bluuebunny/crossref_metadata_2025 huggingface dataset:
Stratigraphic development of an Upper Jurassic deep marine syn‐rift succession, Inner Moray Firth Basin, Scotland
Authors: McArthur Adam D. , Hartley Adrian J. , Jolley David W.
Published: July 2012

The stratigraphic development of an Upper Jurassic syn‐rift succession exposed at outcrop in the Inner Moray Firth Basin has been investigated using high‐resolution biostratigraphy and sedimentology. A continuous 970 m thick section, exposed in the hangingwall of the Helmsdale Fault was logged in detail. The succession spans 8 Ma and contains eight lithofacies types, which indicate deposition in a deep marine setting. Boulder beds contain large, angular clasts, with bed thicknesses typically >2 m and poor sorting suggesting deposition by debris flows. An inverse clast stratigraphy is observed; the oldest boulder beds contain sandstone clasts of Upper Old Red Sandstone (ORS) with younger debris flows containing clasts of Middle ORS calcareous siltstone. A marked change from siliciclastic to carbonate dominated sedimentation occurred during the Early Tithonian, interpreted primarily as a result of change in lithologies in the footwall catchment from sandstone to calcareous siltstone, which reduced supply of siliciclastic sediment. Secondary factors are identified as increased aridity in the Early Tithonian, which reduced sand supply from the hinterland and a third‐order Early Tithonian eustatic sea‐level rise, which trapped coarser clastic sediment within the hinterland. Biostratigraphy allows calculation of variations in sedimentation rates with recognition of: (1) an early rift phase characterised by sandy turbidite deposition, when sedimentation rates averaged 0.08 m/ky, (2) a rift climax phase from the Early Kimmeridgian where sedimentation rates increased steadily to a maximum of 0.64 m/ky in the Early Tithonian, with strata dominated by boulder scale clast‐supported debris flows and (3) a late stage of rifting from the mid Tithonian, where sedimentation rates decreased to 0.07 m/ky. Overall sedimentation rates are comparable to those of other deep marine rift basins. Unroofing a resistant lithology on the footwall of a rift has important implications for siliciclastic sediment supply in rift basins.
The acute and chronic bronchodilator effects of ephedrine in asthmatic patients.
Authors: May CS , Pickup ME , Paterson JW
Published: July 2012

In eight asthmatic patients, there was no change in the bronchodilator response to a single dose of ephedrine (22 mg) given alone or in a compound tablet, after treatment with ephedrine (11 mg three times a day) or one tablet three times a day for 2 weeks. 2 There was no deterioration in lung function during the 2 week treatment period with either ephedrine or the compound tablet. 3 An inter‐patient variation was noted in the plasma ephedrine concentraition required for bronchodilatation. 4 The half‐life of theophylline did not change after chronic treatment with the tablets, one three times a day for 2 weeks.
Effect of indomethacin in asthma: evidence against a role for prostaglandins in its pathogenesis.
Authors: Smith AP
Published: July 2012

1. A clinical trial of the effects of indomethacin (200 mg daily) failed to show any objective evidence of improvement in six patients. 2. The same dose failed to inhibit exercise and antigen challenge induced bronchoconstriction, and this was considered to be evidence against the hypothesis that prostaglandins act as chemical mediatros in the pathogenesis of asthma.
Pharmacokinetics of a single dose of phenytoin in man measured by radioimmunoassay.
Authors: Robinson JD , Morris BA , Aherne GW , Marks V
Published: July 2012

1. Serum concentrations of phenytoin were studied by radioimmunoassay in five normal volunteers following a single oral dose of phenytoin sodium (100 mg). 2. Two distinct peaks were found at 2.5‐3.5 and 10‐12 h after ingestion. Maximum serum concentrations ranged from 1.56 mug/ml. The mean plasma half‐life of the drug under these conditions was 9.81 +/‐ 0.66 (s.e. mean) hours.
The use of isoniazid as a marker to monitor the self‐administration of medicaments.
Authors: Stark JE , Ellard GA , Gammon PT , Fox W
Published: July 2012

1. Isoniazid was used as a marker to monitor the regularity of drug self‐administration in a trial of chemoprophylaxis against natural influenza infection. Two hundred and sixty‐two volunteers were treated for five weeks with a synthetic isoquinoline compound (U.K. 2371) or a matching placebo. 2. Five marker tablets containing isoniazid (150 mg) were incorporated into each regimen and their ingestion monitored by testing for acetylisoniazid in the urine. 3. Positive evidence of marker tablet consumption was obtained on 75% of the occasions on which urine samples were requested. The results obtained among the volunteers from each treatment group who returned urine specimens as requested (92%) indicated that they had swallowed at least 81% of their prescribed tablets. 4. The findings of the study suggest that when used in this way isoniazid is a very suitable compound for use on a few occasions for monitoring the self‐administration of drugs in clinical trials.
Digoxin pharmacokinetics: multicompartmental analysis and its clinical implications.
Authors: Sumner DJ , Russell AJ
Published: July 2012

