bluuebunny/crossref_metadata_2025 huggingface dataset:
Haemodynamic effects of cigarette smoking during chronic selective and non‐selective beta‐adrenoceptor blockade in patients with hypertension.
Authors: Houben H , Thien T , Van 'T Laar A
Published: July 2012

1 Haemodynamic effects of cigarette smoking before and during chronic treatment with propranolol and metoprolol were studied in 16 patients with essential hypertension. 2 Smoking of cigarettes induced an increase in blood pressure of the same degree in all experimental sessions. Heart rate increased by 16 beats/min during smoking alone, but increased significantly less, when a beta‐adrenoceptor blocker was used. Forearm blood flow decreased during smoking in both medication periods. 3 Plasma adrenaline rose significantly during smoking from 0.37 nmol/l to 0.77 nmol/l; plasma noradrenaline did not change. 4 It is concluded that the blood pressure changes induced by smoking are not essentially altered during chronic treatment with selective or non‐ selective beta‐adrenoceptor blockade. Only the increase in heart rate is significantly less pronounced during treatment with both drugs.
Pharmacokinetics of single doses of sulphinpyrazone and its major metabolites in plasma and urine.
Authors: Bradbrook ID , John VA , Morrison PJ , Rogers HJ , Spector RG
Published: July 2012

1 High pressure liquid chromatographic assays for the estimation of sulphinpyrazone and its sulphide, sulphone and p‐hydroxy metabolites in plasma and urine are described. 2 Five normal volunteers received 200 mg and 400 mg sulphinpyrazone orally. Sulphinpyrazone was rapidly absorbed and eliminated with a half‐life of approximately 4 h irrespective of dose. Peak plasma concentrations and area under the plasma concentration‐time curves (AUC) were consistent with linear pharmacokinetic behaviour. 3 Plasma concentrations of the sulphone were low and peaked before those of the sulphide; its mean half‐life was 3.1 h. The sulphide, which may be the sulphinpyrazone metabolite with activity on platelets, was eliminated with a mean half‐life of 13.4 h. The AUC increases with dose of both metabolites suggested non‐ linearity. 4 Approximately 45‐50% of the administered dose was eliminated in the urine as unchanged drug or as sulphone or p‐hydroxy‐ sulphinpyrazone. The sulphide metabolite was not detected in the urine. The renal clearance of sulphinpyrazone was approximately 18 ml min‐1 and that for the sulphone was similar. Sigma minus plots of the urinary excretion yielded half‐lives of 3.5 h for the sulphone and 1 h for p‐ hydroxy‐sulphinpyrazone.
Antipyrine elimination in saliva after low‐dose combined or progestogen‐ only oral contraceptive steroids.
Authors: Chambers DM , Jefferson GC , Chambers M , Loudon NB
Published: July 2012

1 A ‘low‐dose’ combined oral contraceptive steroid (OCS) preparation containing 30 microgram ethinylo‐estradiol and 150 microgram levonorgestrel was found to reduce significantly antipyrine clearance in a group of women acting as their own controls. 2 An OCS preparation containing only a progestogen (75 microgram norgestrel) did not reduce antipyrine clearance in a second group of women. 3 The evidence suggesting that the oestrogen component of combined OCS preparations could be responsible for the reduction in antipyrine clearance is discussed.
Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.
Authors: Horai Y , Ishizaki T , Sasaki T , Koya G , Matsuyama K , Iguchi S
Published: July 2012

1 Plasma levels of isoniazid (INH) and acetyl INH in plasma were measured with a spectrofluorometric method, and INH and its metabolites (acetyl INH, mono‐acetylhydrazine, diacetylhydrazine and free hydrazine) excreted in urine were measured with a gas chromatography‐ mass spectrometry, respectively, after an oral dose of INH 10 mg/kg in 19 Japanese patients with idiopathic systemic lupus erythematosus (SLE) and in the same number of healthy controls. 2 When phenotyped according to various methods previously reported, 16 to 18 of the SLE and 17 to 19 of the control group were rapid acetylators. Regardless of the phenotyping methods applied, the distribution of acetylator phenotype of SLE patients was not significantly different from the control group or from the data previously reported among normal Japanese population. 3 By phenotyping our subjects with an INH T 1/2 of 110 min or less as rapid acetylators, and more slow acetylators, 3 of SLE patients and 2 of the controls were slow, while the remainder were all rapid. When this antimode was used, the mean apparent kinetic variables of INH and acetyl INH estimated from the plasma concentration‐time data and the mean values for the 24‐h urinary amount of INH and its metabolites, except for monoacetylhydrazine (P less than 0.05), did not significantly differ between the rapid acetylators of SLE and control groups. 4 The distribution of INH T 1/2, acetyl INH to INH ratios in plasma and urine, values in urine for log10 (diacetylhydrazine to monoacetylhydrazine) and for diacetylhydrazine to INH or acetyl INH was similar between the two groups except for one patient who was definitely classified as a slow acetylator regardless of whichever phenotyping methods were used. The excretory patterns of hydrazine compounds reflect, in general, the inactivating ability of INH in each individual. 5 The data suggest that phenotyping by using plasma samples is, in general, better than by using urine samples. The plasma T 1/2 alone is the most satisfactory criterion. 6 We conclude that neither INH disposition nor phenotype distribution assessed by the reported methods using INH as the test compound are altered in idiopathic SLE, and that a search for racial and/or geographical factor(s) likely to result in autoimmune disease may give a clue to the pathogenesis in addition to further exploration for the possible interrelation between idiopathic SLE and genetic slow acetylation.
The effects of domperidone on gastric emptying of liquid in man.
Authors: Bateman DN , Gooptu D , Whittingham TA
Published: July 2012

