bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term experience with captopril in severe hypertension.
Authors: Havelka J , Boerlin HJ , Studer A , Greminger P , Tenschert W , Luescher T , Siegenthaler W , Vetter W , Walger P , Vetter H
Published: July 2012

1 The long‐term effect of the converting‐enzyme inhibitor captopril was investigated in 76 patients with various forms of severe hypertension, most cases being resistant to a standardised triple therapy (100 mg hydrochlorothiazide or 80‐500 mg frusemide; 320 mg propranolol; and 200 mg hydralazine). 2 In each of the three groups examined (essential, renovascular, and renal parenchymatous hypertension) captopril led to a prompt and sustained reduction in systolic and diastolic blood pressure. Up to an observation time of 2 1/2 years patients with renovascular hypertension showed a more pronounced fall in mean diastolic blood pressures than those with essential hypertension. About 90% of all patients required a diuretic and a substantial percentage of patients needed propranolol as a third drug. 3 The most frequent side effects were skin manifestations, taste disturbances, dizziness, and non‐productive cough. Serious adverse effects were rare and included one case of leucopenia and one of the nephrotic syndrome, both of them reversed after withdrawal of captopril. Further analysis showed that side effects occurred mainly in patients with impaired kidney function receiving relatively high dosages of captopril (greater than 200 mg/day). 4 Our results show that captopril is a very potent blood‐ pressure‐lowering agent in severe hypertension, especially in cases with renovascular hypertension.
Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension.
Authors: Weinberger MH
Published: July 2012

1 A placebo‐controlled, randomised double‐blind comparison of captopril 25 mg three times a day, hydrochlorothiazide 15 mg three times a day, and the combination was conducted in 207 patients with essential hypertension with supine diastolic blood pressures of 92‐110 mm Hg. Significant decreases in blood pressure were seen in all three groups; the magnitude of decrease seen with captopril and hydrochlorothiazide was similar, while the combination produced an additive response greater (p less than 0.001) than captopril or hydrochlorothiazide alone. 2 The major side effect reported was a rash in fewer than 6% of patients taking captopril alone or in combination. Loss of taste or proteinuria was not observed. 3 The addition of captopril of hydrochlorothiazide blunted the hypokalaemia and hyperuricaemia observed with hydrochlorothiazide alone in addition to its antihypertensive synergy. These observations indicate that this relatively low dose of captopril is safe and efficacious in the treatment of mild to moderate hypertension alone and particularly when combined with a thiazide diuretic.
Sustained haemodynamic and clinical effects of captopril in long‐term treatment of severe chronic congestive heart failure.
Authors: Ricci S , Zaniol P , Teglio V , Baraldi P , Mattioli G
Published: July 2012

1 The angiotensin‐converting‐enzyme inhibitor captopril is known to produce beneficial haemodynamic effects in patients with chronic congestive heart failure. 2 Twelve patients with chronic congestive heart failure were conventionally treated with digitalis and diuretic therapy plus oral captopril (75‐150 mg/day), and 14 patients were used as a control group. 3 There was no improvement in functional and haemodynamic values in the controls, but the patients treated with captopril showed a significant functional improvement (increase of exercise time and improvement in New York Heart Association functional class), a definitive decrease in systemic vascular resistance (20%), and a significant increase in the cardiac index and ejection fraction (18% and 28% respectively).
The binding of prednisolone in human serum and to recrystallized human albumin in vitro.
Authors: Steele WH , Hawksworth GM , Barber HE
Published: July 2012

1 Prednisolone binding in human serum and to recrystallized human serum albumin was measured by continuous ultrafiltration. 2 At serum concentrations of prednisolone up to 0.6 micron, 95.0% was bound but at higher concentrations the binding became non‐linear falling to 80.5% at 1.8 microns. At even higher concentrations binding in serum became linear again and paralleled the binding to albumin which was linear throughout the entire range of prednisolone concentrations. 3 A binding model was proposed which included a saturable component attributable to binding to transcortin and a non‐saturable binding to albumin. 4 Computer simulations using the experimentally determined binding parameters of the model indicated that binding in serum was critically dependent on transcortin concentration and almost independent of albumin concentration.
Variations in responses to non‐steroidal anti‐inflammatory drugs.
Authors: Scott DL , Roden S. , Marshall T. , Kendall MJ
Published: July 2012

1 This paper assesses the variability in the response of patients with rheumatoid disease to a group of non‐steroidal anti‐inflammatory drugs (NSAID). 2 Thirty six patients were divided into three groups and each group received a set of four NSAID. The different drugs were each given three times daily for a week and the treatment order was randomised. 3 The study demonstrated marked variability and unpredictability in patient responses and cast doubt on the value of comparative trials of different NSAID.
A method for monitoring drug effects on male sexual response: the effect of single dose labetalol.
Authors: Riley AJ , Riley EJ , Davies HJ
Published: July 2012

1 A method for monitoring the effect of drugs on the genital response to stimulation provided by vibration is described. 2 Using this method, the effect on male sexual response of two oral doses (100 mg and 300 mg) labetalol were studied and compared with placebo in six subjects. 3 Labetalol did not affect the attainment or maintenance of erection. 4 Labetalol delayed ejaculation in a dose‐related manner. 5 Labetalol treatment resulted in a significant dose‐related delay in detumescence.
Relationships among timolol doses, plasma concentrations and beta‐ adrenoceptor blocking activity.
Authors: Ferguson RK , Vlasses PH , Koplin J.R. , Holmes GI , Huber P. , Demetriades J. , Abrams WB
Published: July 2012