The kinetics of digoxin have been investigated in healthy volunteers using an isotopic tracer technique. A three compartment open kinetic model has been proposed as the simplest model consistent with the plasma, urinary and faecal data obtained. The renal clearance of digoxin (mean +/‐ s.d.) was found to be 119+/‐10 ml/min, which did not differ significantly from the glomerular filtration rate (110+/‐14 ml/min). Digoxin extra‐renal clearance (mean+/‐s.d.) was found to be 47+/‐7 ml/min. The model predicts that the tissue concentration attained after four 0.25 mg oral doses spread over 24 h can be achieved within a period of 4 h following a single oral loading dose of 1 mg. Maintenance doses can be derived from a simple formula based on the glomerular filtration rate, extra‐renal clearance and bioavailability of the digoxin preparation used.
The influence of premedication, anaesthesia, age and weight on glucose uptake into human isolated skeletal muscle.
Authors: Kirby MJ , Leighton M , Turner P
Published: July 2012

The effect of the anaesthetic procedures and of the sex, age and weight of each patient on glucose uptake and glycogen content of human skeletal muscle has been studied in vitro in the presence and absence of insulin. Statistical analysis indicated that the relationships between age and both glucose uptake and the response to insulin were significant, older patients in general having higher uptakes. The blucose uptake was highly correlated with the three obesity indices (ponderal index, body mass index and percentage of the ideal weight). The anaesthetic agents had no significant effect on glucose uptake. The choice of premedication appeared to have a small effect on the basal glucose uptake level, but as the choice of premedication was also age related and age itself was a significant factor, this effect may not be of importance. It is concluded that the age and the degree of obesity of the patients ought to be taken into account when studying samples of human muscle.
Assessment of antipyrine kinetics by measurement in saliva.
Authors: Fraser HS , Mucklow JC , Murray S , Davies DS
Published: July 2012

The half‐life of antipyrine has been estimated from saliva samples in ten subjects by a gas chromatographic method. Half‐life, apparent volume of distribution and total body clearance estimated from saliva and plasma concentrations of antipyrine are not significantly different. The concentration of antipyrine in saliva is independent of flow rate within the range expected in healthy subjects in response to mechanical and sapid stimuli. Antipyrine estimation in saliva could facilitate many areas of phaamacokinetic research limited by the difficulty of obtaining serial plasma samples.
How double blind is double blind? And does it matter?
Authors: Huskisson EC , Scott J
Published: July 2012

In an apparently double blind crossover study, two experienced measurement technicians were able to identify many of the treatment periods. They most often correctly identified aspirin, a drug with prominent effects and side effects. It is argued that in many circumstances it is better to use a blind observer who is not concerned with the giving of treatment or the collection of side effects.
Agonist and antagonist effects of Sar1‐ala8‐angiotensin II in salt‐ loaded and salt‐depleted normal man.
Authors: MacGregor GA , Dawes PM
Published: July 2012

1 Three normal subjects were infused with Sar1‐ala8‐angiotensin II (Saralasin, P113) whilst on a high sodium (200 mEq + normal diet) and a low sodium (10 mEq diet) intake. 2 On the high sodium intake when angiotensin II and plasma renin activity (PRA) were suppressed, P113 infusion (5‐10 mug kg‐1 min‐1) caused a slight rise in BP and a marked drop in urine flow and sodium excretion, with a fall in glomerular filtration rate, and effective renal plasma flow. 3 On the low sodium intake, when angiotensin II and PRA were increased, P113 infusion (5‐10 mugkg‐1 min‐1) caused no change in blood pressure, urine flow or sodium excretion. However, when P113 was infused at an incremental rate starting at 0.25 mug kg‐1 min‐1 there was a fall in standing BP, which was maximal at an infusion rate of 1 mug kg‐1 min‐1, and this fall in standing BP was largely abolished as the rate of infusion was increased to 10 mug kg‐1 min −1. 4 These results show firstly that angiotension II is involved in maintaning standing blood pressure during dietary sodium depletion in normal man and secondly that P113 does have agonist as well as antagonist activity in normal man, the effect depending on the level of angiotension II and sodium intake. When looking for angiotensin II mediated hypertension it may ne important to use an incremental rate of infusion of P113 as the agonist activity of larger doses may mask its hypotensive action.
Studies on the metabolism of meptazinol, a new analgesic drug.
Authors: Franklin RA , Aldridge A
Published: July 2012

1 The absorption, metabolism and excretion of the new analgesic meptazinol has been studied in male volunteers following oral and intravenous administration of a mixture of the [1‐14C] and [7‐3H] labelled compound. 2 After oral dosage, absorption from the gastrointestinal tract was rapid as evidenced by the early attainment of peak plasma radioactivity levels and near complete as shown by only small amounts of radioactivity recovered in the faeces. 3 Although the absorpiton of the drug was good, the systemic bioavailability was relatively low. Plasma levels of the unchanged drug remained below the limit of detection (20 ng/ml) after an oral dose of 200 mg. However, after intravenous administration of only 20 mg the peak plasma level was approximately 58 ng/ml. Subsequent elimiantion was rapid and proceeded in an apprarently mono exponential manner with a half‐life of approximately 2 hours. 4 Excretion of radioactivity was rapid irrespective of the dosage route and took place chiefly via the urine. Over 60% of the administered radioactivity was recovered in the 0‐24 h urine collection. Less than 10% of the administered dose was excreted in the faeces. 5 Less than 5% of the drugs was excreted unchanged. The major metabolite appeared to be the glucuronide conjugate of the parent durg. No evidence was found for N‐demethylation of the compound. A minor metabolite of the drug which accounted for approximately 7% of the recovered radioactivity has been tentatively identified as 6‐ethyl ‐ 6 ‐ (3‐hydroxyphenyl) ‐ 1 ‐ methyl‐hexahydroazepin ‐ (2H)‐2‐ONE.
Factors determining the potency of mydriatic drugs in man.
Authors: Smith SA
Published: July 2012