1 The effects of domperidone (20 mg) i.v. and saline i.v. on gastric emptying of 500 ml of fluid have been compared in a blind study in six normal male volunteers. 2 Gastric emptying was measured by real‐time ultrasound. 3 Domperidone significantly reduced the volume in the stomach 5 min after the drink (domperidone 306 +/‐ 17 ml, saline 404 +/‐ 31 ml, P less than 0.02). 4 Domperidone had no significant effect on the half‐life of gastric emptying measured between 5 and 60 min (T1/2 domperidone 21.2 +/‐ 1.17 min, T1/2 saline 21.3 +/‐ 1.58 min). 5 A similar pattern of gastric emptying to that produced by domperidone could be produced by giving a drink of a smaller volume.
An in vitro model for studying the effects of pharmacological agents on human ciliary beat frequency: effects of lignocaine.
Authors: Rutland J , Griffin W , Cole PJ
Published: July 2012

1 The effects of lignocaine hydrochloride on ciliary beat frequency (CBF), measured photometrically in vitro, using human epithelium obtained by nasal brushing was studied in 20 healthy subjects. Above lignocaine concentrations of 2.5 × 10(‐3) g/ml cilio‐inhibition occurred in a dose‐dependent manner. Concentrations greater than 2 × 10(‐2) g/ml caused ciliostasis. 2 Lignocaine aerosol was sprayed in vivo on the mucosa of one nasal cavity in five healthy subjects and five patients premedicated for bronchoscopy. CBF, measured in vitro in nasal brushings, was not different for treated and untreated sides. 3 Variation of intrinsic CBF with time after nasal brushings were taken was studied in ten normal subjects. No significant change in CBF was found until after 24 h. 4 We conclude that lignocaine hydrochloride, at concentrations three orders of magnitude above drug levels encountered in clinical practice, inhibits human CBF in a dose‐dependent manner. Aerosolised lignocaine hydrochloride in doses which produce local nasal mucosal anaesthesia, does not inhibit CBF subsequently measured in vitro. Lignocaine is a suitable local anaesthetic for use at fibreoptic bronchoscopy when samples are being obtained for study of ciliary function. 5 The measurement of CBF in nasal mucosal brushings provides an in vitro model suitable for studying the effects of pharmacological agents on human ciliary activity.
Estimation of biliary excretion of ureidopenicillins in healthy volunteers using marker dilution technique.
Authors: Gundert‐Remy U , Frohnapfel F , Jourdan W , Weber E , Stiehl A
Published: July 2012

1 Aspiration of duodenal fluid and estimation of recovery by a marker dilution technique was adapted to measure the biliary excretion of two chemically related ureidopenicillins, mezlocillin and azlocillin, in healthy volunteers. 2 The drug was infused intravenously at a constant rate over a period of 6 h during which duodenal fluid was aspirated through the distal opening of a triple‐lumen polyvinyl tube. 3 Drug levels in plasma, urine and duodenal fluid were determined by h.p.l.c. 4 Biliary excretion rate was calculated by multiplying the concentration in the duodenal fluid by the dilution factor resulting from the dilution of marker substance infused through the proximal opening of the triple‐lumen tube. 5 Since the results obtained by the marker dilution technique are comparable to data obtained by studies in patients with t‐tube drainage following biliary surgery, it can be concluded that the method is useful to measure the biliary excretion of drugs in man.
The effect of fever on antipyrine metabolism in children.
Authors: Forsyth JS , Moreland TA , Rylance GW
Published: July 2012

1 The elimination of antipyrine from saliva was measured in six children aged 5 months to 5 years during fever and during a control period 2‐4 weeks after the cessation of fever. 2 The mean (+/‐ s.d.) saliva antipyrine clearance during fever, 32 +/‐ 13 ml kg‐1 h‐1, was nearly 50% less than that when the children were afebrile, 50 +/‐ 22 ml kg‐1 h‐1 (P less than 0.02). The mean saliva antipyrine half‐life during fever, 15.20 +/‐ 5.40 h, was almost twice as long as that found when body temperature was normal, 9.18 +/‐ 2.49 h (P less than 0.01). The apparent volume of distribution of antipyrine was not significantly affected by fever. 3 These findings indicate that drug metabolising ability in children is impaired during fever.
The effect of renal disease on the pharmacokinetics of diethylcarbamazine in man.
Authors: Adjepon‐Yamoah KK , Edwards G , Breckenridge AM , Orme ML , Ward SA
Published: July 2012

1 The pharmacokinetics of diethylcarbamazine (DEC) were studied in twelve patients with chronic renal function impairment. 2 Selected pharmacokinetic parameters, plasma half‐life (T1/2), area under the plasma concentration‐time curve (AUC), elimination rate constant (Kel) and 24 h urinary excretion were regressed versus parameters indicative of renal function. 3 Significant negative correlations were observed between creatinine clearance and both plasma T1/2 and log10 T1/2. 4 Significant positive correlations were obtained between (a) creatinine clearance and elimination rate constant of DEC and (b) reciprocal serum creatinine and l/T1/2. Creatinine clearance was significantly and positively correlated with 24 h urinary excretion of DEC. 5 No significant correlations were observed between age, sex or weight and renal function but DEC excretion did appear to decrease with increasing urinary pH. 6 Plasma half‐life, and area under the plasma concentration‐ time curve were increased and 24 h urinary excretion of DEC was significantly reduced in patients with chronic renal function impairment, compared with normal volunteer subjects receiving an identical dosage of DEC at acidic urinary pH.
Duration of effect of single daily dose methyldopa therapy.
Authors: Wright JM , Orozco‐Gonzalez M , Polak G , Dollery CT
Published: July 2012