1 We investigated the relationships among dose, plasma concentration and beta‐adrenoceptor blockade after single and repeated doses (0.5‐20 mg) of timolol and placebo in six normal men. 2 Maximal suppression of exercise‐induced tachycardia (bicycle ergometry) was dose‐dependent and greater at 2 than at 6 h after dosing; activity up to 12 h was evident on the last dosing day. 3 Attenuation of exercise‐induced tachycardia was strongly correlated with the timolol dosage over the 0.5 to 5‐10 mg range. 4 A plasma timolol concentration of 27 ng/ml was associated with maximal suppression of exercise‐induced tachycardia. 5 Suppression of exercise‐induced tachycardia and areas under the plasma concentration‐ time curves did not differ significantly on the first and last dosing days.
CENTRAL α2‐ADRENOCEPTORS AND BLOOD PRESSURE REGULATION IN MAN: STUDIES WITH GUANFACINE (BS100‐141) AND AZEPEXOLE (BHT 933)
Authors: REID J.L. , RUBIN P.C. , HOWDEN C. W.
Published: July 2012

The haemodynamic and sedative actions of guanfacine and azepexole, two α2 adrenoceptor agonists, have been examined in hypertensive patients and normotensive subjects, respectively.

After oral dosing both drugs lowered supine and erect blood pressure, reduced plasma noradrenaline and caused subjective drowsiness lasting for 6–8 h.

The duration of hypotensive action of a single dose of guanfacine was 24–30 h allowing single daily dosing in several patients, while the duration of effect of azepexole was shorter (8 h).

After 8–10 weeks treatment with guanfacine was stopped. There was a gradual return of blood pressure to pre‐treatment levels over 4 days.

Both the sedative effect and the centrally mediated fall in blood pressure appear to result from activation of adrenoceptors of the α2 subtype.
Epoprostenol (prostacyclin, PGI2) binding and activation of adenylate cyclase in platelets of diabetic and control subjects.
Authors: Shepherd GL , Lewis PJ , Blair IA , de Mey C , MacDermot J
Published: July 2012

1 The binding of epoprostenol (prostacyclin, PGI2) to isolated fractured human platelets has been studied using tritiated PGI2. 2 High and low affinity binding sites for PGI2 have been identified (Kd values = 16 and 382 nM). 3 Analysis of the prostacyclin‐dependent activation of adenylate cyclase suggests that enzyme activation is mediated by the high affinity binding site. 4 Platelet PGI2 receptor binding and adenylate cyclase activation by PGI2 are unchanged in diabetic and normal human platelets. 5 This work suggests that hyperaggregability of diabetic platelets is not due to any alteration of platelet prostacyclin receptor numbers or their activation.
Effect of digoxin on the sensitivity to flickering light.
Authors: Guignard C , Van Toi V , Burckhardt CW , Schelling JL
Published: July 2012

1 The sensitivity to flickering light at various light frequencies (DeLange curve) was determined in 20 controls and 45 patients receiving maintenance doses of digoxin. 2 Flicker thresholds (mean percentage of maximal light modulation +/‐ s.d.; F 30 Hz) were 7.6 +/‐ 1.7 in controls and 9.4 +/‐ 1.7 in patients with optimal plasma digoxin levels (0.5‐1.9 ng/ml), but they rose to 15.5 +/‐ 1.9 at subtoxic levels (2.0‐ 3.0 ng/ml), and to 21.8 +/‐ 2.6 at toxic levels (above 3.0 ng/ml). 3 Flicker sensitivity was inversely correlated with plasma digoxin levels and returned to baseline values when the administration of digoxin was interrupted. 4 The DeLange curve seems to be a valuable tool to measure the toxic effects of digitalis on the visual system.
Sulphate conjugation of p‐hydroxytriamterene by platelet phenol sulphotransferase: assay conditions and correlation with metabolism in man.
Authors: Reiter C , Werness PG , Van Loon J , Smith LH , Weinshilboum RM
Published: July 2012

1 Sulphate conjugation catalyzed by phenol sulphotransferase (PST) is an important pathway in the metabolism of many drugs including triamterene. Variations in PST activity in an easily obtained tissue such as the platelet might reflect individual differences in the sulphate conjugation in other organs and tissues. Human platelets contain at least two forms of PST, a thermolabile (TL) form for which dopamine is a substrate and a thermostable (TS) form for which low concentrations of p‐nitrophenol serve as a substrate. 2 p‐OH‐ triamterene, the major metabolite of triamterene, is conjugated with sulphate in vivo. p‐OH‐triamterene was a substrate for platelet PST with an apparent Michaelis‐Menten value of 26 microM. Thermal stability studies indicated that p‐OH‐triamterene was a substrate for only the TS form of platelet PST. 3 When platelet homogenates from 29 individual subjects were tested, there was a significant correlation between PST activities measured with 4 microM p‐nitrophenol and with p‐OH‐ triamterene (r = 0.985, P less than 0.0001) but not between activities measured with dopamine and with p‐OH‐triamterene (r = 0.023, P greater than 0.2). These results confirmed that p‐OH‐triamterene was a substrate for only the TS form of human platelet PST. 4 The same 29 subjects were treated with 1 mg/kg of triamterene orally. 24‐h urinary excretions of triamterene, p‐OH‐triamterene and p‐OH‐triamterene sulphate averaged 15.3%, 6.3% and 78.4%, respectively, of the total of triamterene plus measured metabolites excreted. The excretion of triamterene plus the two metabolites averaged 43.1 +/‐ 2.6% (mean +/‐ s.e. mean) of the ingested dose. There was not a significant correlation between the proportion of p‐OH‐triamterene excreted as sulphate conjugate and the activities of either the TS or TL forms of platelet PST activity.
Effects of naloxone on post‐operative pain and steroid‐induced analgesia.
Authors: Skjelbred P , Lokken P
Published: July 2012