1 The mydriasis resulting from topical application of five atropine‐ like drugs was measured photographically in man. Drug potency was obtained from log dose‐response curves. 2 The in vitro potency of eight cholinoceptor blocking drugs, including those studied in man, was obtained by measuring their affinity constants for binding to the receptors of an isolated preparation of the rabbit sphincter pupillae. Values agreed closely with those obtained for the muscarinic receptors of guinea‐pig ileum. 3 In vitro and in vivo potency was compared to obtain a quantitative measure of the relative ease with which drugs gain access to the receptors after topical application. 4 The large differences that occur in the intensity and duration of the mydriatic response to atropine‐like drugs is primarily the result of differences in their ability to blcok the receptors. Only with tropicamide does its relatively high accessibility affect its potency in man.
Residual effects and skills related to driving after a single oral administration of diazepam, medazepam or lorazepam.
Authors: Seppala K , Korttila K , Hakkinen S , Linnoila M
Published: July 2012

Psychomotor skills and visual functions related to driving were measured double‐blind cross‐over in ten healthy volunteers before, and 1,3,5 and 7 h after a single oral administration of diazepam (10mg), medazepam (15 mg) or lorazepam (2.5 mg). The late effects of lorazepam were tested in seven other subjects 12 and 24 h after the administration. Lorazepam impaired almost all the measured skills more (P less than 0.05 to 0.001) than diazepam, medizepam or the placebo. The lorazepam impairment of reactive skills and flicker fusion discrimination remained statistically significant (P less than 0.05) for as long as 12 h. Medazepam impaired only reactive skills and flicker fusion, the latter remaining impaired (P less than 0.05) for as long a 5 h after the administration. The magnitude and duration of the effects of diazepam were intermediate between those of lorazepam and medazepam. Diazepam impaired perceptual speed and reactive and co‐ ordinative skills as well as flicker fusion discrimination and visual parameters related to driving. Slight impairments in performance were measurable for up to 5 h after administration but at 7 h the results resembled those measured after the placebo. The lack of alterations in adaptation to darkness, sensitivity to brightness or visual discrimination ability in bright counterlight at a time when flicker fusion discrimination was severely depressed suggests that an impaired ability to discriminate flickering light is of no or little clinical significance to driving ability. It is concluded that patients receiving a 2.5 mg dose of lorazepam should not drive or operate machinery for 24 h after the administration. After diazepam (10 mg) or medazepam (15 mg) patients should refrain from driving or participating inskilled performances for only 5 to 7 hours.
Hydrallazine or phentolamine as adjuncts to beta‐adrenoceptor blockade/thiazide therapy in hypertension.
Authors: Winchester JF , Ward DM , McKillop JH , Kennedy AC
Published: July 2012

Ten patients not maximally controlled on an oxprenolo/cyclopenthiazide regimen for moderately severe hypertension were treated in a double blind crossover trial with either hydrallazine (75‐150 mg/day) or phentolamine (60‐120 mg/day) or placebo in addition to their other therapy. Additional phentolamine therapy did not lower blood pressure significantly when compared with placebo. Additional hydrallazine (75‐ 150 mg/day) produced an approximate 10 mm, Hg fall in diastolic blood pressure, but no significant fall in systolic blood pressure. Pulse rates did not alter with the addition of hydrallazine or phentolamine. In patients who fail to attain optimal blood pressure response to beta‐ adrenoceptor blocking drugs it is suggested that the addition of hydrallazine is a useful measure.
A trial of brolitene in the treatment of spasticity.
Authors: Perkin GD , Aminoff MJ
Published: July 2012

A new anti‐spasticity agent, brolitene, has been assessed in patients with spasticity of spinal or cerebral origin. Twenty‐seven patients were entered in a double‐blind cross‐over trial lasting 6 weeks, using a fixed dose of six tablets (1200 mg brolitene) per day. Clinical assessment failed to show any therapeutic effect in the seventeen patients completing the trial, except in one with multiple sclerosis. Ten patients had to be withdrawn from the trial, six while being treated with the active agent.
A radioimmunoassay method for prednisolone: comparison with the competitive protein binding method.
Authors: Chakraborty J , English J , Marks V , Dumasia MC , Chapman DJ
Published: July 2012

Cross reactivity of prednisolone with an antiserum raised against dexamethasone‐21‐hemisuccinate conjugated with bovine serum albumin was utilized to develop a radioimmunoassay for prednisolone in unextracted plasma. The results are in good agreement with those obtained with a standard competitive protein binding method employing prior extraction and separation of the synthetic from endogenous steroids.
Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man.
Authors: George KA , Dundee JW
Published: July 2012

1. Ten postcards were shown to groups of ten to twenty patients over 60, 90 or 270 min after intravenous injection of saline, diazepam (10 and 20 mg), flunitrazepam (1 and 2 mg) and lorazepam (4 mg). 2. Incidence of amnesia was estimated by the patients' ability to recall or recognize these cards and to recall various other incidents in the para‐anaesthetic period. 3. The use of a dummy confirmed the reliability of the method of testing for amnesia in man. 4. Flunitrazepam produced a dose‐related incidence of amnesia slightly longer than with the equivalent (1 × 10) dose of diazepam. 5. The onset of amnesia was slower with lorazepam (4 mg) but appeared to last for up to four hours. 6. This amnesic action of lorazepam was paralleled by a useful sensitive effect but there was no similar correlation for diazepam and flunitrazepam. 7. With three drugs of different duration of action it should be possible to produce amnesia for any required clinical situation.
Plasma concentrations of benzodiazepines.
Authors: Bond AJ , Hailey DM , Lader MH
Published: July 2012