1 Methyldopa has a short plasma half‐life, but longer duration of antihypertensive effect. A single bedtime dose of methyldopa has been recommended to improve compliance and decrease side effects. 2 This double‐blind crossover study was designed to determine the duration of antihypertensive effect of methyldopa by comparing hourly supine and standing blood pressures, throughout the day during placebo, single morning dose, and single evening dose methyldopa therapy in 10 patients. The major side effects, drowsiness and dry mouth were assessed by visual analogue scale. Exercise blood pressures were measured 6, 12, 18 and 24 h after the dose. 3 The antihypertensive effect of methyldopa peaked after 6‐9 h and declined thereafter with a half‐life of approximately 10 h. Little antihypertensive effect remained 24‐26 h after the dose. The time course of the reduction in blood pressure during exercise and of the major side effects paralleled the antihypertensive effects. 4 The results suggest that the duration of antihypertensive effect of methyldopa is long enough to permit twice daily dosing, but that single daily dosing cannot be recommended for most patients. The study illustrates the importance of knowing the time of the last methyldopa dose when assessing blood pressure measurements in patients taking the drug.
Response of the systemic pulmonary circulation to labetalol at rest and during exercise.
Authors: Fagard R , Lijnen P , Amery A
Published: July 2012

1 Labetalol was administered to 18 hypertensive patients for an average duration of 2.44 weeks, with an average final daily dose of 1.65 g (principally to study its short‐term haemodynamic effects). 2 Labetalol decreased resting heart rate by 16% and maximal exercise heart rate by 21%; the phenylephrine‐induced increase in systolic brachial arterial pressure was reduced by 36%. 3 During labetalol treatment brachial arterial pressure was decreased by 29/15 mmHg in the recumbent position, by 41/23 mmHg at rest sitting and by 53/23 mmHg at maximal exercise; total peripheral resistance was not significantly affected at rest recumbent but was reduced at sitting and at exercise; cardiac output was decreased in all conditions. 4 Labetalol reduced mean pulmonary arterial and capillary wedge pressures only in the sitting position. Pulmonary vascular resistance remained unchanged. 5 The drug produced significant decreases in plasma renin activity and in plasma aldosterone concentration.
A review of the haemodynamic effects of labetalol in man.
Authors: Cohn JN , Mehta J , Francis GS
Published: July 2012

1 Labetalol at a dose of 800 to 1600 mg daily inhibited isoprenaline‐ induced tachycardia and phenylephrine‐induced elevation in arterial pressure in hypertensive subjects. The beta‐adrenoreceptor effect was four times more potent than the alpha‐adrenoreceptor effect. 2 Isoprenaline‐induced tachycardia was more effectively blocked than isoprenaline‐induced inotropism, thereby raising the possibility of a subselective effect on cardiac beta‐adrenoceptors. 3 Labetalol reduced blood pressure in hypertensive subjects with no change in cardiac output in the supine or upright position and with marked inhibition of the heart rate and blood pressure response to treadmill exercise. 4 Labetalol administered in single doses to patients with stable, treated congestive heart failure impaired blood pressure support during exercise. 5 The unique adrenoceptor and haemodynamic effects of labetalol make it a potentially attractive drug for management of hypertension and other cardiovascular disorders.
Blood pressure response to labetalol in twice and three times daily administration during a 24‐hour period.
Authors: Mancia G , Pomidossi G , Parati G , Bertinieri G , Grassi G , Navone F , Ferrari A , Gregorini L , Zanchetti A
Published: July 2012

1 The anti‐hypertensive effect of labetalol given twice or three times daily was evaluated in ambulant subjects with essential hypertension by recording blood pressure directly for 24 h before and after 15 d of labetalol administration (daily dose 600‐1800 mg). 2 Labetalol reduced 24 h systolic and diastolic blood pressures by about 20%. The reduction was evident throughout the whole 24 h period, although it was less marked during sleep. The hypotensive effect was similar when the drug was given twice or three times daily. 3 The 24 h heart rate was reduced during labetalol treatment. However, this effect was less marked than the hypotensive effect and was not present in all subjects. 4 There was a reduction in the standard deviations of blood pressure and heart rate values. However, in neither case was the coefficient of variation altered, indicating that labetalol did not have any significant effect on the shape of the 24 h blood pressure measurements.
Labetalol in essential hypertension.
Authors: Breckenridge A , Orme M , Serlin MJ , Maciver M
Published: July 2012

1 Labetalol is an effective agent in essential hypertension as documented in open studies and controlled studies in which its efficacy has been compared with both placebo and a variety of other anti‐ hypertensive drugs. 2 Labetalol given by mouth lowers blood pressure rapidly. There is no evidence of tolerance to its anti‐hypertensive action. 3 Adverse effects include excessive hypotension, but only when the drug is given in large doses. Epigastric discomfort and scalp tingling have been documented especially after intravenous administration. 4 From a pharmacokinetic and pharmacodynamic point of view, labetalol can be given once daily, but postural hypotension after large (greater than 1 g) single doses may limit the usefulness of once daily regimes. Twice daily administration appears an acceptable compromise.
Labetalol steady‐state pharmacokinetics in hypertensive patients.
Authors: McNeil JJ , Anderson AE , Louis WJ , Raymond K
Published: July 2012

