bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of chronic drug administration on hepatic enzyme induction and folate metabolism.
Authors: Labadarios D , Dickerson JW , Parke DV , Lucas EG , Obuwa GH
Published: July 2012

1 Patients on prolonged treatment with anticonvulsant and phenothiazine drugs exhibited lower than normal concentrations of folate in serum and erythrocytes, and showed increased urinary FIGLU excretion after histidine loading; urinary excretion of D‐glucaric acid was also increased suggesting induction of the hepatic microsomal enzymes. 2 Folate deficiency by enzyme‐inducing drugs was seen to be determined more by the duration of therapy than by the nature of the drugs. Excretion of FIGLU was increased by 70% by 2‐5 years of treatment with anticonvulsant, phenothiazine or tricyclic drugs, and by 200% after 6 or more years. 3 Hepatic microsomal enzyme induction, as measured by D‐ glucaric acid excretion, was greatest after 2‐5 years treatment. 4 It is suggested that the increased requirements for folate, resulting from microsomal enzyme induction, lead to folate deficiency and this subsequently limits enzyme induction, leading to adverse drug side‐ affects. 5 The dietary folate of hospitalized patients would seem to be generally inadequate for patients on long term treatment with enzyme‐ inducing drugs.
The effect of vitamin supplementation upon antipyrine metabolism in the elderly.
Authors: Smithard DJ , Langman MJ
Published: July 2012

1 Antipyrine plasma half‐life and clearance rates were studied in 19 elderly patients shortly after admission to a geriatric ward and again 2 weeks after a course of dietary supplementation with Vitamins A, B complex, C and D. 2 Antipyrine half‐life fell and clearance increased in the nine who had sub‐clinical evidence of ascorbic acid deficiency. No correlation was found with other indices of nutritional status. 3 Vitamin supplementation in elderly people with no demonstrable deficiencies did not alter the metabolism of antipyrine.
Desensitization of the beta‐adrenoceptor of lymphocytes from normal subjects and asthmatic patients in vitro.
Authors: Greenacre JK , Schofield P , Conolly ME
Published: July 2012

1 A lymphocyte culture method has been developed for studying in vitro the effect of prolonged exposure (24 h) to isoprenaline (10(‐8) to 10(− 6) mol/l) and prostaglandin E1 (PGE1; 2.8 x 10(‐6) mol/l). 2 The cyclic AMP response to isoprenaline is reduced by prolonged exposure to isoprenaline. The degree of desensitization is in proportion to the concentration of isoprenaline in the culture medium. 3 Culture with isoprenaline does not reduce the cyclic AMP response to PGE1. 4 Culture for 24 h with PGE1 (2.8 x 10(‐6) mol/l) reduces the cyclic AMP response to PGE1. It also significantly reduces the response to isoprenaline. 5 Lymphocytes from asthmatic patients show a similar degree of desensitization to isoprenaline (after 24 h culture with isoprenaline) to that seen in lymphocytes from normal subjects. 6 A modified assay for phosphodiesterase (PDE) activity was developed. PDE activity increased 24.5% (P less than 0.02) after culture with PGE1 but was not significantly affected by culture with isoprenaline. 7 It is concluded that desensitization caused by prolonged exposure to various stimulators of adenylate cyclase is an event dependent on several components, not all of which are yet defined.
Characterization of beta‐adrenoceptor subtype mediating the metabolic actions of salbutamol.
Authors: Berend N , Marlin GE
Published: July 2012

1. The following four intravenous treatments were administered in a balanced, randomized, Latin square design to four healthy volunteers: (1) saline injection (10 min); salbutamol infusion (0.15 microgram kg‐1 min‐1 for 60 min) (sS), (2) propranolol injection (0.3 mg kg‐1 for 10 min); salbutamol infusion (pS), (3) practolol injection (2 mg kg‐1 for 10 min); salbutamol infusion (PS) and (4) saline injection; saline infusion (ss). 2. Heart rate was recorded and venous blood taken for estimation of insulin, glucose and potassium before and after each injection (0 and 12‐15 min) and at various times during the infusion (30,45,60 and 75 min). 3. The mean, peak % heart rate changes from baseline, control were +65.8%, +23.0%, −10.9% and −12.1%, the mean, peak % glucose changes, +61.0%, +7.1%, +3.6% and +6.9%, and the mean, peak % insulin changes, +298%, +28%, −28% and −43% during the infusions for sS, PS, ss and pS respectively. 4. The mean serum potassium levels before the injections and at the completion of the infusions were 3.98 and 3.08 4.03 and 3.63, 4.07 and 4.15, and 4.03 and 4.13 meq/l for sS, PS, ss and pS respectively. 5. Propanolol completely abolished the cardiac and metabolic responses of salbutamol. 6. Practolol produced only partial cardiac beta‐adrenoceptor blockade, but completely inhibited the metabolic actions of salbutamol.
Bumetanide and frusemide: a comparison of dose‐response curves in healthy men.
Authors: Ramsay LE , McInnes GT , Hettiarachchi J , Shelton J , Scott P
Published: July 2012