1. Twenty anxious patients were treated with medazepam, diazepam, chlordiazepoxide, amylobarbitone and placebo, each given in flexible dosage for 2‐4 weeks. 2. At the end of each treatment, a series of clinical, physiological and behavioural variables were measured and plasma samples were taken for estimation of the appropriate drug and metabolite concentrations. 3. Nordiazepam was shown to be an important metabolite of both medazepam and diazepam: the ratio of medazepam to noradiazepam was 0.14 and the ratio of diazepam to nordiazepam following diazepam administration was 0.72. 4. No significant correlations were found between the plasma concentrations of any of the treatments and the clinical ratings or behavioural measures. 5. Some relationship was shown between levels of medazepam and its physiological effects.
The pharmacokinetics of ciclazindol (Wy 23409) in human volunteers.
Authors: Swaisland AJ , Franklin RA , Southgate PJ , Coleman AJ
Published: July 2012

1. The pharmacokinetics and metabolism of ciclazindol, a potential anti‐ depressant drug, have been studied after oral administration of the compound to male and female volunteers. 2. The mean +/‐ S.E. mean maximum plasma concentration of the unchanged drug was 422 +/‐ 31 ng/ml. This level was seen between 2 and 4 h after dosing. 3. Elimination of the ciclazindol from plasma was apparently monexponential with a half‐life of approximately 32 h. A large proportion of the drug‐related substances in the plasma was unchanged drug. 4. Excretion of radioactivity took place predominantly via the renal route, less than 15% of the dose being recovered in the faeces. The urinary elimination process was apparently monoexponential with a half‐life of 28 h. 5. Daily dosing with ciclazindol for 3 weeks did not appear to induce the enzymes of its own metabolism.
The bronchodilator effect of NAB 365.
Authors: Kamburoff PL , Prime FJ , Schmidt OP
Published: July 2012

1. Dose response relationships for salbutamol and a new bronchodilator drug NAB 365 have been obtained in patients with reversible airways obstruction. These show that the latter is about one hundred times more potent than the former. 2. NAB 365 has a very long half‐life. The implications of this are discussed.
Comparative beta‐adrenoceptor blocking effects and pharmacokinetics of penbutolol and propranolol in man.
Authors: Giudicelli JF , Richer C , Chauvin M , Idrissi N , Berdeaux A
Published: July 2012

1 The beta‐adrenoceptor blocking effects of penbutolol were compared with those of propranolol and a placebo in a double‐blind trial involving six healthy volunteers. 2 Heart rate (HR), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 7 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and plasma levels of penbutolol and propranolol were determined. 3 Penbutolol proved to be a non‐cardioselective beta‐ adrenoceptor blocking drug, antagonizing exercise‐induced tachycardia, reducing exercise‐induced increase in PEFR and decreasing PRA. The beta‐ adrenolytic potency of penbutolol was shown to be four‐fold that of propranolol but the duration of its effect was similar. 4 The peak plasma level of penbutolol was reached 1 h after administration and its half‐life was 4.5 h. 5 Comparison of plasma levels and biological activity of penbutolol revealed that after oral administration this drug is transformed into an active metabolite in man.
The metabolism, distribution and elimination of chlorphentermine in man.
Authors: Beckett AH , Belanger PM
Published: July 2012

1 A gas‐liquid chromatography procedure for the determination of chlorphentermine (I), N‐hydroxychlorphentermine (II) and alpha, alpha‐ dimethyl‐alpha‐nitro‐beta‐(4‐chlorophenyl)ethane (IV) in urine has been developed. Also methods are reported to determine conjugated II and the total N‐oxidized metabolites of I, i.e. II, conjugated II, alpha, alpha‐ dimethyl‐alpha‐nitroso‐beta‐(4‐chlorophenyl)ethane (III) and IV in urine. 2 The synthesis of alpha, alpha‐dimethyl‐alpha‐nitroso‐beta‐(4‐ chlorophenyl)ethane (III) and its properties are reported. 3 The kinetics of urinary excretion of I and its metabolic products after the oral administration of I to a human subject on separate occasions have been studied. Under normal conditions of urinary pH, metabolism by N‐ oxidation was the main elimination route of I; acidifying the urine increased the urinary excretion of unchanged I at the expense of the N‐ oxidized products. 4 The importance of the N‐oxidation metabolic route in the distribution of chlorphentermine (I) in man is discussed.
Age as a factor affecting lithium therapy.
Authors: Hewick DS , Newbury P , Hopwood S , Naylor G , Moody J
Published: July 2012

1 We examined the case notes of 82 psychiatric out‐patients (aged 21‐84 years) receiving lithium prophylaxis and with steady‐state plasma lithium levels. 2 The mean weight‐related daily dose of lithium prescribed decreased by about 50% between the third and eight decades. 3 The corresponding steady‐state plasma lithium levels showed a less marked tendency to decrease, this only being seen in the seventh and eighth decades. 4 In patients aged 50 years or over the daily lithium dose required to give a plasma level of 1 mmol l‐1 (0.50 mmol kg‐1) was significantly lower than that (0.65 mmol kg‐1) in patients aged under 50 years (P less than 05, Student's t‐test). In patients aged 70‐79 years this dose was 31% lower than in patients under 50 years. However, interindividual variation was great and it was estimated that age only contributed about 14% to the total interpatient variation. 5 Of the 36 patients under 50 years of age, 42% had minor lithium side‐effects and 17% were not optimally controlled with lithium. The corresponding figures for the 46 ‘older’ patients were 46% and 28%. 6 Generally the 50% dosage reduction seemed necessary to compensate for an age‐related decrease in lithium excretion and to reduce lithium side effects to a level comparable to that acceptable in younger patients.
The effect of metoclopramide on neonatal gastric emptying.
Authors: Blumenthal I , Costalos C
Published: July 2012