1 During chronic treatment of hypertensive patients observed mean steady‐state plasma labetalol levels in ten patients were consistently and significantly higher than predicted from initial acute pharmacokinetic analysis. 2 Mean steady‐state levels varied from 36 to 183 ng/ml on a chronic dose of 200 mg twice daily. 3 Patients with lower steady‐state levels on a fixed dose of labetalol usually required higher maintenance doses to control blood pressure.
Pindolol‐a beta‐adrenoceptor blocking drug with partial agonist activity: clinical pharmacological considerations.
Authors: Aellig WH
Published: July 2012

1 Pindolol is a beta‐adrenoceptor antagonist equally effective on beta 1‐ and beta 2‐adrenoceptors which has a relatively long duration of action. It is practically completely absorbed and, unlike most other beta‐adrenoceptor blockers, is only metabolized to a small extent during the first passage through the liver. 2 Pindolol possesses partial agonist activity (intrinsic sympathomimetic activity, ISA). This means that apart from blocking beta‐adrenoceptors it produces some stimulation. Pindolol therefore only slightly influences normal sympathetic drive at rest but effectively reduces the effects of elevated sympathetic activity. 3 Various therapeutic advantages have been attributed to the partial agonist activity of pindolol: no or only slight alterations in normal cardiac output, heart rate and peripheral blood flow occur. Peripheral resistance is reduced during chronic oral therapy. No alteration of HDL/LDL cholesterol ratio has been observed. Rebound phenomena on sudden withdrawal of therapy and bronchoconstriction in susceptible patients are less likely than with drugs devoid of ISA.
Vasodilating properties of beta‐adrenoceptor blockers with intrinsic sympathomimetic activity.
Authors: Thulesius O , Gjores JE , Berlin E
Published: July 2012

1 In vitro experiments have been performed using 33 preparations of human arteries and veins and 10 human umbilical artery preparations. Changes in the tone of helical strips of vasculature were recorded isometrically following contraction of the tissues by exposure to 5‐ hydroxytryptamine (10(‐6)‐10(‐5) M) or potassium (127 mM). 2 Isoprenaline included concentration‐dependent relaxation and this effect could be competitively antagonized by propranolol or sotalol. 3 The beta‐adrenoceptor antagonists pindolol and celiprolol, both of which possess intrinsic sympathomimetic activity, produced concentration‐dependent relaxations of arteries and veins but not of umbilical vessels. 4 The relaxation produced by pindolol or celiprolol could be antagonized but not abolished by pretreatment with propranolol or sotalol. 5 It is concluded that the vascular relaxation produced by beta‐adrenoceptor antagonists with intrinsic sympathomimetic activity is the result of beta 2‐adrenoceptor stimulation. In the case of pindolol the relaxant effects were seen at concentrations within the range encountered after administration of normal therapeutic doses suggesting that this effect may contribute to the haemodynamic responses to pindolol seen in man.
The effect of pindolol on myocardial blood flow, metabolism and function during rest and pacing in patients with coronary heart disease.
Authors: Kupper W , Hamm CW , Bleifeld W
Published: July 2012

1 The study was designed to elucidate further the mechanism by which beta‐adrenoceptor antagonism with pindolol relieves the symptoms of angina pectoris in patients with coronary heart disease. 2 Pindolol administration was associated with an elevated threshold for angina pectoris and improved myocardial lactate metabolism during supraventricular pacing. 3 This beneficial effect of pindolol was independent of changes in myocardial blood flow and was not mediated by haemodynamic effects. 4 The results suggest that in angina pectoris, in addition to the recognized beneficial effects of beta‐adrenoceptor blockade, the actions of pindolol also result from, as yet, poorly described phenomena such as redistribution of myocardial blood flow or metabolic effects.
Assessment of beta‐adrenoceptor antagonists in asthmatic patients.
Authors: Ruffin RE , McIntyre EL , Latimer KM , Ward HE , Crockett AJ , Alpers JH
Published: July 2012

1 Bronchial smooth muscle, skeletal muscle and cardiac beta‐ adrenoceptor antagonism have been compared in twelve asthmatic patients after three beta‐adrenoceptor antagonists at two dose levels. The non‐ selective antagonist propranolol (40 and 160 mg), the non‐selective antagonist with partial agonist activity pindolol (5 and 20 mg) and the beta 1‐selective antagonist atenolol (50 and 200 mg) were studied on separate occasions. 2 Six placebo days were used in this double‐blind crossover study to allow interpretation of individual as well as group results. 3 Bronchial smooth muscle effects were assessed by resting spirometry, histamine inhalation test and spirometric response to inhaled fenoterol. Skeletal muscle effects were assessed by resting tremor and fenoterol induced tremor. 4 Cardiac beta‐adrenoceptor antagonism was assessed by measuring the effect on resting heart rate and on maximum heart rate in a standard exercise test. 5 Pindolol tended to cause least change from placebo in resting spirometry, caused significant tremor response, inhibited the fenoterol airway response, and tended to protect against inhaled histamine. 6 Atenolol 60 mg was the only drug to allow a fenoterol airway response similar to placebo. Atenolol increased the inhaled histamine responsiveness. 7 Propranolol 160 mg caused the most reduction in spirometry but also tended to cause the maximum reduction in exercise heart rate. Propranolol caused increased inhaled histamine responsiveness. 8 Initial sensitivity to inhaled histamine did not necessarily predict significant reduction in an asthmatics' spirometry by a beta‐adrenoceptor antagonist. The effect of a beta‐adrenoceptor antagonist on histamine responsiveness does not correspond to its effect on inhaled beta 2‐adrenoceptor agonist responsiveness.
Beta‐adrenoceptor blockade and psychic stress in man. A comparison of the acute effects of labetalol, metoprolol, pindolol and propranolol on plasma levels of adrenaline and noradrenaline.
Authors: Trap‐Jensen J , Carlsen JE , Hartling OJ , Svendsen TL , Tango M , Christensen NJ
Published: July 2012

