bluuebunny/crossref_metadata_2025 huggingface dataset:
Chenodeoxycholic acid therapy for hypertriglyceridaemia in men.
Authors: Bateson MC , Maclean D , Evans JR , Bouchier IA
Published: July 2012

1 Ten consecutive patients with hypertriglyceridaemia who adhered to a low carbohydrate diet without complete control of serum triglycerides were started on chenodeoxycholic acid 750 mg daily and followed monthly for 6 months. Nine of these patients were then followed for a further month on placebo capsules and thereafter monthly for a further 6 months on clofibrate 2 g daily. 2 The mean serum triglyceride level fell by 36% after dietary treatment alone (P less than 0.05) and by 47% from initial values on diet plus chenodeoxycholic acid (P less than 0.01). In the nine patients who proceeded to clofibrate therapy there was a rise in triglyceride levels on placebo capsules to the level achieved by diet alone, and a further fall on diet plus clofibrate of 47% of initial values (P less than 0.05). 3 Chenodeoxycholic acid therapy is effective in the management of hypertriglyceridaemia not completely cured by dietary measures, and may be as efficacious as clofibrate.
Prednisone or prednisolone for the treatment of chronic active hepatitis? A comparison of plasma availability.
Authors: Davis M , Williams R , Chakraborty J , English J , Marks V , Ideo G , Tempini S
Published: July 2012

1 The plasma availability of prednisolone after oral doses of prednisolone and its precursor, prednisone, were compared in ten normal controls and twenty‐five patients with chronic active hepatitis by estimation of the area under the plasma concentration‐time curve for the drug (AUC). 2 In controls, values for AUC were significantly more variable after prednisone than prednisolone, and two subjects showed markedly inefficient conversion of prednisone to prednisolone. In patients, variability was similarly wide after both preparations, but overall bioavailability after both prednisone and prednisolone was similar to that found in controls, although three patients showed subnormal values after both preparations, possibly as a result of impaired intestinal absorption. 3 Patients with biochemical and histological evidence of active hepatocellular necrosis showed evidence of impaired activation of prednisone, but this was compensated for by a decreased rate of elimination of prednisolone from the plasma. 4 It is concluded that plasma prednisolone levels will be more predictable after prednisolone than after prednisone in subjects without hepatic dysfunction. In the presence of liver disease, because of the marked variability in plasma prednisolone levels after either drug, estimation of these could be of value in those patients whose disease cannot be controlled by normal maintenance doses.
Pharmacokinetics of clonidine and its relation to the hypotensive effect in patients.
Authors: Frisk‐Holmberg M , Edlund PO , Paalzow L
Published: July 2012

1 The kinetics of clonidine and its relation to the blood pressure response after single intravenous doses of 75 micrograms–275 micrograms in hypertensive patients were determined. 2 Clonidine disposition could be described by a two compartment open model and pharmacokinetic parameters show a rapid distribution phase of 20–30 min and a mean plasma clearance of 4.6 ml min‐1 kg‐1 (75–200 microgram). The half‐life of the beta‐phase was found to be in the range of 7.4–11.4 h. Indications of dose dependent kinetics were obtained. 3 A dose‐dependent decrease in blood pressure was obtained. 4 The maximal reduction in MAP (mean arterial blood pressure) was significantly (P less than 0.01) related to plasma concentrations of clonidine. 5 The reduction in MAP was always related to plasma concentrations of clonidine (r = 0.88, P less than 0.01) when pseudoequilibrium of distribution of the drug was achieved.
Clobazam–a new hypnotic?
Authors: Kesson CM , Gray JM , Lawson DH
Published: July 2012

1 A double‐blind randomized trial to compare the relative efficacy of the 1,5‐benzodiazepine, clobazam, the 1,4‐benzodiazepine nitrazepam, and placebo as hypnotics was carried out. 2 A preference technique was used and the analyses were performed sequentially. 3. The results confirmed that nitrazepam was superior to placebo as a hypnotic but failed to show that clobazam was superior to either placebo or nitrazepam in a ratio of 2:1. Thus, it seems likely that the hypnotic properties of clobazam are minimal. 4 Clobazam is not suitable for use as a hypnotic in hospitalized patients.
Liver size and indices of drug metabolism in epileptics.
Authors: Pirttiaho HI , Sotaniemi EA , Ahokas JT , Pitkanen U
Published: July 2012

1 The relationship between liver size and in vivo (antipyrine kinetics) and in vitro (cytochrome P‐450) drug metabolism was investigated in twenty‐one epileptics on long‐term anticonvulsant therapy and in controls. 2 The epileptics exhibited significant enlargement of the liver and enhancement of drug metabolism compared to the controls. 3 Liver size correlated to antipyrine kinetics only in controls. Concentration of cytochrome P‐450 in liver biopsy specimens correlated with liver size neither in controls nor in epileptics. 4 The total hepatic cytochrome P‐450, estimated on the basis of liver weight and cytochrome P‐450 concentration of biopsy samples, correlated linearly with antipyrine kinetics, except in patients with the most severely disturbed liver architecture. 5 Measurement of liver size is essential when comparing in vivo and in vitro drug metabolism, but the changes in liver histology are also of great importance.
Adrenocortical suppression by synthetic corticosteroid drugs: a comparative study of prednisolone and betamethasone.
Authors: Downie WW , Dixon JS , Lowe JR , Rhind VM , Leatham PA , Pickup ME
Published: July 2012