1 In a controlled crossover study identical oral surgical procedures were performed on two separate occasions in six patients. 2 Two h after surgery, either 40 mg methylprednisolone (Solu‐Medrol) or placebo (saline) was administered intravenously in a double‐blind randomized fashion. 3 Five h after surgery, three patients received 4 mg naloxone (Nalonee) while 3. Five h after surgery, three patients received 4 mg naloxone (Nalonee) while three patients received placebo (saline) intravenously, followed by a crossover to alternative injections 1 h thereafter. 4 Several measurements/assessments were recorded for a paired comparison of the post‐operative courses. 5 The mean pain assessment (VAS) was reduced by about 50% 45 min after the steroid injection (P = 0.03). 6 Neither increasement of the post‐operative pain nor reversal of the steroid‐induced analgesia could be demonstrated by injection of 4 mg naloxone. 7 Swelling was reduced by 46% on day 3 after the operation when the steroid was injected as compared to placebo (P = 0.06); on day 6 the reduction averaged 60% (P = 0.04). 8 According to overall assessments after the second operation all patients expressed clear preference for the post‐operative course when the steroid was injected. 9 Present and previous results in this model with bilateral oral surgery suggest that short term corticosteroid administration deserves attention as an efficient means which may be of value in reducing pain and excessive inflammation in surgery and traumatology.
Studies on the pharmacokinetics of chlorambucil and prednimustine in man.
Authors: Newell DR , Calvert AH , Harrap KR , McElwain TJ
Published: July 2012

1 Chlorambucil (10 mg) and prednimustine (20 mg), the prednisolone ester of chlorambucil, were administered orally on separate occasions to six patients. 2 Chlorambucil was rapidly absorbed such that the parent compound was observed in the plasma 30 min after administration. 3 A preliminary comparison of chlorambucil levels following oral and intravenous administration, and after repeat oral dosage indicated that chlorambucil was well (greater than 70%) and consistently absorbed. 4 Following prednimustine no parent drug or alkylating metabolites (chlorambucil or phenyl acetic mustard) could be detected in the plasma. 5 In studies with intravenously administered chlorambucil plasma levels of the parent drug were described by a two‐compartment open model with first‐order kinetics. Significant levels of the cytotoxic metabolite phenyl acetic mustard were detected. 6 It is concluded that: a. the bioavailability of orally administered prednimustine is much lower than that of chlorambucil. Thus the use of prednimustine in routine combination therapy is not recommended. b. due to the lower therapeutic index of phenyl acetic mustard in experimental systems, the production of this metabolite in man may be disadvantageous. Thus research aimed at producing chlorambucil analogues, which cannot be metabolised, seems justified.
A method to prevent the loss of isoniazid and acetylisoniazid in human plasma.
Authors: Hutchings A , Monie RD , Spragg B , Routledge PA
Published: July 2012

Plasma concentrations of isoniazid and N‐acetylisoniazid were measured at varying times after addition of both compounds to plasma (5 micrograms/ml) and storage at several different temperatures (−70 degrees C, −20 degrees C, 4 degrees C and 20 degrees C). The concentration of both compounds declined log‐linearly with time and the half‐life of decline was shorter with increasing temperature of storage. Both compounds were stable for at least 5 weeks, however, when stored at −070 degrees C. We conclude that this temperature should be used to prevent loss of both compounds during storage and transport of samples.
Dose‐response study with ibuprofen in rheumatoid arthritis: clinical and pharmacokinetic findings.
Authors: Grennan DM , Aarons L , Siddiqui M , Richards M , Thompson R , Higham C
Published: July 2012

Clinical response and plasma pharmacokinetics were studied in 20 rheumatoid patients receiving three dosages of ibuprofen. There was a significant response to 1600 mg daily of ibuprofen by all three clinical measurements but increasing the daily dosage to 2400 mg produced no overall increase in response. The AUC increased with increasing daily drug dosages from 800 to 2400 mg daily and the dose normalised AUC fell by 15% over the same dosage range. The fraction of ibuprofen not bound to plasma proteins increased with increasing dosage and may contribute to the fall in the dose normalised AUC. There was a considerably inter‐individual variation in the AUC. There was no significant correlation between AUC and clinical response as measured by articular index and there was a weakly significant correlation between AUC and clinical response as measured by a visual analogue pain index. Pharmacokinetic variables probably account for only a small part of the inter‐individual variation in response of rheumatoid patients treated with increasing dosages of the non‐steroidal, anti‐inflammatory drug ibuprofen.
Effects of bupropion, nomifensine and dexamphetamine on performance, subjective feelings, autonomic variables and electroencephalogram in healthy volunteers.
Authors: Hamilton MJ , Smith PR , Peck AW
Published: July 2012