1 Log dose‐responses for the loop diuretics bumetanide and frusemide in healthy subjects deviated significantly from parallelism as regards urine volume and sodium excretion. Ignoring the nonparallelism the best estimate of natriuretic potency (bumetanide: frusemide) was 46:1 in the bumetanide dose range 0.5‐2 mg. 2 For a given natriuresis the urinary potassium excretion following bumetanide was significantly lower than that for frusemide within this dose range. 3 The data illustrate the limitations of studies comparing diuretics at a single dose level. Extrapolation of the observed log dose‐response curves provides one possible explanation for the relative potency (bumetanide: frusemide) of 20:1 reported when the drugs are used at high dosage in patients with renal failure.
The application of HPLC to the determination of some 1,4 benzodiazepines and their metabolites in plasma.
Authors: Skellern GG , Meier J , Knight BI , Whiting B
Published: July 2012

1 A high pressure liquid chromatographic (HPLC) assay has been developed for the measurement of chlordiazepoxide and its metabolites, N‐desmethylchlordiazepoxide and demoxepam in microgram concentrations in human plasma. 2 Another metabolite was detected in appreciable amounts in the plasma from patients receiving high doses of chlordiazepoxide after the first 3 days of treatment. 3 Preliminary studies would indicate that this metabolite is N‐desmethyldiazepam. 4 A modified HPLC system, using a microparticulate column was developed to separate N‐desmethyldiazepam from chlordiazepoxide and its other metabolites in plasma.
The use of dobutamine in myocardial infarction for reversal of the cardiodepressive effect of metoprolol.
Authors: Waagstein F , Malek I , Hjalmarson AC
Published: July 2012

1 Ten patients with acute myocardial infarction were infused dobutamine in increasing doses up to 15 microgram kg‐1 min‐1. 2 Metoprolol (total dose 15 mg) was then given intravenously to nine of these patients and the beta‐adrenoceptor against effects produced by dobutamine were effectively reversed. 3 Nine patients with acute myocardial infarction pretreated with metoprolol (15 mg) were infused dobutamine 15 microgram kg‐1 min‐1 for 10 min. This resulted in effective reversal of the beta‐adrenoceptor antagonist effects induced by metoprolol, without the occurrence of serious arrhythmias or other unwanted effects. 4 Dobutamine may be valuable in counteracting any undesirable cardiodepressive effects of beta‐adrenergic receptor blocking drugs (especially the cardioselective agents) in patients with acute myocardial infarction.
Effect of propranolol on sympathetic nervous activity in hydrallazine‐ treated hypertensive patients.
Authors: Velasco M , Romero E , Bertoncini H , Urbina‐Quintana A , Guevara J , Hernandez‐ Pieretti O
Published: July 2012

1 The effect of propranolol was examined on a) blood pressure and heart rate responses due to i.v. hydrallazine b) modification of these cardiovascular parameters during cold pressor test c) urinary catecholamine excretion rate. 2 Intravenous hydrallazine reduced significantly mean blood pressure by 15.2 mm Hg and increased heart rate by 24.9 beats/min. Propranolol reduced significantly mean blood pressure by 19.0 mm Hg and heart rate by 14.1 beats/min. Hydrallazine plus propranolol caused a significant reduction of mean blood pressure (by 37.7 mm Hg) but this was not accompanied by a significant fall in heart rate (by 3.3 beats/min). 3 During the control period, cold pressor test increased mean blood pressure by 16.0 mm Hg. Heart rate was increased by 12.5 beats/min in four patients. However, there was a reduction in heart rate (5.5 beats/min) in two other patients. During the propranolol period, cold pressor test‐induced increase of mean blood pressure was not reduced but propranolol blocked the increase of heart rate. 4 Urinary catecholamine excretion rate was increased during hydrallazine administration. This excretion was not modified by propranolol.
Comparative trial of atenolol and propranolol in hyperthyroidism.
Authors: McDevitt DG , Nelson JK
Published: July 2012