1 The effect of metoclopramide on gastric emptying was studied on twenty‐five occasions in fifteen low birth weight babies. 2 The serial test‐meal technique was used. 3 The results indicate that metoclopramide does not promote gastric emptying in the newborn period.
Monitoring digoxin therapy: I. Plasma concentrations and an in vitro assay of tissue response.
Authors: Aronson JK , Grahame‐Smith DG , Hallis KF , Hibble A , Wigley F
Published: July 2012

1 An in vitro technique is described for measuring the uptake of 86Rb by human erythrocytes. 2 Fifteen patients were treated with digoxin for atrial fibrillation and other fast arrhythmias. 3 86Rb uptake by the patients' own red cells fell from pre‐treatment values during digitalization. 4 The therapeutic response of patients with atrial fibrillation correlated better with the changes in 86Rb uptake than with plasma digoxin concentrations.
Monitoring digoxin therapy: II. Determinants of the apparent volume of distribution.
Authors: Aronson JK , Grahame‐Smith DG
Published: July 2012

1 In eighteen subjects receiving digoxin therapy the apparent volume of distribution (Vd) of the drug has been calculated. 2 For each subject the sensitivity of the 86Rb transport mechanism of his pre‐treatment erythrocytes to in vitro inhibition by digoxin has been measured (IC50). 3 The Vd of digoxin correlates both with the age of the patients and with the IC50 of their pre‐treatment erythrocytes. 4 The implications of these findings are discussed in terms of the possible determinants of the Vd of digoxin. 5 Digoxin requirements may be predictable before therapy commences if IC50 measurements are performed.
Eye symptoms in patients taking propranolol and other hypotensive agents.
Authors: Dollery CT , Bulpitt CJ , Daniel J , Clifton P
Published: July 2012

1 Four hundred and eighty‐three hypertensive patients being treated with propranolol or other hypotensive drugs were questioned about symptoms of gritty feelings, sore or red eyes, photophobia and use of eye drops. 2 Between 11.6% and 29.8% gave positive answers but there was no difference between the different drug regimes. The complaint of ‘red eyes’ was more common in smokers.
Some effects of injected hyoscine butylbromide: a versatile class experiment in human pharmacology.
Authors: Herxheimer A , de Groot AC
Published: July 2012

1 An experiment with hyoscine butylbromide has been used to demonstrate how drug effects differ in intensity and time course after intravenous (20 mg) and subcutaneous (40 mg) injection with and without massage of the injection site. It also demonstrates how objective and subjective observations may be related, and gives students practice in the interpretation of experimental data. 2 The experiment takes about 2 h, and the effects of the drug have worn off completely after about 3 hours. 3 The structure of the discussion of the experiment and its results with the students are described to draw attention to the questions that can be asked of the data. The results obtained with 41 subjects are summarized to illustrate this discussion. 4 Various ways of modifying the experiment to suit other teaching objectives are mentioned. The need to consult the local Ethics Committee before undertaking experiments on students is emphasized.
Vascular reactions to histamine and compound 48/80 in human skin: suppression by a histamine H2‐receptor blocking agent.
Authors: Marks R , Greaves MW
Published: July 2012

1 The ability of a specific competitive histamine H2‐receptor antagonist, cimetidine, to inhibit vascular responses to histamine in human skin provides new evidence that skin blood vessels possess histamine H2 receptors. 2 Simultaneous systemic administration of cimetidine and chlorpheniramine (an H1‐receptor antagonist) was more effective than either drug alone in inhibition of the erythematous reaction both to exogenous histamine, and endogenous histamine secreted by skin mast cells in response to compound 48/80. 3 These results suggest that combined therapy of histamine‐mediated skin diseases included urticaria and dermatitis using a combination of H1‐ and H2‐ histamine receptor antagonists may be more effective than either class of drug alone.
Fluorimetric assay of cephradine, cephalexin and cephaloglycin.
Authors: Barbhaiya RH , Turner P
Published: July 2012

1 A simple, rapid and reproducible fluorimetric assay for cephradine, cephalexin and cephaloglycin is described. 2 The method involves addition of formaldehyde which catalyses the formation of fluorescent derivatives. 3 The structural similarities between the side chains of these antibiotics and their identical excitation and emission spectra suggest that they may be forming similar fluorescent derivatives.
Effect of clofibrate on glucose tolerance in maturity onset diabetes.
Authors: Barnett D , Craig JG , Robinson DS , Rogers MP
Published: July 2012

1 Fourteen maturity onset diabetics showed improvement of glucose tolerance while on treatment with clofibrate. Fasting blood glucose levels were reduced by 20% after treatment for 14 and 28 days. 2 The effect was found to be independent of concurrent treatment with oral hypoglycaemic drugs. 3 Plasma insulin levels were also lower during clofibrate treatment. 4 Clofibrate may prove to be a useful adjunct to the treatment of maturity onset diabetes.
Carbamazepine and carbamazepine‐10, 11‐epoxide concentrations in human brain.
Authors: Morselli PL , Baruzzi A , Gerna M , Bossi L , Porta M
Published: July 2012