Bupropion, a novel antidepressant, has been compared with nomifensine and dexamphetamine in a controlled double blind trial in 12 healthy volunteers. Signals detected in an auditory vigilance test were increased by dexamphetamine 5 and 10 mg when compared with lactose dummy, but unaffected by bupropion 100 and 200 mg and nomifensine 100 mg. Auditory reaction time was decreased by dexamphetamine but unaffected by bupropion and nomifensine. Heart rate was increased after all active treatments but the largest rise followed dexamphetamine 10 mg which differed from both lactose dummy and all other active treatments. Systolic blood pressure was higher after dexamphetamine 10 mg than all other treatments, none of which differed from lactose. No changes occurred in diastolic blood pressure. Pupil size increased after dexamphetamine 10 mg but no changes followed other treatments. Visual analogue scales showed that subjects were more alert, attentive, proficient, excited, interested and elated after dexamphetamine but no changes followed bupropion or nomifensine. Subjects were able to recognise that they had received an active drug only after dexamphetamine 10 mg. Increased activity was seen in the 7.5‐13.5 Hz and 13.5‐26 Hz frequency bands of the electroencephalogram after dexamphetamine 10 mg but not after bupropion or nomifensine. These findings in man suggest that neither of these two, non‐sedative antidepressants possess amphetamine‐like stimulant activity, and are discussed in relation to the animal pharmacology of the drugs.
Kinetics of oral trifluoperazine disposition in man.
Authors: Midha KK , Korchinski ED , Verbeeck RK , Roscoe RM , Hawes EM , Cooper JK , McKay G
Published: July 2012

The disposition of trifluoperazine (TFP) was studied in five healthy volunteers following oral administration of a 5 mg tablet. Using a very sensitive GC‐MS technique plasma TFP concentrations were measured up until 24 h following drug ingestion. Peak plasma concentrations varied widely (range 0.53‐3.09 ng ml‐1) and were reached 2.8 +/‐ 0.5 h following ingestion of the TFP tablet. The apparent terminal elimination half‐life of TFP was 12.5 +/‐ 1.4 h. The area under the plasma concentration‐time curve differed widely between subjects (range: 5.9‐17.6 ng ml‐1 h) suggesting large individual differences in the extent of presystemic TFP elimination.
Binding of theophylline in human serum determined by ultrafiltration and equilibrium dialysis.
Authors: Brors O , Sager G , Sandnes D , Jacobsen S
Published: July 2012

1 Binding of theophylline (80 mumol/l) was determined in serum from healthy subjects by equilibrium dialysis and by ultrafiltration, using [3H]‐theophylline, at 22 degrees C and at different pH‐values. pH was regulated by gassing with CO2 or by dialysing the serum against a phosphate buffer before use. 2 Binding of theophylline in serum was 34‐ 38% determined by equilibrium dialysis and 41‐45% determined by ultrafiltration at pH 7.4‐7.5. The protein concentration in serum decreased by 12‐16% during equilibrium dialysis and increased by 20% during ultrafiltration. The intersubject variation in binding was small. 3 Binding of theophylline in serum was pH‐dependent with 25‐30% bound at pH 7.0 and 58‐60% bound at pH 8.1‐8.3. Binding was significantly correlated to the fraction of ionized theophylline. 4 The binding of theophylline in normal human serum is about 35‐40% at pH 7.4 and 22 degrees C. The difference in binding observed between equilibrium dialysis and ultrafiltration may be explained by the opposite changes in protein concentration during the experiment. 5 Control of pH is necessary to obtain physiologically relevant data on drug binding in serum.
Reproducibility of saliva and plasma theophylline levels following single dose administration of two sustained release preparations.
Authors: Jackson AH , Edwards C , Cope AS , Stockley RA , Purkiss R
Published: July 2012

1 Concomitant saliva and plasma theophylline concentrations were measured in six healthy male volunteers following single dose administration of two sustained release preparations (Nuelin SA and Phyllocontin Continus). 2 Using mean values, a good correlation was obtained between saliva and plasma drug concentrations. Prediction of plasma values using individual saliva was poor and varied widely. The ratio of saliva to plasma concentrations in the same individual, assessed under standardised conditions, was not always reproducible.
Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.
Authors: Vestal RE , Thummel KE , Musser B , Mercer GD
Published: July 2012

1 The effect of concurrent cimetidine administration on the disposition of theophylline was investigated in eight male patients (56‐78 years) with chronic obstructive pulmonary disease (COPD). 2 The patients, who were taking oral theophylline preparations chronically (384‐1020 mg/day), received a [15N], [13C]‐labelled analogue of theophylline (10 mg i.v.) before and during cimetidine treatment (1200 mg/day p.o.). 3 During cimetidine treatment trough levels of theophylline increased 34% (6.4 +/‐ 0.8 to 8.6 +/‐ 1.0 micrograms/ml, P less than 0.05), half‐life increased 48% (6.5 +/‐ 0.6 to 9.6 +/‐ 0.8 h, P less than 0.001), and total plasma clearance decreased 33% (3.88 +/‐ 0.46 to 2.59 +/‐ 0.33 l/h, P less than 0.001), without a significant change in volume of distribution or protein binding. 4 The effect of cimetidine on plasma levels of theophylline was maximal within 72 h. Levels returned to control values within 48 h after its discontinuation. 5 Although there was no correlation with mean plasma concentrations of cimetidine, the change in clearance of theophylline correlated with initial clearance values (r = 0.72). 6 Cimetidine reduced the plasma clearance of theophylline in patients with COPD to an extent similar to that reported in healthy volunteers.
Comparison of the effect of pindolol and propranolol on heart rate after acute and chronic administration.
Authors: Finch MB , O'Connor PC , Harron DW , Shanks RG
Published: July 2012