1 The use of atenolol, a cardioselective beta‐adrenoceptor antagonist, in the management of hyperthyroidism has been studied by comparing it with propranolol. 2 In a double‐blind cross‐over trial, atenolol (50 mg), propranolol (40 mg) and placebo 4 times daily for 1 week were compared in twenty‐one hyperthyroid patients by sequential analysis. 3. Patients generally preferred atenolol or propranolol to placebo but this preference only achieved significance with propranolol. 4 Judged by their effect on the symptoms and signs of hyperthyroidism, both atenolol and propranolol were significantly better than placebo, but no distinction could be made between the two active compounds. 5 Atenolol and propranolol reduced mean heart rate by 29.8 and 27.1% respectively compared with placebo. 6 Atenolol appeared almost equally effective to propranolol in the management of the peripheral manifestations of hyperthyroidism.
The effect of intravenous heparin infusions on the thyroid stimulating hormone response to thyrotrophin releasing hormone.
Authors: Thomson JE , Baird SG , Beastall GH , Ratcliffe WA , Thomson JA
Published: July 2012

1 The TSH response to TRH is suppressed 24 h after the commencement of i.v. heparin infusion in euthyroid subjects, as compared to repeat testing, both after 7 days of continuous i.v. heparin and after 7 days without heparin but while on warfarin. 2 This suggests that the rise in serum free thyroid hormones, which heparin produces, has a 'metabolic effect'. Possible clinical effects of this action must be considered. 3 Heparin has no effect on the radio‐immunoassay of TSH.
Salicylates and homoeopathy in rheumatoid arthritis: preliminary observations.
Authors: Gibson RG , Gibson SL , MacNeill AD , Gray GH , Dick WC , Buchanan WW
Published: July 2012

This paper reports the results of a pilot study in which 41 patients with rheumatoid arthritis were treated with high doses of salicylate, 3.9 g per day, and the results compared with a further 54 similar patients treated with homoeopathy. Both groups were compared with 100 patients who received placebo. 2 The patients who received homoeopathy did better than those who received salicylate. The design of the trial was such, however, that it was not possible to distinguish between the effects due to the physicians and the effects due to the drugs and a further trial is planned to elucidate this point. 3 Patients on homoeopathic treatment did not experience toxic effects.
Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.
Authors: Bryson SM , Whiting B , Lawrence JR
Published: July 2012

1 Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half‐life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half‐lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. 5 The absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P less than 0.005), the 5–15% difference between the two formulations should not normally be of any clinical significance.
Metabolism of sulphadiazine in malnutrition.
Authors: Shastri Arunkumar R , Krishnaswamy K
Published: July 2012

1. The kinetics of sulphadiazine were studied in well‐nourished and under‐nourished subjects. 2. The metabolic clearance rate of a single dose of sulphadiazine given either orally or intravenously was faster in under‐nourished subjects. 3. The plasma protein binding of the drug was found to be reduced in under‐nourished subjects. 4. Blood concentrations (48 h and 72 h) of sulphadiazine tended to be low in the under‐nourished as compared with well‐nourished subjects after administration of multiple doses of the drug. 5. It is concluded that a revision in the dosage schedule may not be necessary in the treatment of under‐nourished subjects with sulphadiazine, since the blood concentrations were higher than the reporte d minimum to combat infection.
Mesterolone: thrombosis during treatment, and a study of its prothrombotic effects.
Authors: Lowe GD , Thomson JE , Reavey MM , Forbes CD , Prentice CR
Published: July 2012

1. We describe a patient who developed deep vein thrombosis after commencing treatment with the synthetic androgen, mesterolone (Pro‐ Viron). 2. To investigate the potential thrombogenic action of this drug, a 21 day course of mesterolone (100 mg/day) was given to nine healthy male volunteers. 3. No significant change after treatment occurred in any of the blood tests performed (clotting times, Factor VIII coagulant activity, Factor VIII related antigen, antithrombin III activity, fibrinogen, fibrinogen‐fibrin degradation products, plasminogen, euglobulin lysis time, urokinase sensitivity, platelet count, haematocrit, whole blood viscosity and plasma viscosity). 4. We conclude that in a conventional dose taken for 3 weeks mesterolone does not produce a consistent measurable prothrombotic state, nor does it enhance fibrinolysis.
Effects of H1‐ and H2‐receptor blocking agents on histamine‐induced bronchoconstriction in non‐asthmatic subjects.
Authors: Maconochie JG , Woodings EP , Richards DA
Published: July 2012