1 Single‐dose studies were conducted to investigate the relative potency of prednisolone and betamethasone in suppressing adrenocortical function. 2 Betamethasone produced more profound suppression of plasma cortisol than an equivalent anti‐inflammatory dose of prednisolone.
Methods for assessment of the effect of drugs on cerebral blood flow in man.
Authors: James IM
Published: July 2012

The cerebral circulation is not an unimportant vascular bed but it is difficult one to investigate. Methodological difficulties are the main reasons for the paucity of clinical pharmacology studies to date. Of the methods currently available those of the McHenry (1964) and Wyper et al. (1976) appear to be the most useful to the clinical investigator. Increasing use of multiple detectors even with inhalation techniques may give evidence of regional drug effects upon the cerebral circulation. Improvements in methodology in the last few years, particularly the development of atraumatic methods are likely to act as an important spur to research in this field.
The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine‐studies in patients with peptic ulcer disease.
Authors: Bodemar G , Norlander B , Fransson L , Walan A
Published: July 2012

1 The absorption of a single oral dose of cimetidine taken on a fasting stomach or together with a meal was studied in 28 patients before and during 12 weeks treatment with cimetidine. 2 No significant changes in bioavailability were seen during treatment measured as the area under the blood concentration curve (AUC). 3 AUC after a single dose of 400 mg cimetidine was 2.05 times the area after a 200 mg dose. 4 There was a good correlation between AUC and the dose of cimetidine given corrected for body weight (r=0.89). 5 There was no difference in bioavailability if 200 mg cimetidine was taken on a fasting stomach or together with a beef steak meal. 6. During fasting conditions there was a peak in blood concentration at about one hour followed by a second unexplained peak during the third to fifth hour after dose administration. 7 With food the initial rise in blood concentrations was slower and there was only one peak occurring about 2 h after dose administration.
Impairment of hepatic drug metabolism in alcoholics.
Authors: Harman AW , Frewin DB , Priestly BG , Alexander CB
Published: July 2012

1 The effects of chronic ethanol intake on the elimination kinetics of antipyrine were determined in nineteen male alcoholic subjects with comparison made to fourteen male volunteers. 2 Half‐lives were longer and clearance values less in the alcoholic group. 3 Significant rank correlations were found between half‐life and clearance when compared with various biochemical parameters of liver function measured in the plasma of the alcoholics. 4 These results show that a significant proportion of the alcoholics studied had impaired hepatic drug metabolizing capacity and that the activity of hepatic microsomal enzymes may be related to the extent of ethanol induced liver damage in these subjects.
The effect of ageing on the hepatic clearance of propranolol.
Authors: Castleden CM , George CF
Published: July 2012

1. Plasma propranolol concentrations were measured in healthy old and young subjects following single oral doses of 40 mg, single i.v. infusions of 0.15 mg kg‐1 and after nine 40 mg oral doses given four times daily. 2. In each of the three studies, the elderly had higher plasma propranolol concentrations than the young despite having similar apparent volumes of distribution. 3. The terminal half‐life of propranolol was similar in the two groups after oral propranolol but significantly shorter in the young after intravenous dosing (P less than 0.05). 4. The bioavailability assessed from the concentration‐time curves after i.v. and oral dosing was greater in the elderly (P less than 0.05). 5. The differences between peak concentrations observed in old and young subjects after single oral doses were maintained during chronic therapy and there was a correlation between the individual values obtained on multiple therapy with that after a single dose (P less than 0.05). 6. Ageing appears to affect the pharmacokinetics of propranolol in two ways. Firstly, distribution to the tissues appears to be slowed. Secondly, the increased bioavailability following oral administration suggests diminished intrinsic clearance by metabolism.
Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergic drugs.
Authors: Hansen LB , Elley J , Christensen TR , Larsen NE , Naestoft J , Hvidberg EF
Published: July 2012

1. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson treatment. Twenty‐six psychotic patients received various forms of PPZ administration as well as antiparkinson drugs. 2. Biperidine (5 mg) was administered intravenously to each of five patients, who 5 days earlier had had a single dose of PPZ‐ enanthate i.m. No significant alterations in plasma concentrations of PPZ were observed. 3. In fourteen patients receiving oral PPZ treatment the plasma levels of PPZ and its metabolites did not deviate significantly from controls after addition of biperidine or orphenadine given for 3 weeks in fixed oral doses. 4. The ratio between PPZ plasma concentration measured 4 and 7 h after the morning dose was not affected by concomitant antiparkinson therapy. 5. It is concluded that no clinically relevant pharmacokinetic interaction takes place between PPZ and two generally used antiparkinson drugs during steady‐state conditions in psychotic patients.
Rate of onset of hypotensive effect of oral labetalol.
Authors: Serlin MJ , Orme MC , Maciver M , Green GJ , Macnee CM , Breckenridge AM
Published: July 2012

1 Labetalol caused a fall in blood pressure within 2 h or oral doses of 100, 200 and 400 mg in six hypertensive patients. 2 This fall which was dose‐related was maximal by 3 h and was sustained when the drug was given in doses of 100 mg 8 hourly, 200 mg 8 hourly and 400 mg 8 hourly. 3 This rapid fall in pressure when labetalol is given by mouth which contrasts to that seen on administration of pure beta‐adrenoceptor blocking agents is a valuable therapeutic property.
Haemodynamic and electrocardiographic effects of intravenous disopyramide (rythmodan) following acute myocardial infarction.
Authors: Davies GJ , Marrott PK , Muir JR
Published: July 2012