1 Carbamazepine (CBZ) brain and plasma concentrations were measured in twenty‐one patients undergoing brain surgery for tumour removal. The drug was administered prophylactically at doses ranging from 6.9 to 14.8 mg/kg for 4‐5 days before the intervention. 2 In seventeen cases where sample were collected 10‐14 h after dosing, CBZ brain levels ranged from 2.2‐14.5 microgram/g. A significant linear relationship (p less than 0.01) was observed between brain and plasma concentrations with a brain/plasma ratio of 1.1 +/‐ 0.1. 3 Carbamazepine 10,11‐epoxide (CBZ‐Epox), present in all samples, could be quantified in three brain specimens. Its brain concentrations ranged from 1.5‐2.7 microgram/g with a brain/plasma ratio of 1.1‐1.2. 4 Parieto‐occipital areas tended to show higher CBZ concentrations while lower values were found in temporal regions. Very low CBZ levels were found in two gliomas while in meningiomas CBZ levels were similar to those observed in normal tissue. 5 The data, showing a linear relationship between brain and plasma concentrations of both CBZ and its epoxide, give additional significance to the plasma level monitoring of antiepileptic drugs.
The influence of age on the response to anticoagulants.
Authors: Husted S , Andreasen F
Published: July 2012

1 A group of 114 patients on long‐term anticoagulant therapy was studied. The daily maintenance dose of both phenprocoumon, bishydroxycoumarin and warfarin was found to be significantly lower in patients aged between 61 and 70 years than in the those between 50 and 60 years of age. The mean daily dose of bishydroxycoumarin, hower, when expressed on a weight basis, was not significantly lower in the elderly. 2 For bishydroxycoumarin but not for phenprocoumon and warfarin there was found a statistically significant correlation between the daily maintenance dose and the weight of the patient. 3 The mean daily dose of both bishydroxycoumarin and warfarin was 30‐40% lower than that recommended in the literature. 4 ‘Correction’ was made for potential drug interference by excluding patients in continuous medication with order drugs known to influence the treatment with orally administered anticoagulants. The interindividual variation in dosage requirements of coumarin drug was thereby reduced in the age groups above 60 years. 5 The level of vitamin‐k dependent coagulation factors, measured by Owren's ‘P and P’ method (PP%) was significantly lower (P less than 0.001) in patients of advanced age (between 61 and 70 years) than in younger patients (between 50 and 60 years). 6 The plasma concentration of albumin was significantly lower in patients over 60 years than in those under that age. 7 Correlation (P less than 0.01) was found between the daily maintenance dose of phenprocoumon and the plasma concentraction of albumin.
Clobazam, a 1,5‐benzodiazepine, and car‐driving ability.
Authors: Hindmarch I , Hanks GW , Hewett AJ
Published: July 2012

1 The effects of clobazam, a new anxiolytic agent (a 1,5‐ benzodiazepine) on car‐driving ability and other tests of psychomotor performance were investigated in a double‐blind, cross‐over study v. placebo in normal volunteers. 2 Clobazam (20 mg) or placebo was given nightly for six nights to ten volunteers and subjective ratings of sleep and subjective and objective assessments of behaviour and psychomotor performance on the morning following drug ingestion were recorded. 3 Clobazam significantly improved the subjective ratings of sleep induction and quality of induced sleep. 4 Clobazam did not significantly impair performance in a variety of psychomotor tests and car‐driving ability. 5 The validity of the measures used and the relevance of the findings to real life car‐driving situations are discussed.
Pharmacokinetic studies with benoxaprofen in man: prediction of steady‐ state levels from single‐dose data.
Authors: Chatfield DH , Tarrant ME , Smith GL , Speirs CF
Published: July 2012

1 Plasma levels of benoxaprofen were measured in eight subjects 2‐168 h after a single oral dose of 100 mg. Pharmacokinetic parameters were estimated by the NON‐LIN computer programme using the two‐compartment open model. Mean half‐lives of absorption, distribution and elimination were respectively 0.4, 4.8 and 37.6 hours. Volumes of distribution were 6.8 and 3.2 litres for the central and peripheral compartments respectively. 2 Eleven subjects in groups of three or four were given 25 mg/day, 50 mg/day or 100 mg two times daily for 11 days. Their plasma levels were compared with those predicted from the above parameters, which were adjusted for individual body weights and elimination half‐lives. Steady‐state plasma levels were predicted in each case, and a resonable degree of accuracy (mean 91%) achieved. 3 There was no tendency for observed and predicted levels to diverge as the dose was increased, and there was no evidence of any change in the disposition of benoxaprofen on repeated dosing. 4 The pharmacokinetic parameters were used to predict steady state plasma levels for various dosage regimens.
Prevention of adverse drug interactions.
Authors: Howie JG , Jeffers TA , Millar HR , Petrie JC
Published: July 2012

1 The awareness and recognition of adverse interactions between drugs by prescribers is low. 2 A 6‐month prospective study on patients on long‐term outpatient anticoagulant therapy in the Grampian area has been carried out to evaluate a simple and cheap warning system. 3 The practitioners of patients in the test group were issued with warning labels which showed drugs known to interact. A reduction in the initiation of prescriptions for potentially interacting drugs was shown between the test and control groups (no warning labels). 4 The 140 practitioners who completed the study found the system to be convenient and useful. Extension to other high‐risk drugs with the potential to interact with other drugs is planned. This system has the advantage of being drug and patient‐orientated whereas lists of drug interactions or drug discs require more conscious effort by the prescriber.
Plasma protein binding of propranolol and isoprenaline in hyperthyroidism and hypothyroidism.
Authors: Kelly JG , McDevitt DG
Published: July 2012