1 Two studies have been carried out to investigate the effect of H1‐ and H2‐receptor blocking agents on histamine‐induced bronchoconstriction in non‐asthmatic subjects. 2 The H2‐receptor blocker cimetidine administered orally had no effect on histamine‐ induced bronchoconstriction on any of the subjects tested. In three of four subjects, the H1‐receptor blocker, chlorpheniramine given orally, inhibited the effect of the histamine in the lung. 3 The effects of intravenous chlorpheniramine and cimetidine, both alone and in combination, upon histamine‐induced bronchoconstriction, were also studied. Chlorpheniramine inhibited the effect of the histamine and this was significantly dose related. This was not so with cimetidine and there was no evidence that the dose response curve to chlorpheniramine was affected by the additional administration of cimetidine. 4 The results show that histamine‐induced bronchoconstriction in non‐asthmatic subjects is not mediated by H2‐ receptors, but it is likely that H1‐receptors are involved.
Environmental factors affecting antipyrine metabolism in London factory and office workers.
Authors: Fraser HS , Mucklow JC , Bulpitt CJ , Kahn C , Mould G , Dollery CT
Published: July 2012

1 Measurements of antipyrine clearance in saliva have been made in 128 London factory and office workers. 2 Mean antipyrine clearance in 56 Asian immigrants was 40% slower than in 72 White subjects. 3 Although dietary differences existed between the two groups, analysis of their effect independently of race was impossible since all but one of the vegetarians were Asian and the non‐vegetarians were nearly all White. 4 In the White subjects, use of the oral contraceptive reduced clearance by 38% in women, while cigarette smoking increase clearance by 38% in men.
The metabolism of [14C]‐debrisoquine in man.
Authors: Idle JR , Mahgoub A , Angelo MM , Dring LG , Lancaster R , Smith RL
Published: July 2012

1 The synthesis of [14C]‐debrisoquine hydrochloride and 4‐hydroxy‐ debrisoquine sulphate is described. 2 The metabolic fate and excretion profile in both urine and faeces of 14C‐labelled debrisoquine was studied in five healthy human subjects. 3 Investigations showed that the drug is well‐absorbed after a single oral dose of 32 mg and quantitatively eliminated from the body within three days. 4 4‐Hydroxy‐ debrisoquine is the major metabolite of debrisoquine, although significant amounts of 5‐,6‐, 7‐ and 8‐hydroxy‐debrisoquine are also formed. 5 Electron‐capture gas chromatography is a useful method for measuring debrisoquine and its five hydroxylated metabolites in urine at the pg level.
Quinidine dosage, with special reference to an oral loading dose schedule.
Authors: Collste P , Nordlander R
Published: July 2012

1 Plasma concentrations of quinidine were analyzed in 52 cardiac patients after different oral loading doses and during different maintenance dosage intervals using both conventional and sustained release preparations of quinidine. 2 The majority of patients reached therapeutic plasma concentrations in the order of 2–4 microgram/ml within 3 h after the loading dose of 600–800 mg of rapidly absorbed ordinary quinidine sulphate tablets and institution of maintenance therapy with sustained release tablets 1 h after the loading dose. 3 The dosage interval of 12 h during maintenance therapy with sustained release tablets gave as acceptable plasma drug fluctuations as an 8 h interval. 4 A large individual variation in plasma concentrations was noticed. Thus monitoring of therapy by plasma concentration analyses is desirable.
Bioavailability of conventional and slow‐release oxprenolol in fasted and nonfasted individuals.
Authors: Dawes CP , Kendall MJ , Welling PG
Published: July 2012

1 The influence of food and plasma levels of oxprenolol was examined in healthy female volunteers using both conventional and slow‐release formulations. 2 There were no significant trends in plasma drug profiles due to food with either formulation. Elimination half‐lives were longer after food with conventional tablets, presumably due to continued absorption. The opposite effect was seen with slow‐release tablets. 3 Slow‐release oxprenolol is, under the conditions of this study, a reliable and convenient dosage form, providing similar plasma‐ drug profiles in fasted and nonfasted individuals.
Concurrent administration of antacids and prednisone: effect on serum levels of prednisolone.
Authors: Tanner AR , Caffin JA , Halliday JW , Powell LW
Published: July 2012

1 Specific radioimmunoassays have been developed for the measurement of prednisolone and prednisone in serum. 2 Serum prednisolone levels have been measured following the administration of prednisone both with and without antacids. 3 There were no significant differences in the values of Cmax (mean +/‐ s.d.) (251 +/‐ 80 ng/ml with, 245 +/‐ 69 ng/ml without antacid), AUC (1430 +/‐ 469 ng ml‐1 h‐1 with, 1406 +/‐ 530 ng ml‐1 h‐1 without antacid) or Tmax (1.6 +/‐ 0.6 h with, 1.6 +/‐ 0.8 h without antacid). 4 Serum prednisone levels were less than 20% of prednisolone levels at all time intervals in the subjects studied. 5 Concurrent antacid administration has no significant effect on serum prednisolone levels attained.
The gastrointestinal absorption of PRD‐92 Ea, a new anti‐allergy drug.
Authors: Johnson AJ , Beets JL
Published: July 2012