1 The haemodynamic and electrocardiographic effects of intravenous disopyramide were studied in fifteen patients with acute myocardial infarction. 2 Five minutes after drug injection a rise in heart rate, aortic mean and diastolic pressures and systemic vascular resistence was noted which persisted for at least 30 min. A small increase in pulmonary arterial diastolic pressure (mean = 1.5 mm Hg) occurred at 5 min only and no significant change of cardiac output was found throughout the period of the study (1 h). 3 Surface electrocardiograms revealed transient prolongation of the P‐R interval and a sustained increase in the QTc interval. 4 The haemodynamic changes suggest an anticholinergic effect of the drug. There was no definite evidence of a negative inotropic effect in this study, however, these peripheral haemodynamic measurements might not have revealed a modest negative inotropic effect. 5 The electrocardiographic changes are similar to those previously reported in normals and in patients without acute myocardial infarction.
Cinnarizine in the treatment of chronic asthma.
Authors: Emanuel MB , Chamberlain JA , Whiting S , Rigden BG , Craven AH
Published: July 2012

1 Cinnarizine, an inhibitor of calcium ion transport across smooth muscle cell membrane, has been shown to exert an anti‐asthmatic effect in patients with chronic asthma. 2 It is postulated that antagonism to calcium ion transport across the mast cell membrane may cause the compound to have a pharmacological effect similar to sodium cromoglycate. 3 Cinnarizine is orally active and its therapeutic effect is demonstrated in a double‐blind, cross‐over, placebo controlled study. 4 Patient benefit was shown by a significant improvement in peak flow rate. A non‐significant trend towards a reduction in symptomatic bronchodilator usage and a decrease in asthma symptom score was also shown. 5 It is concluded that cinnarizine could well prove to be the first of a new family of anti‐asthmatic drugs offering a protective effect when taken systemically.
Interaction of halothane with non‐depolarizing neuromuscular blocking drugs in man.
Authors: Hughes R , Payne JP
Published: July 2012

1 Tetanic and single twitch contractions of the adductor pollicis muscles, in response to indirect stimulation of each ulnar nerve, were recorded in patients anaesthetized with thiopentone and nitrous oxide in oxygen. 2 Concentrations of 1 and 2% halothane were administered for 10 min during recovery from neuromuscular paralysis by tubocurarine, dimethyl tubocurarine and gallamine. 3 During exposure to halothane, the peak contraction of the tetanic response was reduced and tetanic fade was increased whereas the single twitch was unaffected. 4 The effects of halothane on the tetanic responses were readily antagonized by intravenous neostigmine preceded by atropine. 5 Halothane could act post‐synaptically by a non‐depolarizing block or by desensitizing the post‐synaptic receptors, but a pre‐synaptic action seems more likely since neuromuscular block was only evident when tetanic stimulation was applied. Such an effect could be caused by impairment of the release of acetylcholine.
The effect of beta‐adrenergic receptor blocking drugs on cerebral blood flow.
Authors: Griffith DN , James IM , Newbury PA , Woollard ML
Published: July 2012

1 Cerebral blood flow (CBF) was measured by the 133xenon inhalation method in 33 newly‐diagnosed hypertensive patients prior to commencing therapy. 2 Blood pressure was treated by using a varying sequence of four different drugs, namely labetalol, metoprolol, oxprenolol and sotalol, each of which is a beta‐adrenergic receptor blocking agent, but with differing additional properties. 3 CBF measurements were repeated when blood pressure was controlled. No significant change in CBF was found with any of the four drugs, in contrast to the fall which has been reported when drugs of this type are administered acutely.
Preliminary studies on nasal decongestant activity from the seed of the shea butter tree, Butyrospermum parkii.
Authors: Tella A
Published: July 2012

1 The seed of Butyrospermum parkii yields shea butter which according to local traditional healers relieves inflammation of the nostrils. 2 Since there is as yet no absolutely satisfactory nasal decongestant in clinical use, it was decided to investigate the effects of shea butter in nasal congestion. The substance was prepared in the laboratory. 3 The human subjects used were those suffering from rhinitis with moderate to severe nasal congestion. They were divided into the test group which received shea butter, the control group which was treated with xylometazoline and the 'placebo' group which received white petroleum jelly B.P. 4 The results showed that nasal congestion was relieved more satisfactorily in the test group than in the other two groups. 5 It is concluded that shea butter may prove more efficacious in nasal congestion than conventional nasal drops.
The pressor actions of noradrenaline, angiotensin II and saralasin in chronic autonomic failure treated with fludrocortisone.
Authors: Davies B , Bannester R , Sever P , Wilcox C
Published: July 2012

1 Treatment of postural hypotension due to chronic autonomic failure with fludrocortisone increased the pressor sensitivity to intravenous noradrenaline. Fludrocortisone increased the blood pressure in the standing but not the lying position. These effects of fludrocortisone may be the result of increased sensitivity of vascular receptors to noradrenaline. 2 The pressor action of angiotensin II, to which patients were supersensitive, may have involved the stimulation of alpha‐adrenoceptors since it was partially antagonised by phentolamine. 3 Saralasin had a marked, paradoxical, pressor effect. This may have been mediated by vascular alpha‐adrenoceptors because log dose‐response curves of saralasin‐induced increases in systolic pressure were shifted to the right in a parallel fashion after phentolamine. 4 Fludrocortisone treatment increased the pressor sensitivity to intravenous saralasin but not to angiotensin‐II.
The interaction of varying doses of dipyridamole and acetyl salicylic acid on the inhibition of platelet functions and their effect on bleeding time.
Authors: Rajah SM , Penny AF , Crow MJ , Pepper MD , Watson DA
Published: July 2012