1. The possibility that thyroid disease might result in alterations in the plasma proteins binding of drugs has been investigated by studying the binding of propranolol and isoprenaline in patients with hyperthyroidism and hypothyroidism. 2. Plasma protein binding of propranolol and isoprenaline has been measured in seven hyperthyroid patients and ten hypothyroid patients. Plasma binding was estimated by equilibrium dialysis at 37 degree C using triatiated propranolol and isoprenaline, both when the patients had thyroid dysfunction and again when they were euthyroid. 3. In the hyperthyroid group, mean propranolol binding varied from 86 +/‐ 1.7% when hyperthyroid to 88.4 +/‐ 0.8% when euthyroid. The comparable isoprenaline figures were 65.1 +/‐ 3.2% and 68.1 +/‐ 1.4% respectively. Neither difference was significant. 4. Isoprenaline binding was significantly lower (64.3 +/‐ 1.6%) when patients were hypothyroid than when they became euthyroid (68.8 +/‐ 1.2%). Propranolol binding was not altered by hypothyroidism. 5. It is concluded that clinically important alterations in free drug concentrations of propranolol or isoprenaline do not occur in hyperthyroidism or hypothyroidism.
Effects of piretanide, bumetanide and frusemide on electrolyte and urate excretion in normal subjects.
Authors: Roberts CJ , Homeida M , Roberts F , Bogie W
Published: July 2012

1. The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide. Subjects received 6 mg piretanide/day, 40 mg frusemide/day or 1 mg bumetanide/day for a period of 1 week. 2. Comparison of effects following the first dose administered showed that 6 mg piretanide is of similar potency to 40 mg frusemide in terms of diuresis, natriuresis and kaliuresis but is less potent than 1 mg bumetanide. 3. All three diuretics caused a decrease in urate excretion and a rise in serum uric acid. 4. Piretanide was well tolerated. Further investigation is required to ascertain what clinical advantage it offers over frusemide and bumetanide.
Methods for the assessment of the effects of drugs on coronary blood flow in man.
Authors: Swanton RH , Coltart DJ
Published: July 2012

The methods currently available for measurement of coronary blood flow in man are reviewed and their advantages and limitations discussed. Most of the techniques are invasive and involve cardiac catheterization. The least invasive isotope techniques are either not quantitative or involve expensive equipment not available in many centres. Two of the most suitable methods for assessing the effects of drugs on coronary flow are coronary sinus thermodilution and isotope washout curves using 133xenon or [125I]‐iodo‐antipyrine. The ideal technique for measuring coronary blood flow has yet to be developed.
The effects of low doses of diazepam on human performance in group administered tasks.
Authors: Jones DM , Lewis MJ , Spriggs TL
Published: July 2012

1. The effects of diazepam in 5 mg dosage were assessed on a range of psychological tasks. Seventy‐eight healthy subjects were tested in an independent groups design; subjects were randomly assigned to either control, placebo or drug group. Treatments were administered orally under double blind conditions. 2. Auditory vigilance performance was unimpaired, in terms of (a) correct detections, (b) false alarms or (c) the subjects' estimates of the duration of the task. 3. The short term retention of digit strings was impaired by diazepam (P less than 0.05), especially for those digits presented in the middle of the sequence. 4. Searching for a few letters among many was significantly impaired by diazepam (P less than 0.01). 5. Diaepam had no effect on performance at a mental arithmetic task; neither was there a placebo effect. 6. Results were discussed in the light of the characteristics of drug sensitive tasks. It was concluded that characteristics such as feedback of results, monotony, and memory load are more likely to be drug sensitive when in combination than in isolation.
Direct measurement of propranolol bioavailability during accumulation to steady‐state.
Authors: Wood AJ , Carr K , Vestal RE , Belcher S , Wilkinson GR , Shand DG
Published: July 2012

1. A high performance liquid chromatographic method for the determination of propranolol in human plasma and blood has been developed and used to confirm that cumulation occurred during chronic oral administration, steady‐state being achieved within 48 h of beginning 80 mg of the drug every 8 h. 2. The method was adapted to measure [H3]‐propranolol and native drug in the same blood sample and was applied to determine simultaneously the disposition of i.v. ([H3]‐ propranolol) and orally (non‐labelled) administered drug after single oral dose of 80 mg and when steady‐state had been established on an 80 mg, 8‐hourly regimen. 3. Using this approach it was possible to show that a reduced oral clearance at steady‐state was associated with a smaller reduction in systemic (i.v.) clearance and no change in liver blood flow. A direct estimate of bioavailability was also possible and was found to be increased at steady‐state compared with a single oral dose. 4. We conclude that the accumulation of propranolol during the attainment of steady‐state is due to a reduction in intrinsic clearance, resulting in reduced presystemic hepatic extraction.
Acebutolol in hypertension‐double‐blind trial against placebo.
Authors: Martin MA , Phillips CA , Smith AJ
Published: July 2012