1 A random double‐blind study was performed in healthy volunteers. The immediate effects of three different beta‐adrenoceptor blocking agents, metoprolol, pindolol and propranolol, on the plasma concentrations of adrenaline and noradrenaline were compared in a situation of pleasant psychic stimulation during a television‐game of tennis. The immediate effects of labetalol in a group of patients with arterial hypertension were studied in a similar experimental situation. 2 During psychic stress the plasma concentration of noradrenaline rose significantly by 85% after placebo, by 95% after labetalol, by 63% after metoprolol and by 55% after propranolol. After pindolol the noradrenaline concentration remained unchanged. 3 During psychic stress the plasma concentration of adrenaline rose significantly by 135% after labetalol, by 110% after metoprolol and by 83% after propranolol. After pindolol and placebo the adrenaline concentration remained unchanged. 4 The present results are taken to indicate that the intrinsic sympathomimetic activity possessed by pindolol prevents the rise in plasma noradrenaline normally seen during psychic stress. It is suggested that beta‐adrenoceptor blockers with strong intrinsic sympathomimetic effect reduce the release of catecholamines during psychic stress.
HDL cholesterol and beta‐adrenoceptor blocking agents in a 5 year multifactorial primary prevention trial.
Authors: Miettinen TA , Vanhanen H , Huttunen JK , Naukkarinen V , Mattila S , Strandberg T , Kumlin T
Published: July 2012

1 Serum HDL cholesterol measured at the end of a 5 year multifactorial primary prevention trial, aimed to reduce risk factor levels and incidence of ischaemic heart disease, revealed quite low values in drug‐ treated subjects. 2 Analysis of subgroups treated with beta‐ adrenoceptor blocking agents (mainly pindolol) alone or in different combinations with diuretics showed inconsistent effects of beta‐ adrenoceptors blockers on serum HDL cholesterol. HDL cholesterol levels in patients treated with pindolol with or without a diuretic were not different from those of the risk‐free control group. 3 Subjects on combined beta‐adrenoceptor blocker‐hypolipidaemic treatments had lower HDL‐cholesterol than those on hypolipidaemic agents alone. 4 Withdrawal of pindolol at the end of the trial caused a small but significant increase in serum HDL cholesterol in a small subgroup of mildly hypertensive patients. Thus, pindolol appears to have slightly reduced serum HDL cholesterol but the relevance of this small decrease on the incidence of ischaemic heart disease is questionable.
Effect of pindolol on serum lipids and lipid metabolizing enzymes.
Authors: Lehtonen A , Hietanen E , Marniemi J , Peltonen P , Niskanen J
Published: July 2012

1 The effect on plasma lipids of pindolol given orally over a 6 month period to 20 patients with essential hypertension was studied. 2 During therapy an adipose tissue biopsy was taken from nine patients for the determination of lipoprotein lipase (LPL) activity and serum samples were taken for lecithin cholesterol acyltransferase (LCAT) assays. An additional biopsy and serum samples were taken after a 3 weeks' break in pindolol treatment. 3 Plasma free fatty acid and triglyceride concentrations remained similar during treatment. 4 Plasma total cholesterol was slightly lower (P less than 0.05) at 6 months than at 1 month. 5 HDL cholesterol concentration and the ratio of HDL to total cholesterol increased slightly, and the increase of HDL‐cholesterol was significant (P less than 0.05) at 1 month. 6 LCAT activity was significantly higher (P less than 0.01) during pindolol treatment than after the break in it. No significant changes in adipose tissue LPL activities were found before and after the break of treatment.
Biliary excretion of amoxycillin and ceftriaxone after intravenous administration in man.
Authors: Maudgal DP , Maxwell JD , Lees LJ , Wild RN
Published: July 2012

1 Plasma and biliary concentrations of amoxycillin and ceftriaxone were measured after bolus intravenous administration (500 mg) in four subjects with normal hepato‐biliary and renal function. 2 The mean plasma elimination half‐life for ceftriaxone (t 1/2 = 330 +/‐ 30 min) was considerably longer than that for amoxycillin (t 1/2 = 60 +/‐ 9 min). 3 The biliary concentration of ceftriaxone was above plasma concentration of the drug throughout the study period, whereas amoxycillin concentration in the bile was lower than that in plasma. 4 Both plasma and biliary concentrations of ceftriaxone were substantially higher than previously determined minimum inhibitory concentration (MIC) values for E. coli (and several other common biliary tract pathogens) for over 6 h following drug administration. Amoxycillin concentration in plasma fell below MIC by 2 h, and did not reach inhibitory concentrations in bile.
Metabolism of digoxin and absorption site.
Authors: Magnusson JO , Bergdahl B , Bogentoft C , Jonsson UE
Published: July 2012

After oral intake of enteric‐coated granules containing [3H]‐digoxin extensive metabolism was observed. Maximum 66% of the 24 h urinary excretion was identified as [3H]‐dihydrodigoxin, using high performance liquid chromatography for the analysis. It is suggested that metabolism of digoxin may depend on the absorption site.
The influence of the menstrual cycle on the metabolism and clearance of methaqualone.
Authors: Wilson K , Oram M , Horth CE , Burnett D
Published: July 2012