1 In normal volunteers maximum reductions in platelet functions, collagen aggregation, adhesion and PF4 availability, were achieved using combined doses of 50 mg three times daily dipyridamole + 180 mg ASA or 75 mg three times daily dipyridamole + 120 mg ASA daily. 2 These doses did not prolong the bleeding time. 3 A synergistic effect has been demonstrated with 25 mg dipyridamole three times daily and 60 mg ASA. 4 At higher doses the effects on platelet functions were additive up to the maximal response. 5 The effect of low doses of ASA on platelet function was cumulative. 6 As lower doses of ASA in the combination studied inhibit platelet functions maximally without altering the bleeding time and probably without inhibiting prostacyclin, we suggest that these combinations of dipyridamole and ASA merit consideration in future clinical trials.
Probenecid: an unexplained effect on cephalosporin pharmacology.
Authors: Welling PG , Dean S , Selen A , Kendall MJ , Wise R
Published: July 2012

1 The influence of probenecid on serum levels and urinary excretion of orally administered cephradine and cefaclor has been investigated. 2 Probenecid caused serum levels of both antibiotics to be increased and also prolonged. Urinary excretion of antibiotic activity was slightly but not significantly decreased by probenecid during the initial 6 h postdosing. It was significantly increased in 6‐12 h urine, but only a small percentage of the doses were excreted during that period. 3 The increased serum levels of antibiotic were greater than could be accounted for by reduced elimination rate alone. Possible mechanisms to account for increased circulating levels of antibiotic in the presence of probenecid are discussed in the light of previous observations on probenecid induced changes in tissue distribution of beta‐lactam antibiotics.
The aspirin‐ibuprofen interaction in rheumatoid arthritis.
Authors: Grennan DM , Ferry DG , Ashworth ME , Kenny RE , Mackinnon M
Published: July 2012

1 This was a double‐blind crossover trial of ibuprofen and soluble aspirin against each drug alone and against placebo in patients with rheumatoid arthritis. Two dosage regimes were tested. 2 A weak clinical additive effect was demonstrated between soluble aspirin and ibuprofen in patients with rheumatoid arthritis using moderate (1600 mg ibuprofen and 3.6 g aspirin daily) but not low (800 mg ibuprofen and 2.4 g aspirin daily) dosages of both drugs. 3 A significant correlation between clinical efficacy and serum ibuprofen but not salicylate level was found in the single drug periods of the trial. 4 No consistent effect of ibuprofen administration on serum salicylate levels was found. 5 Concurrent salicylate administration produced significant lowering of serum ibuprofen levels without affecting elimination half‐ lives of the drug.
Decreased plasma protein binding of phenytoin in patients on valproic acid.
Authors: Dahlqvist R , Borga O , Rane A , Walsh Z , Sjoqvist F
Published: July 2012

1 Plasma protein binding of phenytoin and of valproic acid were measured in ten epileptic patients on this drug combination. Ten other epileptics not on valproic acid served as controls. All patients had normal kidney function. 2 The measured free fraction of phenytoin among the patients on valproic acid ranged from 12.5 to 23.2% and after recalculation to a plasma albumin level of 45 g/l from 12.5 to 20.0 (median 15.4%). This differed significantly (P = 0.002, Mann‐ Whitney U‐ test) from the control patients where the normalized values ranged from 9.9 to 13.9% with a median value of 11.8%. 3 The measured free fractions of phenytoin and of valproic acid showed a significant correlation which, however, was due to the quantitative relation between the degree of binding of both these drugs and the concentration of plasma albumin. There was no discernable relation in this material between the free concentration of valproic acid and the free fraction of phenytoin. 4 It is concluded that patients on combined treatment with phenytoin and valproic acid have an unpredictably raised free fraction of phenytoin. This drug interaction therefore can complicate the important plasma level monitoring of phenytoin in epileptic patients unless the free concentration of this drug can be analysed or estimated.
Comparison of propranolol and metoprolol in the management of hyperthyroidism.
Authors: Murchison LE , How J , Bewsher PD
Published: July 2012

1 Propranolol and metoprolol were both effective in controlling the symptoms and signs of hyperthyroidism. 2 Propranolol caused a highly significant increase in serum reverse T3 concentrations with lesser changes in other serum thyroid hormone levels, whereas metoprolol did not have this effect. 3 Steady‐state plasma propranolol and metoprolol levels showed marked inter‐individual variation. Metoprolol concentrations showed relatively little intra‐individual variability, and could be related to the clinical efficacy of the drug, whereas no such relationship was demonstrated for propranolol.
Quantitative assessment of bronchial beta‐adrenoceptor blockade in man.
Authors: Gribbin HR , Baldwin CJ , Tattersfield AE
Published: July 2012

1. We describe a method for assessing bronchial beta‐adrenoceptor blockade quantitatively in man. Specific airway conductance is measured after increasing doses of inhaled salbutamol and the extent to which the dose‐response curve is displaced to the right after beta‐ adrenoceptor blocking drugs is used to assess bronchial beta‐ adrenoceptor blockade. 2. Salbutamol dose‐response curves were plotted for six normal subjects by measuring sGaw 15 min after increasing doses of inhaled salbutamol. Salbutamol produced a 30‐70% increase in sGaw. 3. Salbutamol dose response curves were obtained 2 h after oral practolol (100 mg and 200 mg) and oral propranolol (40 mg and 80 mg) on separate days and were displaced to the right. 4. The mean dose ratios for practolol 100 mg and 200 mg were 1.2 and 2.1 and for propranolol 40 mg and 80 mg they were 21 and 61 respectively.
Onset and duration of beta‐adrenergic receptor blockade following single oral dose acebutolol hydrochloride (Sectral).
Authors: Watson RD , Littler WA
Published: July 2012