1 The present study compared the effects in healthy volunteers of the acute and chronic administration of placebo, pindolol and propranolol to see if the partial agonist activity of pindolol was reduced by the beta‐adrenoceptor blocking activity of pindolol on chronic administration. 2 Five subjects received in random order for 8 days placebo, propranolol 160 mg and pindolol 10 mg; on days 1 and 8 treatments were given twice at 0 and 2 h. Heart rate in supine position and at end of exercise was recorded before dosing and at 2 and 4 h post‐ dosing on days 1 and 8. 3 Propranolol and pindolol reduced exercise heart rate to the same extent on days 1 and 8. 4 Propranolol reduced supine heart rate more than pindolol on days 1 and 8 but the difference was only significant on day 8.
Prolonged variability in plasma protein binding of disopyramide after acute myocardial infarction.
Authors: David BM , Ilett KF , Whitford EG , Stenhouse NS
Published: July 2012

1 Disopyramide plasma binding was determined in vitro in plasma from 20 patients with acute myocardial infarction (aged 35‐79 years) and in 20 age and sex matched healthy subjects. Plasma samples were collected on days 1, 5 and 12 after infarction and when the patient returned to the outpatient clinic. 2 In healthy subjects there was a significant negative correlation between disopyramide free fraction and plasma alpha 1‐acid glycoprotein (AAG) concentration. A similar correlation was observed in the patients with myocardial infarction, however this correlation was dependent on time elapsed after infarction. Disopyramide free fraction did not correlate with albumin concentration in either group. 3 Mean plasma AAG concentrations were increased by 63% within 5 days after infarction and had returned to initial levels some months later (73.5 +/‐ 7.8 days). On each of the four sampling days, a two to four fold individual variability in plasma AAG concentrations was observed. 4 Maximum increases in disopyramide plasma binding were shown on days 5 and 12 after infarction. These increases were dependent on both drug and AAG concentrations. Increases in fraction bound were greater at the higher drug concentrations. Within the usual therapeutic plasma range for disopyramide (2 to 5 mg/l), the mean increases in fraction bound, compared to day 1 data, varied from 22 to 45% respectively. 5 Sequential alteration in AAG concentration after infarction indicates that disopyramide plasma binding may not reach a steady state until some months after infarction. Prediction of the time to achieve this steady state would be difficult due to inter‐ and intra‐ patient variability in binding.
Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.
Authors: Vermeulen NP , Rietveld CT , Breimer DD
Published: July 2012

1 Hexobarbitone plasma kinetics were determined in six healthy volunteers, who received 500 mg hexobarbitone orally. In addition urinary excretion rate and cumulative excretion were measured of its three major metabolites: 3′‐hydroxyhexobarbitone, 3′‐ketohexobarbitone and 1,5‐dimethylbarbituric acid. 2 The mean plasma elimination half‐ life of hexobarbitone was 3.7 +/‐ 0.9 h (n = 6). Assuming complete absorption, the volume of distribution and the metabolic clearance were 81.3 +/‐ 20.5 1 and 16.4 +/‐ 2.9 1/h, respectively. The mean maximal plasma concentration was 7.1 +/‐ 2.1 micrograms/ml and was reached 1.2 +/‐ 0.4 h after drug administration. 3 3′‐Hydroxyhexobarbitone and 3′‐ ketohexobarbitone, which are products of allylic side‐chain oxidation of hexobarbitone, were excreted in 24 h to the extent of 4.7 +/‐ 1.3 and 32.1 +/‐ 11.9% of the dose, respectively. In the same period, 1,5‐ dimethylbarbituric acid, which is the end product of the epoxide‐diol pathway, was excreted to 18.0 +/‐ 7.8% of the dose. The ratio of the sum of 3′‐hydroxy‐ and 3′‐ketohexobarbitone vs 1,5‐dimethylbarbituric acid excreted varied with time and amounted ultimately in 24 h urine to 2.3 +/‐ 1.0. 4 The half‐lives of 3′‐hydroxyhexobarbitone and 1,5‐ dimethylbarbituric acid, calculated from their renal excretion rate curves, amounted 5.2 +/‐ 0.9 and 6.6 +/‐ 1.3 h and were significantly longer than the half‐life of hexobarbitone in plasma. The half‐life of 3′‐ketohexobarbitone was 4.2 +/‐ 0.8 h. The maximum excretion rate of 1,5‐dimethylbarbituric acid was reached at 7.7 +/‐ 1.0 h after administration of hexobarbitone. 3′‐Hydroxy‐ and 3′‐ketohexobarbitone were excreted with a maximal rate at 2.2 +/‐ 0.8 and 2.8 +/‐ 0.4 h respectively.
The effect of alcoholic cirrhosis on the activities of microsomal aldrin epoxidase, 7‐ethoxycoumarin O‐de‐ethylase and epoxide hydrolase, and on the concentrations of reduced glutathione in human liver.
Authors: Woodhouse KW , Williams FM , Mutch E , Wright P , James OF , Rawlins MD
Published: July 2012