1 The rate of methaqualone metabolism in women was shown to be significantly increased at the time of ovulation. 2 The apparent first order rate constants for the formation of five C‐monohydroxy metabolites of methaqualone on day 15 of the menstrual cycle were approximately double that on day 1. 3 The N‐oxidation of methaqualone showed considerable inter‐individual variation in its sensitivity to the menstrual cycle, and in a group of ten women the difference in N‐ oxide excretion between days 1 and 15 was not statistically significant. 4 The serum clearance of methaqualone on day 15 was higher (mean value 94.6 ml min‐1 on day 1, 176.0 ml min‐1 on day 15), serum half‐life shorter (mean t1/2 beta 16.3 h on day 1, 11.6 h on day 15) and the AUC alpha smaller (mean value 44.0 micrograms ml‐1 h on day 1, 24.4 micrograms ml‐1 h on day 15) than on day 1. 5 The relative importance of the five hydroxy metabolites was unchanged during the menstrual cycle but the C/N oxidation ratio was greater on day 15 than on day 1. 6 The data for methaqualone metabolism in a control group of men was similar to than in women on day 1 of a menstrual cycle.
Enalapril maleate and a lysine analogue (MK‐521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system.
Authors: Biollaz J , Schelling JL , Jacot Des Combes B , Brunner DB , Desponds G , Brunner HR , Ulm EH , Hichens M , Gomez HJ
Published: July 2012

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK‐421 and of its lysine analogue (MK‐521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK‐421 and the lysine analogue were determined by radioimmunoassay and MK‐421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK‐421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK‐421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed (r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).
The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta‐adrenoceptor blockade in man.
Authors: Hassan S , Pickles H , Fish A , Burke C , Warrington S , O'Grady J
Published: July 2012

1 Atenolol 0.2 mg/kg i.v., propranolol 0.2 mg/kg i.v. or placebo were given in a double‐blind crossover study to six healthy male subjects, and the effects of a subsequent infusion of epoprostenol (prostacyclin, PGI2) 0‐6 ng kg‐1 min‐1 monitored. 2 PGI2 caused a tachycardia, a fall in diastolic blood pressure, a rise in pulse pressure, reduction in pre‐ ejection period (PEP) and rise in left ventricular ejection time index (LVETI), headache and facial flushing at doses of PGI2 greater than 2 ng kg‐1 min‐1, (P less than 0.05). 3 Beta‐adrenoceptor blockade did not prevent the tachycardia in response to PGI2, and did not interact with any of the other dynamic effects of PGI2. 4 In vitro, PGI2 at 1 and 2 ng/ml inhibited platelet aggregation to ADP (P less than 0.01), although no significant effect on platelet aggregation was seen in the in vivo study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect this in vitro study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect in vitro effect of PGI2 on platelet aggregation. 5 Pretreatment with atropine 0.04 mg/kg i.v. in three subjects did not attenuate the tachycardia caused by PGI2 infusion, even though the baseline heart rate was increased. 6 Adverse effects to PGI2 infusion included sudden bradycardia, pallor and sweating, suggesting that the Bezold‐Jarisch reflex seen in animals in response to PGI2 may also occur in humans. 7 Neither increased sympathetic drive nor vagal withdrawal are likely causes of the tachycardia following PGI2 infusion.
An oral preparation to release drugs in the human colon.
Authors: Dew MJ , Hughes PJ , Lee MG , Evans BK , Rhodes J
Published: July 2012

1 A colonic delivery system is described to deliver orally ingested drugs to the colon and release them at that site by coating with an acrylic based resin (Eudragit S). The technique is validated using X‐ ray evidence and serum levels of a convenient marker, sulphapyridine. 2 This colonic delivery system is particularly suitable for drugs such as 5‐amino salicylic acid or steroids in the management of patients with colitis.
Blood quinidine levels and cardiac effects in white British and Nigerian subjects.
Authors: Olatunde A , Evans Price DA
Published: July 2012

1 Differences between whites and blacks have been described in the incidence and patterns of cardiac disease and in electrocardiographic features. 2 The objective of the present study was to see if the ECG response to the same plasma and red blood cell quinidine concentration differed between whites and blacks. 3 It was found that following a standard single oral dose of quinidine both plasma and red blood cell quinidine concentrations tended to be lower in seven healthy white British subjects than in seven healthy Nigerians. 4 The change in QTc interval (delta QTc) after quinidine, however, tended to be greater in the white British subjects than in the Nigerians. 5 At a single plasma quinidine concentration the delta QTc tended to be higher in white British subjects than in Nigerians. 6 At a single blood cell quinidine concentration, delta QTc was significantly higher in British white subjects than in Nigerians. 7 The inter‐ethnic differences found could be due to both environmental and genetic factors. Further work will be required to decide the relative importance of both these factors on plasma quinidine levels and QTc responses.
A placebo‐controlled study to determine the efficacy of oral disopyramide phosphate for the prophylaxis of ventricular dysrhythmias after acute myocardial infarction.
Authors: Kumana CR , Rambihar VS , Tanser PH , Cairns JA , Gupta RN , Wildeman RA , Johnston M , Johnson AL , Gent M
Published: July 2012