1. The onset and duration of action of once daily acebutolol (400 mg) on resting and exercise heart rate and blood pressure were studied in normal subjects in a double‐blind, cross‐over trial against placebo. Subjects were studied 1.5, 3, 8 and 24 h after the first dose and 24 h after the fifth dose. 2. Resting and exercise heart rate and blood pressure were significantly reduced within 90 min of the first dose. 3. A significant reduction in these variables persisted throughout 24 h after the fifth daily dose. However, at 24 h the effects were considerably attenuated, the falls in resting and exercise systolic blood pressure being only 5%. 4. A linear relationship was noted between log serum drug level and percentage reduction of exercise heart rate.
A comparison of the clinical and psychological effects of diazepam and amylobarbitone in anxious patients.
Authors: Tansella CZ , Tansella M , Lader M
Published: July 2012

1. Twenty‐four anxious inpatients were treated with diazepam, amylobarbitone sodium and placebo in flexible dosage for 1 week. They each received all three treatments according to a fully‐balanced design, using double‐blind procedures. 2. The clinical and the psychological effects of the drugs were assessed by the comprehensive battery of psychiatrist's ratings, subjective and psychological tests before treatment and at the end of each week of treatment. The tests included self‐rating of anxiolytic and hypnotic effects, reaction‐time, card sorting, coding and cancellation tasks, arithmetic and tappin. 3. Diazepam improved significantly subjective anxiety and insomnia, while amylobarbitone improved only the self‐rated quality of sleep. Occasion effects were absent on clinical measures, indicating that the patients did not respond to non‐specific temporal factors. Performance on motor tasks improved over time because of the expected practice effect, but an impairment relative to placebo was detected on two motor tests after the barbiturate and on four other tests with a cognitive component after the benzodiazepine.
A clinical study of low molecular weight‐hydroxyethyl starch, a new plasma expander.
Authors: Mishler JM , Parry ES , Sutherland BA , Bushrod JR
Published: July 2012

1. The pharmacokinetics of a new plasma expander, low molecular weight‐ hydroxyethyl starch (LMW‐HES) were examined in six normovolaemic men. 2. One hour post‐infusion, 13.5% of the total dose of LMW‐HES injected was excreted in the urine, 50.2% was present in the intravascular space, and 36.3% was unaccounted for. 3. Twenty‐four hours post‐ infusion, 65.5% of the total dose of injected LMW‐HES had been excreted in the urine, 4.1% remained intravascularly, and 30.4% was unaccounted for. 4. The plasma volume increased rapidly from a mean value of 45.7 ml kg‐1 to a maximum value of 57.9 ml kg‐1 immediately post‐injection, then gradually returned to normal over 24 h. 5. The infusion of an average of 58.1 g had no effect on ESR, renal and hepatic biochemical indices. 6. LMW‐HES appears to be safe and effective, and should be of value clinically when rapid and short‐lived augmentation of the plasma volume is required.
Variability of plasma catecholamine levels: age, duration of posture and time of day.
Authors: Saar N , Gordon RD
Published: July 2012

1. In order to define factors which influence plasma catecholamine levels, and which might be controlled in the interests of reproducability and comparability, plasma noradrenaline plus adrenaline (NA + A) was measured repeatedly in normal subjects by a double isotope technique. 2. Age and posture were important determinants for plasma NA + A levels, whereas time of day was less important. 3. Levels were higher in old men aged 70‐92 years than in young men aged 19‐28 years, measured after 30 min or 9 h (overnight) recumbency, or after 5 min standing. 4. Duration of recumbency and of upright posture were both important. Recumbent levels were lower after 9 h (overnight) than after 30 min (mid‐morning). Upright posture caused an increase in levels within 2 min. Levels peaked between 5 and 20 min, were lower after 12 h than after 20 min, but upright levels were always higher than levels after 9 h recumbency. 5. During continuous recumbency, levels were lowest at 24.00 h, and increased thereafter. During a second hospitalisation, levels at 09.00 h were again higher than levels at 06.00 h after overnight recumbency. 6. Variability of levels obtained by repeated sampling was lower while sitting, during a normal upright day, than after 30 min recumbency. Upright legels may be a better index of cardiovascular sympathetic activity.
The characteristics of the binding of 12‐alpha‐[3H]‐digoxin to the membranes of intact human erythrocytes: relevance to digoxin therapy.
Authors: Ford AR , Aronson JK , Grahame‐Smith DG , Rose JA
Published: July 2012

1 The characteristics of the binding of 12‐alpha‐[3H]‐digoxin to the membranes of intact human erythrocytes are described. 2 Only one class of binding site can be demonstrated. Binding is time‐ and temperature‐ dependent, saturable and slowly reversible; it is inhibited by other cardiac glycosides and by potassium. 3 Pre‐incubation with unlabelled digoxin reduces the subsequent binding of 12‐alpha‐[3H]‐digoxin in stoichiometric fashion. 4 The possible application of the measurement of the binding of 12‐alpha‐[3H]‐digoxin to the study of biochemical pharmacological events occurring during digoxin therapy is discussed.
Clinical evaluation of a new antihypertensive vasodilating agent PR‐G 138 Cl.
Authors: Vos J. , Dorhout Mees EJ
Published: July 2012