Activities of the microsomal mono‐oxygenases 7‐ethoxycoumarin O‐de‐ ethylase (EOC) and aldrin epoxidase (AE), together with microsomal epoxide hydrolase (EH) activity and concentrations of reduced glutathione (GSH) have been measured in liver from patients with alcoholic cirrhosis and in normals. Activities of both mono‐oxygenases were significantly reduced in alcoholic cirrhosis. EOC activity (pmol 7‐ OH coumarin formed/mg microsomal protein/min) was 108.0 +/‐ 10.6 (n = 8) in normals and 60.9 +/‐ 11.6 (n = 8) in alcoholic cirrhosis (P less than 0.01). AE activity (pmol dieldrin formed/mg microsomal protein/min) was 58.9 +/‐ 9.5 (n = 11) in normal liver biopsies and 29.9 +/‐ 8.6 (n = 9) in alcoholic cirrhosis (P less than 0.05). Microsomal EH activity (nmol styrene glycol formed/mg microsomal protein/min) was similar in normals (39.2 +/‐ 4.4, n = 11) and alcoholic cirrhosis (40.5 +/‐ 9.1, n = 6). GSH concentrations (microgram GSH/g liver tissue) were lower (P less than 0.01) in alcoholic cirrhosis (792 +/‐ 73, n = 10) compared to normals (1182 +/‐ 76, n = 6).
Doxazosin, an alpha 1‐adrenoceptor antagonist: pharmacokinetics and concentration‐effect relationships in man.
Authors: Vincent J , Elliott HL , Meredith PA , Reid JL
Published: July 2012

The effects of single doses of doxazosin, a quinazoline derivative similar to prazosin, were studied in six normotensive volunteers. Both 1 mg (i.v.) or 2 mg (oral) doxazosin caused a fall in blood pressure which was most apparent in the erect posture at 5‐6 h following drug administration. The maximum fall in blood pressure following i.v. doxazosin was from 123/81 to 106/69 mm Hg associated with a rise in heart rate from 81 to 107 beats/min. The terminal elimination half‐life following oral and intravenous doxazosin was about 9 h. Pressor responsiveness to the alpha 1‐adrenoceptor agonist, phenylephrine, showed no significant difference between oral and i.v. doxazosin suggesting that the route of administration did not influence alpha 1‐ adrenoceptor antagonism at the doses used. Using a pharmacodynamic modelling technique in individual subjects, there was a significant correlation between the change in doxazosin concentration in the effect compartment and its hypotensive effect. With the modelling technique it was possible to show a significant correlation between the pressor responsiveness to the alpha 1‐adrenoceptor agonist phenylephrine and the concentration of doxazosin in the effect compartment. This is consistent with the concept that the hypotensive effect of doxazosin is mediated by alpha 1‐adrenoceptor blockade.
Ranitidine influences the uptake of oral midazolam.
Authors: Elwood RJ , Hildebrand PJ , Dundee JW , Collier PS
Published: July 2012

In a randomised crossover study in volunteers plasma midazolam levels were estimated for 24 h following 15 mg by mouth, either preceded by no medication or following 24 h therapy with ranitidine. Administration of the H2‐receptor blocker significantly increased bioavailability of the benzodiazepine and resulted in higher plasma levels for the first 6 h after taking midazolam. This was accompanied by a greater soporific effect.
Dystonic reactions and the pharmacokinetics of metoclopramide in children.
Authors: Bateman DN , Craft AW , Nicholson E , Pearson AD
Published: July 2012

The pharmacokinetics of metoclopramide have been studied in nine children receiving the drug as prophylaxis for cytotoxic induced vomiting. Plasma concentrations of metoclopramide have also been studied in three children with dystonic reactions to the drug. The pharmacokinetics in children were similar to those reported in healthy adults. There was no difference in the plasma concentration of metoclopramide of children with dystonia when compared to those without this adverse effect. Kinetic differences in childhood do not explain the occurrence of dystonia, which in the individual appears to be related to factors other than plasma drug concentrations.
The effect of hyoscine butylbromide on the swallowing of capsules.
Authors: Channer KS , Wolinski A , Kaye B , Virjee J
Published: July 2012

Hyoscine butylbromide (20 mg) given intravenously to 48 patients with normal oesophageal motility significantly reduced oesophageal transit of hard gelatin capsules when swallowed in the erect and supine positions with 15 ml and 60 ml water when compared to an age/sex matched group. Delayed capsule transit and possible failed or slowed drug absorption occurring as a consequence of anti‐cholinergic drugs on the oesophagus, constitutes a new drug interaction.
Human blood platelet behaviour after inhibition of thromboxane synthetase.
Authors: Heptinstall S , Fox SC
Published: July 2012

1 We have determined the extent to which sodium arachidonate (NaAA) induces a release reaction in platelet‐rich plasma (PRP) from different individuals and have studied the ability of the thromboxane synthetase inhibitor UK 34787 to modify this release. We have also determined the extent of the platelet release reaction induced in PRP from different individuals by preparations of platelet‐derived thromboxane A2 (TXA2). 2 The release of [14C]‐serotonin induced by NaAA is more extensive in PRP from some individuals than from others. 3 There is a direct relation between the extent of the release reaction induced in different PRPs by NaAA and TXA2. 4 UK 34787 prevents the NaAA‐induced release reaction in PRP from some individuals (“responders”) but not in PRP from others (“non‐responders”). 5 The mean extent of the NaAA‐ induced release reaction for the “non‐responders” was significantly higher than that for the “responders” even in the absence of UK 34787, but there was some overlap between the individual results. 6 Platelets from “responders” and “non‐responders” did not differ in the amount of malondialdehyde (MDA) produced or in the effectiveness with which UK 34787 inhibited MDA production. 7 Platelet‐derived TXA2 from “responders” and “non‐responders” did not have markedly different effects when tested in a single preparation of PRP.
Effects of dazoxiben and low‐dose aspirin on platelet behaviour in man.
Authors: Jones EW , Cockbill SR , Cowley AJ , Hanley SP , Heptinstall S
Published: July 2012

