer rifampicin (600 mg/day for 21 days) than in the control uninduced state. Although cimetidine was capable of rapidly reversing the effect of rifampicin on antipyrine clearance, following withdrawal of both rifampicin and cimetidine there was still evidence of enzyme induction. These results suggest that the effect of cimetidine on oxidative metabolism is dose dependent, is more marked in enzyme induced subjects, is independent of the duration of pretreatment and is of similar magnitude in young and elderly subjects.
Nifedipine increases and glyceryl trinitrate decreases apparent liver blood flow in normal subjects.
Authors: Feely J.
Published: July 2012

The effects of sublingual nifedipine (10 mg) and of glyceryl trinitrate (500 micrograms), which produce arterial and venous vasodilatation respectively, on indocyanine green estimated apparent liver blood flow (LBF) were studied in six healthy volunteers. Nifedipine significantly increased (33 +/‐ 12%; mean +/‐ s.e. mean) and glyceryl trinitrate significantly reduced (18 +/‐ 3%) LBF. There was a positive relationship (r = 0.92, P less than 0.05) between the reduction in mean arterial pressure produced by nifedipine and the percentage increase in LBF. These results show that single doses of nifedipine and glyceryl trinitrate significantly alter LBF.