1 The cardiovascular effects of a new substance (PR‐G 138) with vasodilating action were analysed in 12 patients with moderately severe essential hypertension on a 60 mEq sodium diet in a metabolic ward. To prevent tachycardia, propranolol 40 mg four times daily was given during the control period until blood pressure (BP) was stabilized, and continued throughout the study. 2 The compound was effective in every patient except one, who also was resistant to hydrallazine and diazoxide. Mean arterial pressure was lowered from a mean control value of 121 +/‐ 11 supine and 118 +/‐ 13 standing to 98 +/‐ 18 and 95+/‐ 15 mm Hg (P less than 0.001) respectively after a single oral dosage of 5 to 15 mg PR‐G 138. The effect was maximal after 1–2 h and lasted up to 6 h. 3 With adequate dosage, there was no orthostatic reaction. Pulse rate and plasma renin activity did not rise during PR‐G 138 treatment, and cardiac output increased only slightly, doubtlessly as a result of the propranolol therapy. In most patients 5 mg of the drug was sufficient to cause a drop of BP to normal levels. Exercise tolerance (bicycle ergometry) was constant or improved during drug action. One patient complained of headache, but no other side effects were seen provided that propranolol was taken when the drug was given. During 3 months treatments on an out‐patient basis the effect was sustained in four of eight patients. No toxic effects have been noticed.
Individual and group dose‐responses to intravenous omeprazole in the first 24 h: pH‐feedback‐controlled and fixed‐dose infusions.
Authors: Wilder‐Smith CH , Bettschen HU , Merki HS
Published: July 2012

1. Individual responses to intravenous boli of omeprazole have shown considerable variability. Data on the individual responses to the new omeprazole infusion formulation are lacking. 2. Individual dose‐ responses in the first 24 h of fixed‐dose and pH‐feedback‐controlled infusions of omeprazole were assessed in two randomised, third‐party blinded, cross‐over studies, using two separate groups of eight healthy subjects. In study A, feedback‐controlled infusions of omeprazole (target pH 5, dose range 0‐12 mg h‐1) and fixed‐dose infusions (8 mg h‐ 1) were compared, both with an initial bolus of 80 mg. Omeprazole plasma concentrations were measured. Study B assessed the effect on individual pH‐control of a loading bolus of either 40 mg or 80 mg omeprazole, followed by feedback‐controlled infusions. 3. Study A: the median % time of pH > 5 was 71.2 (total range: 48.9‐83.2) with feedback infusions and 57.9 (28.0‐95.3) with fixed‐dose infusions (P = 0.06). The mean 24 h infusion doses were 173.1 mg (44.5‐253.1) in the feedback group and 192 mg in the fixed‐dose group. The AUC of omeprazole plasma concentrations ranged widely, but correlated with the % time of pH > 5 during fixed‐dose infusions. Study B: initial boli of 40 mg and 80 mg of omeprazole resulted in similar 24 h median % of time with pH > 5, 69.2 (49.9‐78.8) and 69.6 (44.4‐87.7), respectively. Mean omeprazole doses infused by feedback pump were 187.6 mg (83.1‐253.6) after 40 mg boli and 159.9 mg (61.8‐227.0) after 80 mg boli.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic tobacco smoking and gender as variables affecting amantadine disposition in healthy subjects.
Authors: Wong LT , Sitar DS , Aoki FY
Published: July 2012

Amantadine HCl (3 mg kg‐1) was administered orally to 20 young healthy adults. Its apparent volume of distribution (V2/F) was higher in smokers than nonsmokers, 6.05 +/‐ 0.86 vs 4.87 +/‐ 0.85 l kg‐1; (mean +/‐ s.d., 10/group, P < 0.011), and no gender‐associated effect was observed. Renal clearance did not vary with time‐interval, but urinary recovery at 48 h was higher in men than in women (60.2 +/‐ 7.5% vs 47.0 +/‐ 15.0%, P < 0.032). Males had higher renal clearances than females when normalised for body mass index (BMI, 0.492 +/‐ 0.284 vs 0.248 +/‐ 0.137 l‐1 BMI h‐1, (10/group, P < 0.032)). On combining data from a previous study, the weight normalised renal clearance was also higher in men than in women, 0.160 +/‐ 0.075 vs 0.102 +/‐ 0.053 l kg‐1 h‐1 (19/group, P < 0.01). Chronic tobacco smoking did not alter the plasma or renal amantadine clearance. We conclude that gender and tobacco smoking are independent variables effecting amantadine disposition.
Assessment of arylamine N‐acetyltransferase (NAT1) activity in mononuclear leukocytes of cystic fibrosis patients.
Authors: Cribb AE , Tsui B , Isbrucker R , Michael RT , Gillespie CT , Brown‐Bonomo J , Barrett P , Levatte T , Renton KW
Published: July 2012

The clearance of sulphamethoxazole (SMX), a compound metabolised primarily by the N‐acetyltransferase NAT1, is increased in cystic fibrosis (CF) patients. We assessed the activity and kinetic properties of NAT1 in lysates of peripheral blood mononuclear leukocytes (MNL) from CF (n = 17) and control (n = 22) subjects using SMX and p‐ aminobenzoic acid (PABA) as test substrates. The Km and Vmax values of both substrates in MNL from CF patients and control subjects were not significantly different. The acetylation of PABA (100 microM) by intact MNL from CF patients (n = 4) was not different from the observed in intact MNL from controls (n = 9) (25 +/‐ 3 pmol h‐1 per 10(6) MNL vs 27 +/‐ 4 pmol h‐1 per 10(6) MNL). These results suggest that there are not systemic changes in this enzyme in CF. The increased metabolic clearance of SMX may therefore be related to factors other than alterations in the level of activity of the N‐acetyltransferase NAT1.
The bioavailability and disposition of 1‐(beta‐D‐arabinofuranosyl)‐5‐(1‐ propynyl)uracil (882C87), a potent, new anti‐varicella zoster virus agent.
Authors: Peck RW , Wootton R , Lee DR , Jackson SH , Posner J
Published: July 2012