1 We have studied the effects on platelet behaviour of ingestion of the thromboxane synthetase inhibitor dazoxiben (UK 37248), by healthy subjects, and compared the results with the effects of a low dose of aspirin (a cyclo‐oxygenase inhibitor), and of a combination of dazoxiben and a low dose of aspirin. 2 Dazoxiben ingestion prevented the release reaction induced by sodium arachidonate (NaAA) in platelet‐ rich plasma (PRP) from some individuals (“responders”) but not in PRP from others (“non‐responders”). In vitro testing of PRP from the same subjects, incubated with 10(‐4)M dazoxiben, correlated with the effect of dazoxiben ingestion on NaAA‐induced release. Platelets from “non‐ responders” tended to undergo a more extensive release reaction than platelets from “responders” even in the absence of any drug although there was some overlap between the results in the two groups. Platelets from “non‐responders” required significantly lower concentrations of NaAA to induce release reaction than platelets from “responders”. Platelets from “responders” and “non‐responders” did not differ in the amount of malondialdehyde (MDA) produced or in the effectiveness with which dazoxiben ingestion inhibited MDA production. 3 Low dose aspirin had comparable effects on NaAA‐induced release to dazoxiben, but in contrast to dazoxiben, the effectiveness of low‐dose aspirin in inhibiting NaAA induced release reaction was related to its effectiveness in inhibiting MDA generation. 4 Neither dazoxiben nor low‐ dose aspirin significantly affected the release reaction induced by adenosine diphosphate (ADP), although both drugs significantly inhibited adrenaline‐induced release. 5 A combination of dazoxiben and low dose aspirin had a greater effect on platelet behaviour in response to NaAA, ADP, and adrenaline than either drug alone.
Dazoxiben examined for platelet inhibitory effect in an artificial circulation.
Authors: Goldman M , Hall C , Hawker RJ , McCollum CN
Published: July 2012

1 Platelet inhibitory therapy may protect patency in prosthetic arterial grafts. 2 The effect of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on 113Indium‐labelled platelet deposition on Dacron arterial grafts was examined in an artificial circulation containing human blood which mimics the haemodynamics of femoropopliteal bypass. The influence of this drug on thromboxane production and platelet reactivity was measured during the experiment. The study was controlled and performed in two parts to assess in vitro and ex vivo drug effect. 3 Both in vitro and ex vivo dazoxiben reduced plasma thromboxane by about 80% and in citrated ex vivo blood increased mean (+/‐ s.e. mean) platelet aggregation threshold to collagen from control values of 4.8 +/‐ 1.7 mg/ml to 10.6 +/‐ 3.3 mg/ml (P less than 0.01). Dazoxiben, however, had no effect on platelet deposition on the arterial grafts. 4 Selective thromboxane inhibition failed to exert an antithrombotic effect in this model.
Effects of dazoxiben on exercise performance in chronic stable angina.
Authors: Reuben SR , Kuan P , Cairns J , Gyde OH
Published: July 2012

1 We have performed a double‐blind, randomized, 7‐d cross‐over study of the thromboxane synthetase inhibitor dazoxiben (UK 37248) in 20 patients with stable coronary heart disease. 2 All patients had a history of exertional angina of greater than two years duration and no patient had suffered a myocardial infarction in the preceding twelve months. 3 All patients had a positive exercise stress test for myocardial ischaemia and 15 had undergone coronary angiography. All these patients had a 50% narrowing in at least one vessel. 4 All patients were on conventional anti‐anginal medication and the doses of their various therapies remained unchanged in the three months prior to and during the study period. 5 Therapy with dazoxiben 200 mg four times daily produced no alteration in the subjective or objective features of angina in these patients. There was no alteration in angina attack rate, glyceryl trinitrate consumption or duration of treadmill exercise. 6 Dazoxiben produced a highly significant reduction in both the resting and the post‐exercise levels of serum thromboxane B2 levels, although there was no significant difference between the pre‐ exercise and post‐exercise values. 7 Dazoxiben is an effective inhibitor of the synthesis of thromboxane but it has no effect on the subjective or objective features of stable coronary disease. This would suggest that the production of thromboxane and the development of circulating platelet aggregates play no part in the mechanism of angina in patients with stable coronary heart disease.
Pharmaco‐EEG profiles of antidepressants. Pharmacodynamic studies with fluvoxamine.
Authors: Saletu B , Grunberger J , Rajna P
Published: July 2012

1 Antidepressant drugs produce significant changes in human brain function as reflected in the quantitatively analysed EEG. Two main types of pharmaco‐EEG profiles may be differentiated: a thymeretic (desipramine‐like) profile characterised mainly by an alpha increase suggesting activating properties and a thymoleptic (imipramine‐ or amitriptyline‐like) profile showing a concomitant increase of slow and fast activities and a decrease in alpha activity indicating also sedative qualities. A small number of compounds exhibit still different profiles. 2 Aside from determining the type of EEG changes, the pharmaco‐EEG method seems to be of value in determining time and dose efficacy relations at the target organ, the human brain. Moreover, the relationships between pharmacodynamics and pharmacokinetics may be determined. 3 Fluvoxamine, a selective 5‐hydroxytryptamine (5‐HT) re‐ uptake inhibitor from the new class of 2‐aminoethyloximethers of aralkylketones, produced a typical thymoleptic pharmaco‐EEG profile after oral doses of 75 mg in a double‐blind placebo‐controlled study involving 10 healthy volunteers. Fluvoxamine (75 mg) induced less augmentation of slow activity than 75 mg imipramine, indicating less sedative properties of fluvoxamine than imipramine. 4 After 75 mg fluvoxamine psychometric tests demonstrated a tendency towards an improvement in attention, concentration, psychomotor activity, after‐ effect and mood and a significant increase in critical flicker fusion frequency as compared with placebo. Comparison with the reference drug, 75 mg imipramine, revealed a significant superiority of fluvoxamine regarding concentration, psychomotor activity, tapping, reaction time, mood and affectivity. 5 Side‐effects (mostly tiredness) were seen in five out of 10 subjects after 75 mg fluvoxamine and in eight out of 10 subjects after 75 mg imipramine. There were no clinically relevant changes in pulse, systolic and diastolic blood pressure.
A double‐blind placebo‐controlled study of fluvoxamine and imipramine in out‐patients with primary depression.
Authors: Itil TM , Shrivastava RK , Mukherjee S , Coleman BS , Michael ST
Published: July 2012