1 To evaluate oral disopyramide phosphate in the prophylaxis of dysrhythmias occurring in acute myocardial infarction (MI) patients (presenting within 12 h of symptoms, age 21‐70 years), a placebo‐ controlled, randomized double‐blind, in hospital trial was conducted. After prognostic stratification (anterior and non‐anterior MI at each of 4 regional hospitals) patients were randomly assigned to receive oral disopyramide phosphate (loading dose 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh less than 55, 55‐85, or greater than 85 kg, respectively or matching placebo. The primary exclusion criteria were overt heart failure, systolic BP less than 100 mmHg, significant heart block or history of urinary retention. Active drug or placebo was continued for 7 days or until (a) detection of ‘warning arrhythmias’ requiring i.v. lignocaine intervention (greater than 5 for 7 days or until (a) detection of ‘warning arrhythmias’ requiring i.v. lignocaine intervention (greater than 5 premature ventricular contractions (PVCs)/min, R on T PVCs, multifocal PVCs, bigeminal PVCs, ventricular tachycardia or ventricular fibrillation) or (b) onset of exclusion criteria. In addition, plasma drug concentrations were determined and 24 h electrocardiographic tapes were obtained on day 1, and on one of days 4‐7 but these results are not presented here. 2 Out of 121 patients entering the trial, 101 had confirmatory ECG and enzyme changes. Of these, 9 of 47 patients receiving disopyramide phosphate required lignocaine compared to 20 of 54 receiving placebo (19% v 37%; P = 0.047). Corresponding numbers for patients discontinuing trial medication for other non‐fatal complications of MI were 5 and 3, and for those dying, were 3 (2 infarct extensions and 1 massive infarction), and 0, respectively. Respective numbers discontinuing trial medication for possible drug side effects (viz. urinary retention requiring catheterization) were 6 and 1 (P = 0.031). 3 In circumstances where i.v. therapy is deemed impractical, use of oral disopyramide phosphate given prophylactically in patients with acute MI may reduce the incidence of ‘warning arrhythmias’ by a clinically significant extent.
Do lorazeam‐induced deficits in learning result from impaired rehearsal, reduced motivation or increased sedation?
Authors: File SE , Lister RG
Published: July 2012

1 The effects of 1.0 mg and 2.5 mg lorazepam on learning performance were examined in a double‐blind cross‐over study using student volunteers. 2 Test conditions were manipulated to prevent rehearsal and to vary the subjects' motivation to perform well. Self‐ratings of alertness, motivation to perform well and state anxiety were obtained prior to each test. 3 Performance in arithmetic tasks of varying difficulty was also studied. 4 Lorazepam produced dose‐related deficits in verbal and nonsense‐syllable learning tasks. A greater proportion of errors in the number of problems attempted in the arithmetic tests reflected an impairment in cognitive function. Lorazepam reduced the number of arithmetic problems that were correctly solved as well as increasing the percentage of errors in the problems attempted. 5 Lorazepam did not significantly decrease motivation to perform well and the lorazepam impairment was found even when the test conditions were manipulated so as to prevent rehearsal. Therefore the learning deficits cannot be explained solely by changes in motivation or impairments in rehearsal. 6 Performance in the learning tasks correlated with ratings of alertness and therefore the deficits observed after administration of lorazepam seem likely to result from the non‐specific sedative effect of the drug.
Serum protein binding of diazepam in maternal and foetal serum during pregnancy.
Authors: Lee JN , Chen SS , Richens A , Menabawey M , Chard T
Published: July 2012

1 The serum binding capacity for diazepam was significantly lower in pregnancy and there was a linear correlation with gestational age. 2 The binding of diazepam was not correlated to albumin during pregnancy. 3 In cord sera there was a significantly reduced binding capacity for diazepam with albumin levels of less than 40 g/l.
Double‐blind comparison of the respiratory and sedative effects of codeine phosphate and (+/‐)‐glaucine phosphate in human volunteers.
Authors: Redpath JB , Pleuvry BJ
Published: July 2012

1 Two antitussive agents (+/‐)‐glaucine phosphate and codeine phosphate have been compared with placebo with respect to ventilation, ventilatory response to carbon dioxide, pulse, blood pressure, digit symbol substitution, sedation score and the Zahlen‐Verbindung test performance in ten healthy volunteers (22‐36 years). The study was double‐blind and the two doses of each antitussive agent and the placebo were administered as a syrup. 2 Both codeine phosphate and (+/‐)‐glaucine phosphate displaced the ventilatory response to carbon dioxide to the right. 3 The effect of codeine phosphate on the ventilatory response to carbon dioxide was not dose dependent: 30 mg produced greater effects than the 60 mg dose. 4 Only the highest dose of (+/‐)‐glaucine phosphate (60 mg) caused respiratory depression and this was associated with sedation and decreased performance in the digit symbol substitution test. 5 Neither antitussive agent had significant effects upon pulse or blood pressure and codeine phosphate had no detectable sedative activity.
Pharmacokinetic studies of various preparations of glyceryl trinitrate.
Authors: Bashir A , Lewis MJ , Henderson AH
Published: July 2012