1. The bioavailability and disposition of 882C87, an anti‐varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. 2. The mean bioavailability of a 200 mg tablet was 21.1% in the young (range 13.3‐33.0%, n = 10) and 24.6% in the elderly (range 14.4‐38.4%, n = 8), which is sufficient to achieve plasma concentrations well above the IC50 for anti‐VZV activity. 3. Plasma concentrations of 882C87 after 50 mg i.v. were higher in the elderly than in the young, associated with a significantly longer half‐life (13.7 vs 11.8 h) and decreased renal clearance (0.11 vs 0.14 ml min‐1 kg‐1) and total clearance (0.15 vs 0.17 ml min‐1 kg‐1). 4. After intravenous administration, the main route of elimination of 882C87 was renal with 81.6% recovered unchanged in urine in the young and 71.2% in the elderly. The pyrimidine base, 5‐propynyluracil (5‐PU) was unquantifiable in plasma and only present in trace amounts in urine. 5. After oral administration to four healthy volunteers, only 17% of a dose of [14C]‐882C87 was recovered unchanged in urine and 58% as 5‐PU, with total recovery in urine accounting for 86% of the dose. There was a lag of 4‐12 h before the appearance of 5‐PU in plasma, peak concentrations were one‐third to a half those of 882C87. The data suggest that 5‐PU is formed from unabsorbed 882C87 in the gut lumen and then absorbed and excreted in urine. 6. 882C87 is a potential once daily treatment for shingles.
Protein binding of propranolol and verapamil enantiomers in maternal and foetal serum.
Authors: Belpaire FM , Wynant P , Van Trappen P , Dhont M , Verstraete A , Bogaert MG
Published: July 2012

The protein binding of the enantiomers of propranolol and verapamil was measured in 19 pairs of maternal and foetal serum obtained at delivery. The binding of the enantiomers of both drugs was lower in foetal than in maternal serum. In maternal serum the mean (+/‐ s.d.) unbound percentages were 22.4 +/‐ 6.2 and 20.7 +/‐ 6.6 for R‐ and S‐ propranolol, and 16.8 +/‐ 5.5 and 22.5 +/‐ 6.2 for R‐ and S‐verapamil; in foetal serum the values were 38.8 +/‐ 8.6 and 40.4 +/‐ 10.6 for R‐ and S‐propranolol, and 34.7 +/‐ 10.5 and 44.8 +/‐ 10.7 for R‐ and S‐ verapamil. For propranolol, in maternal, but not in foetal serum, the difference between the binding of the R‐ and S‐enantiomers was significant; the R/S ratio was significantly (P < 0.01) larger in the mother (1.099 +/‐ 0.072) than in the foetus (0.973 +/‐ 0.068). For verapamil, the difference in binding between the R‐ and S‐enantiomers was significant in both maternal and foetal serum, but the R/S ratio was similar in mother (0.735 +/‐ 0.098) and foetus (0.763 +/‐ 0.070). Serum alpha 1‐acid glycoprotein (AAG) concentrations were markedly higher and albumin concentrations slightly lower in maternal than in foetal samples. The binding of the four enantiomers in maternal and foetal serum was correlated (P < 0.001) with the AAG concentration (r propranolol: R 0.749, S 0.746; r verapamil: R 0.753, S 0.782). Our findings show that measurement of concentrations of total, unresolved drug allow a reasonably accurate assessment of transplacental gradients of individual isomers.
Cholecystokinin and anxiety in normal volunteers: an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist L‐365,260.
Authors: Lines C , Challenor J , Traub M
Published: July 2012

1. Two studies were undertaken to develop a model of experimentally induced anxiety in normal volunteers based on cholecystokinin (CCK) receptor agonism/antagonism. 2. In Study 1 rapid intravenous injections of the CCK receptor subtype B (CCKB) agonist pentagastrin (0.15, 0.3 and 0.6 micrograms kg‐1) were found to produce dose‐related increases in subjective ratings of anxiety compared with placebo. 3. In Study 2 the effects of pre‐treatment with two doses of the CCKB receptor antagonist L‐365,260 (10 mg, 50 mg p.o.) on the anxiety induced by pentagastrin 0.3 micrograms kg‐1 i.v. were investigated. Detailed measurements of blood pressure and pulse rate were also undertaken. Pentagastrin produced changes in blood pressure and pulse rate which had a similar time course to that observed for subjective anxiety ratings. L‐365,260 reversed both the autonomic and anxiogenic effects of pentagastrin. 4. The pentagastrin model would appear to be a useful tool for investigating potential anxiolytics in normal volunteers.
Halofantrine pharmacokinetics in Kenyan children with non‐severe and severe malaria.
Authors: Watkins WM , Winstanley PA , Mberu EK , Kokwaro G , Murphy SA , Newton CJ , Mwangi I , Forster D , Marsh K
Published: July 2012