1 A double‐blind placebo‐controlled study of fluvoxamine and imipramine was performed in a group of depressed patients. Twenty‐two patients received fluvoxamine (mean dose 101 mg/day), 25 received imipramine (mean dose 127 mg/day) and 22 received placebo. 2 Apart from an increase in the SGOT and SGPT values of four imipramine patients, no statistically significant changes in haematology or urinalysis were judged to be medically relevant. Fluvoxamine exhibited fewer anticholinergic side effects than imipramine. 3 Both fluvoxamine treated patients and imipramine‐treated patients exhibited a statistically significant improvement at the end of the 28‐day treatment period with respect to the placebo patients, as measured using the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Evaluations of the results of the Beck Depression Inventory and the Profile of Mood States revealed a statistically significant improvement for imipramine patients with respect to placebo at week 4, but not for fluvoxamine patients. It is postulated on the basis of quantitative pharmaco‐EEG findings, that the slight superiority of imipramine over fluvoxamine was due to underdosing of the latter.
Magnitude and mechanisms of the antihypertensive action of labetalol, including ambulatory assessment.
Authors: Bellamy GR , Hunyor SN , Roffe D , Massang J
Published: July 2012

The blood pressure (BP) effect and modes of action of a twice daily regimen of labetalol (mean 450 mg/day) were assessed in ten mild to moderate hypertensives using continuous ambulatory BP monitoring. The reflex control of BP during physiological interventions was examined just prior to the next dose of medication to estimate the residual alpha‐ and beta‐adrenoceptor blockade. Global 24 h BP was reduced by 15/9 mm Hg, and home pressures by 13/11 mm Hg. The predominant antihypertensive effect was noted during the waking hours. During dynamic exercise significant inhibition of the heart rate and blood pressure rise occurred. Coupled with a reduction of the post‐release BP ‘overshoot’ in Valsalva's manoeuvre, the response resembles that seen with beta‐adrenoceptor blockade. A small alpha‐adrenoceptor blocking action was evident in one patient's response to the Valsalva manoeuvre.
The absorption and conjugation of methyldopa in patients with coeliac and Crohn's diseases during treatment.
Authors: Renwick AG , Higgins V , Powers K , Smith CL , George CF
Published: July 2012

The absorption and elimination of a single 500 mg dose of methyldopa has been studied after oral administration to 10 normal volunteers, 10 patients with coeliac disease, who were on a gluten‐free diet, and to five patients with Crohn's disease. In patients with Crohn's disease the percentage of the dose recovered in urine (24%) was about one‐half of normal (50%). This decreased absorption was associated with reduced plasma concentrations of both free and conjugated methyldopa and a decreased pharmacological response. In patients with coeliac disease the percentage of dose recovered in urine (43%) was similar to normals, indicating a normal absorption of the drug. However, the plasma concentrations of both free and conjugated methyldopa were significantly higher than normal, although there was no increase in drug‐related effects. These findings confirm the importance of using indices other than drug plasma concentrations in the assessment of bioavailability in disease states.
Pharmacokinetics of valproic acid in young and elderly subjects.
Authors: Bryson SM , Verma N , Scott PJ , Rubin PC
Published: July 2012

The disposition of valproic acid was studied following single dose intravenous administration in seven young male volunteers aged 20‐35 years and six elderly male in‐patients aged 75‐87 years. Following administration of 400 mg sodium valproate, blood samples were collected for 48 h and valproic acid concentrations analysed by enzymatic immunoassay. The median elimination half‐life was 7.2 h in the young subjects but 14.9 h in the elderly patients (P less than 0.01). However, clearance did not differ significantly between groups, the values for young and old being 0.69 and 0.58 1/h respectively. The prolonged half‐life resulted from a greater volume of distribution in the elderly. The median values (1/kg) for young and old were 0.13 and 0.19 respectively (P less than 0.01). These pharmacokinetic changes are unlikely to be of clinical importance.
The effect of diet upon serum concentrations of theophylline.
Authors: Thompson PJ , Skypala I , Dawson S , McAllister WA , Warwick M Turner
Published: July 2012

Eight patients with airways obstruction were investigated to determine if dietary components had any significant effect upon serum concentrations of theophylline when taking a slow release formulation. A high carbohydrate, low protein diet, given for 1 week, resulted in the area under the concentration time curve for 12 h being 33.3% greater than a high protein low carbohydrate diet given under the same conditions. In contrast to two previous studies no significant effect upon the elimination half‐life was detected after changing from one diet to the other and an effect of dietary components upon absorption and/or distribution needs to be considered. Morning and afternoon trough levels were significantly different from each other on both diets suggesting that theophylline kinetics are different at night. Individualising of theophylline dosing is particularly needed when treating patients on a varied dietary intake.