1 The pharmacokinetics and pharmacodynamics of five pharmaceutical preparations of glyceryl trinitrate (GTN) have been studied in six healthy volunteers. 2 Peak plasma GTN levels of 1.4 +/‐ 0.1 ng/ml were achieved at 3 min after sublingual administration (0.5 mg); 2.8 +/‐ 0.6 ng/ml and 2.5 +/‐ 0.3 ng/ml at 2 h and 4 h after Nitrocontin (6.4 mg) and Sustac (6.4 mg) respectively; 2.7 +/‐ 0.1 ng/ml and 2.5 +/‐ 0.2 ng/ml at 30 min after the cream (23 mg) and ointment (35 mg) respectively. 3 The mean times to reach half peak plasma GTN levels were 4.2 +/‐ 0.7 min after sublingual GTN, 6.5 +/‐ 0.9 h after Nitrocontin, 4.1 +/‐ 0.7 h after Sustac, 46.1 +/‐ 10.2 min after the ointment and 50.2 +/‐ 39.2 min after the cream. 4 Plasma nitrate (NO3) levels were undetectable after sublingual administration; peak NO3 levels were 0.48 +/‐ 0.03 microgram/ml at 4 h after Nitrocontin, 0.45 +/‐ 0.02 microgram/ml at 6 h after Sustac, 0.68 +/‐ 0.04 microgram/ml at 6 h (end of study) after the ointment and 0.63 microgram/ml at 4 h after the cream. 5 Plasma nitrite (NO2) was undetectable after sublingual GTN and peak NO2 levels were 0.48 +/‐ 0.04 microgram/ml at 2 h after Nitrocontin, 0.48 +/‐ 0.02 microgram/ml at 2 h after Sustac, 0.69 +/‐ 0.02 microgram/ml at 1 h after the ointment and 0.64 +/‐ 0.02 microgram/ml at 1 h after the cream. 6 Blood pressure (BP) declined throughout the 11 min of the study after sublingual GTN but did not change significantly after Nitrocontin or Sustac. After the ointment and the cream BP fell to the lowest level 30‐60 min after administration and remained low throughout the 6 h of the study. 7 Heart rate (HR) increased to a maximum 5 min after sublingual administration with no significant increase after Nitrocontin or Sustac. After the ointment and the cream HR increased gradually to a maximum 30‐60 min after administration remaining high throughout the rest of the study.
The effect of glyceryl trinitrate ointment on heart rate–corrected systolic time intervals in angina pectoris.
Authors: Struthers AD , Whiting B , Hillis WS , Kelman AW
Published: July 2012

1 Individual systolic time intervals (STI) v heart rate regression equations were determined using small doses of intravenous atropine in seven patients with angina pectoris. 2 Regression lines of the form LVET = A + B.HR and QS2 = C + D.HR were calculated. There was no significant correlation between PEP and HR. The values of parameters A C and D were significantly different from a group of previously studied normal volunteers. 3 STI changes were recorded for 5 h after the application of GTN or placebo ointment. The active drug caused shortening of LVET and QS2 with the peak effect occurring between 105 and 180 min. After 180 min neither LVET nor QS2 were significantly shortened. There was no significant effect on PEP or heart rate.
Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition.
Authors: Silberbauer K , Stanek B , Templ H
Published: July 2012

1 A study was carried out to investigate the possible contribution of prostaglandins in captopril‐induced hypotension. 2 Healthy volunteers and patients with essential hypertension were given single oral doses of 25 mg and 50 mg captopril respectively before and after cyclo‐ oxygenase inhibition with indomethacin. 3 The acute hypotensive effect of captopril was not associated with changes in heart rate. As expected, captopril led to an increase in plasma renin activity, decrease in plasma angiotensin II, and decrease in plasma aldosterone concentration. 4 After acute indomethacin pretreatment the acute hypotensive effect of captopril was significantly blunted in volunteers and in the 14 hypertensive patients. Changes in plasma renin activity and angiotensin II were significantly lower from a lower baseline. 5 Prostaglandins may therefore be mediators of the initial captopril effect. The blunting effect of indomethacin should be taken into account under clinical conditions.
Captopril in the treatment of mild essential hypertension.
Authors: Fernandez‐Cruz A , Otero Luque M , Pinilla Fernandez C , Claros Martell N
Published: July 2012

1 Among 34 patients with mild essential hypertension treated for four weeks with captopril alone the blood pressure of 47% returned to normal. By the end of the fourth week chlorthalidone had been added to captopril in 18 of the patients; 15 then achieved normal blood pressure, and only three failed to achieve diastolic blood pressures of under 100 mm Hg. 2 Among the 16 patients who continued to take captopril alone after the fourth week all achieved a return to normal blood pressure during the next 12 months of treatment. 3 Side effects of captopril were essentially limited to rash, taste alteration, and nausea and vomiting, which were usually mild and transient.
Long‐term treatment of congestive heart failure with captopril.
Authors: Komajda M , Eugene M , Evans J , Drobinski G , Laurenceau JL , Grosgogeat Y
Published: July 2012

1 The efficacy of the converting‐enzyme inhibitor captopril in the management of severe congestive heart failure was assessed in 14 patients over 360‐885 days by clinical evaluation, M‐mode echocardiography, systolic time intervals, plasma renin activity, and plasma aldosterone. 2 As compared with baseline values, a significant reduction was observed in heart rate, mean arterial pressure, left ventricular end‐diastolic and end‐systolic diameters, left ventricular pre‐ejection period, tension time index, body weight, and plasma aldosterone. Significant increases in left ventricular ejection time and fractional circumferential shortening (p less than 0.01) were also observed. 3 The functional and haemodynamic benefit provided by captopril was therefore sustained during long‐term therapy without severe untoward effects or attenuation.
Logistics and management of clinical trials.
Authors: Greenberg G.
Published: July 2012

This chapter is concerned with some of the more mundane aspects of the day to day design, planning, documentation, and management of clinical trials, rather than with the finer points of trial design which are dealt with in detail elsewhere. The points considered here, taken individually, seem obvious and trivial but it is hoped that some may be helpful in obtaining the maximum return for the work invested in running a trial.