1. Kenyan children with uncomplicated malaria given oral halofantrine (HF; non‐micronised suspension; 8 mg base kg‐1 body weight 6 hourly for three doses) showed wide variation in the disposition of HF and desbutylhalofantrine (HFm). 2. Eight Kenyan children with severe (prostrate) falciparum malaria who were receiving intravenous quinine, were given the same HF regimen by nasogastric tube. One patient had undetectable HF and two had undetectable HFm at all times after drug administration. 3. The mean AUC(0,24 h) of HF in prostrate children was half (7.54 compared with 13.10 micrograms ml‐1 h) (P = 0.06), and that for HFm one‐third (0.84 compared with 2.51 micrograms ml‐1 h) (P < 0.05) of the value in children with uncomplicated malaria. 4. Oral HF may be appropriate for some cases of uncomplicated falciparum malaria in Africa, but in patients with severe malaria, the bioavailability of HF and HFm may be inadequate.
Metabolism of theophylline by cDNA‐expressed human cytochromes P‐450.
Authors: Ha HR , Chen J , Freiburghaus AU , Follath F
Published: July 2012

1. Theophylline metabolism was studied using seven human cytochrome P‐ 450 isoforms (CYPs), namely CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH), expressed in human B‐ lymphoblastoid cell lines. 2. At a high theophylline concentration of 10 mM four CYPs (1A1, 1A2, 2D6, 2E1) catalyzed the metabolism of theophylline. 3. Theophylline had the highest affinity (apparent Km range 0.2‐1.0 mM) for the CYP1A subfamily and the kinetics of metabolic formation mediated by CYP1A2 indicated substrate‐inhibition (Ki range 9‐ 16 mM). 4. CYP1A2 catalyzed the demethylation of theophylline as well as its hydroxylation, and was associated with the highest intrinsic clearance (1995 l h‐1 per mol CYP) to 1,3‐dimethyluric acid (DMU). Therefore, this isoform can be considered to be the most important enzyme involved in theophylline metabolism in vitro. 5. CYP2E1 was responsible for a relatively high intrinsic clearance by 8‐ hydroxylation (289 l h‐1 per mol CYP). The apparent Km value of this reaction was about 15 mM, suggesting that CYP2E1 may be the low‐ affinity high‐capacity isoform involved in theophylline metabolism. 6. The affinity of theophylline for CYP1A1 was comparable with that of its homologue 1A2. When induced, the participation of CYP1A1 in theophylline metabolism may be important. 7. CYP2D6 played only a minor role and CYP3A4 was not active in the in vitro metabolism of theophylline. 8. Our findings confirm the major role of CYP1A2 in theophylline metabolism and explain why in vivo the elimination kinetics of theophylline are non‐linear and in vitro theophylline metabolism by human liver microsomes does not obey monophasic kinetics. 9. The data suggest also that not only tobacco smoking but also chronic alcohol intake may influence theophylline elimination in man as ethanol induces CYP2E1.
Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.
Authors: Cutler N , Sramek J , Veroff A , Block G , Stauffer L , Lines C
Published: July 2012

The effects of equi‐efficacious doses of the cholesterol‐lowering drugs simvastatin (20 mg day‐1) and pravastatin (40 mg day‐1) on tests of cognitive function were investigated in a double‐blind, placebo‐ controlled, 2‐period (4 weeks per period), incomplete block, crossover study of 36 patients (24 per treatment) with hypercholesterolaemia. After 4 weeks neither of the active treatments differed significantly from placebo on any cognitive measure.
Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers.
Authors: Rolan PE , Mercer AJ , Wootton R , Posner J
Published: July 2012

1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double‐blind, placebo‐controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 48 h intervals intended to modify 15, 25 and 32.5% of a subject's haemoglobin to a high affinity form (%MOD). 4. Mean peak %MOD was 34%. Mean Cmax values in plasma and erythrocytes were 81.4 and 1459 micrograms ml‐1, respectively. 5. Heart rate, compared with baseline, increased in the tucaresol group with the greatest changes at the highest %MOD and workload. There were no differences between groups in psychometric test performance. 6. Three volunteers on active drug developed fever, rash and tender cervical lymphadenopathy with onset 7‐ 10 days from the start of dosing, suggesting an immune mechanism. 7. The acute increase in oxygen affinity with tucaresol is physiologically well‐tolerated, but the utility of tucaresol in the management of sickle cell disease will depend on the identification of a dosing regimen with a lower incidence of drug allergy.
The role of S‐mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides.
Authors: Wright JD , Helsby NA , Ward SA
Published: July 2012

The effects of the CYP2C19 substrates, mephenytoin, methsuximide and mephobarbitone on the metabolism of proguanil and chlorproguanil by human liver microsomes were studied. All of the CYP2C19 substrates significantly inhibited (P < 0.05) the formation of both cycloguanil and chlorcycloguanil from their parent compounds. In the presence of mephenytoin (50 and 100 microM) the extent of proguanil cyclisation was decreased by 66% and 67% whilst the cyclisation of chlorproguanil was decreased by 51% and 70%, respectively. Methsuximide (50 and 100 microM) inhibited cycloguanil formation by 68% and 77% and chlorcycloguanil formation by 43% and 58%, respectively. In the presence of mephobarbitone (50 and 100 microM) the cyclisation of proguanil and chlorproguanil to their active metabolites was reduced by 24% and 42% and 48% and 63%, respectively. In addition, proguanil and chlorproguanil were shown to be mutual competitive inhibitors of metabolism to their triazine metabolites. In the presence of proguanil (50 and 100 microM) the Km value for chlorcycloguanil production was increased by 118% and 200%, respectively, with little change in Vmax. Similarly, chorproguanil (50 microM) increased the Km for the in vitro cyclisation of proguanil by 50% with no alteration in Vmax. These data suggest that both chlorproguanil and proguanil are metabolised in vitro by mephenytoin hydroxylase, CYP2C19.