1. Eleven hypertensive patients were studied in a double‐blind comparison of acebutolol, a beta‐adrenoceptor blocker, and placebo. 2. Optimum dosage defined in an open assessment varied from 200–600 mg twice daily. 3. Blood pressure and pulse rate fell significantly while patients were lying, standing and after exercise. 4. Blood pressure remained as well controlled on each patient's optimum daily dose when taken once daily, and assessed 24 h post dose. 5. There was no correlation between blood pressure reduction and changes in heart rate. On once daily therapy while blood pressure remained unchanged at 24 h post dose there was a signficant reduction in beta‐adrenoceptor blockade as measured by percentage reduction in exercise tachycardia. 6. There was no significant change in urinary catecholamine excretion or echocardiographically estimated cardiac output. 7. A correlation was found between the change in plasma renin activity (log transformed) and blood pressure reduction.
Comparison of the effect of drugs upon some commonly used measures of bowel transit time.
Authors: Rogers HJ , House FR , Morrison PJ , Bradbrook ID
Published: July 2012

1 To study the effect of drugs on methods of assessment of gut transit time a double‐blind study of the effect of single doses of placebo, oxyphenisatin, anthracene purgatives, (+)‐norpseudoephedrine and a combined preparation of (+)‐norpseudophedrine and senna was carried out in ten normal volunteers. Gut transit time was assessed by dye and radio‐opaque marker methods. 2 It was possible to demonstrate the effect of the anthracenes but not oxyphenisatin on gut transit time. 3 More sophisticated statistical techniques were required to demonstrate the retarding effect of the sympathomimetic amine and its reversal by senna. 4 Statistical analysis shows that assessment of intestinal transit time by dye or pellet methods gives identical information.
The inotropic effects of UK 14,275, a phosphodiesterase inhibitor, in man.
Authors: Jackson PG , Jackson G , Kitson D , Jewitt DE
Published: July 2012

1. UK 14,275 (Pfizer) an inotropic agent with cardiac phosphodiesterase inhibitory activity, was administered to ten healthy male volunteers. 2. The inotropic activity was assessed by non‐invasive measurement of systolic time intervals (STI). 3. The compound had significant inotropic activity in the doses administered, as judged by the shortening of pre‐ejection period (PEP), without any significant chronotropic activity. 4. The inotropic effect was abolished when measurements were repeated following beta‐adrenoceptor blockade with oral propranolol. 5. The inotropic activity was compared to that of intravenous isoprenaline.
A controlled release papaverine tablet (Papacontin): a study in normal volunteers.
Authors: Miller RB , Leslie ST , Black FM , Boroda C
Published: July 2012

1. A controlled release tablet containing 300 mg of papaverine hydrochloride was compared with a capsule containing the same dose. 2. The in vitro release pattern showed a steady dissolution of the tablet, with release of the papaverine over 10 h, whereas the capsule release time was 40 min. 3. Plasma levels in volunteers who were given the tablet showed a rapid rise to therapeutic levels (150‐300 ng/ml) within 1 h, and maintenance of these levels for 10‐12 h, with no accumulation on repeated 12 hourly dosage. Administration of the capsule produced early peaking and a subsequent rapid fall in plasma levels.
Drug metabolism in epileptics: in vivo and in vitro correlations.
Authors: Sotaniemi EA , Pelkonen RO , Ahokas J , Pirttiaho HI , Ahlqvist J
Published: July 2012

1. The effect of inducing drug therapy on the relationship between in vitro (cytochrome P‐450 content) and in vivo (antipyrine kinetics) was investigated by comparing eleven consecutively treated epileptics with two groups of controls, eleven subjects with normal liver histology and eleven disease matched non‐epileptics, all underwent diagnostice liver biopsy. 2. The epileptics had significantly higher cytochrom P‐450 level in biopsies and they also metabolized antipyrine faster than the controls. 3. Decrease in antipyrine half‐life in epileptics was related with alterations in liver histology, whereas the level of cytochrome P− 450 was not. 4. There was a linear relationship between these two indices of enzyme induction when regressed on logarithmic data.
Contribution of individual differences in gastric emptying to variability in plasma propranolol concentrations.
Authors: Castleden CM , George CF , Short MD
Published: July 2012

1 No correlation was found between the rate of gastric emptying and peak plasma propranolol concentrations in six hypertensive patients after single oral doses of 80 mg. 2 In four normal subjects given oral propranolol the peak plasma concentration was highest when a simultaneous injection of metoclopramide and lowest when propantheline was given. The mean time to peak was 1.5 h after metoclopramide, 2.8 h after normal saline and 4.5 h after propantheline. 3 Gastric emptying has some influence on the time of peak plasma propranolol concentrations but individual variation in its bioavailability is determined mainly by first‐pass metabolism in the liver.
The effects of atenolol and propranolol upon lipolysis.
Authors: Deacon SP
Published: July 2012

1 The effects of selective and non‐selective beta‐adrenoceptor blockade upon plasma non‐esterified fatty acid concentrations in the fasting state and following insulin stress have been studied in normal subjects. 2 Atenolol, propranolol and placebo were compared in a double‐ blind cross‐over trial in eight normal subjects. 3 Atenolol and propranolol significantly lowered plasma non‐esterified fatty acid concentrations by a similar degree in the fasting, non‐stressed state. This finding suggests that beta1‐adrenoceptors are involved in the control of basal lipolysis. 4 Following insulin‐induced stress, lower plasma non‐esterified fatty acid concentrations were observed with propranolol than with atenolol. This difference may be due to beta2‐ adrenoceptor involvement in the stress mechanisms controlling lipolysis, or to the differences in the water‐lipid solubility properties of these drugs.