1 The absorption of PRD‐92 Ea, a new anti‐allergy drug, was studied in volunteer subjects. 2 The 14C‐labelled drug was administered orally and the radioactivity measured in plasma, urine and faeces. 3 Mean peak plasma concentration was 3.3 micrograms/ml, with a concentration of over 1 micrograms/ml maintained 4 h after administration. 4 The mean plasma half‐life (T 1/2) was 114 min. 5 The mean percentage recovery in the urine was 9.5%. 6 Oral administration leads to significant and sustained plasma concentrations, and the oral route should be suitable for drug evaluation in clinical practice.
Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia.
Authors: Harris AL , Potter C , Bunch C , Boutagy J , Harvey DJ , Grahame‐Smith DG
Published: July 2012

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara‐C in patients with newly diagnosed untreated AML, using a bioassay and GC‐MS method to measure the plasma concentrations. 2 Most patients showed a bi‐ or tri‐phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC‐MS method, and terminal half‐lives varied from 7‐ 107 min. 3 There was poor correlation of the GC‐MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara‐C. 4 Plasma concentrations were measured by GC‐MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara‐C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara‐C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.
Biliary excretion of erythromycin after parenteral administration.
Authors: Chelvan P , Hamilton‐Miller JM , Brumfitt W
Published: July 2012

1 The biliary excretion of erythromycin has been studied following parenteral administration in 23 patients. 2 Mean bile levels of the drug were approximately ten times higher than corresponding serum concentrations 1 h after i.v. (erythromycin lactobionate) and i.m. (erythromycin ethylsuccinate) injection. 3 Thus, unlike many antimicrobial agents, these compounds are well concentrated in the bile.
A gastroscopic and pharmacological study of the disintegration time and absorption of pivampicillin capsules and tablets.
Authors: Hey H , Matzen P , Andersen JT , Didriksen E , Nielsen B
Published: July 2012

1 An in vitro investigation showed that pivampicillin tablets disintegrated more rapidly than pivampicillin capsules. This result was demonstrated and confirmed by gastroscopy in a cross‐over study in healthy volunteers. 2 There were no differences in serum levels of ampicillin obtained with the two preparations, but compared with non‐ gastroscoped volunteers, there was delay of 0.5–1.5 h in the appearance of peak serum ampicillin concentrations after gastroscopy. 3 Half of the volunteers receiving pivampicillin capsules developed hyperaemia, interstitial bleeding or erosions of the gastric mucous membrane. No such reactions were seen after pivampicillin tablets. 4 In one volunteer, a pivampicillin capsule was trapped in a not previously noticed hiatus hernia and local changes and pain occurred.
Pharmacokinetics and pharmacodynamics of warfarin at steady state.
Authors: Routledge PA , Chapman PH , Davies DM , Rawlins MD
Published: July 2012

1 The relationship between warfarin dose, total and free plasma warfarin concentration, and anticoagulant effect was examined at several steady‐state levels in fifteen patients during withdrawal of warfarin therapy. 2 Total plasma clearance was significantly correlated with the free fraction in plasma (r=0.955). 3 There was an age related decline in the dose of warfarin, and in the total and free plasma warfarin concentrations required to produce the same anticoagulant effect. However, neither total nor free plasma warfarin clearances varied with age. 4 Individual patients' log concentration‐effect relationships were linear above a prothrombin ratio of 1.2 and there was a significant correlation (r=‐0.586) between the slope and the free fraction of warfarin in plasma. It is suggested that plasma protein binding may reflect the interaction between warfarin and its effector site in the hepatocyte.
A double‐blind comparison of a novel indanone diuretic (MK‐196) with hydrochlorothiazide in the treatment of essential hypertension.
Authors: Wilhelmsson CE , Vedin JA , Moerlin C , Lund‐Johansen P , Vorburger C , Enenkel W , Lutterbeck PM , Bolognese J , Cirillo VJ , Tempero KF
Published: July 2012

1 The antihypertensive effect and tolerability of MK‐196 (10 mg and 15 mg daily) was compared to hydrochlorothiazide (HCT; 50 mg daily) in a 4‐ week multiclinic, double‐blind study involving 42 patients with mild to moderate, essential hypertension. 2 Both doses of MK‐196 were as effective and sometimes more effective than HCT in lowering standing and supine systolic and diastolic blood pressures. 3 HCT consistently brought about significant increases in serum uric acid and significant decreases in serum potassium; both doses of MK‐196 produced similar but less frequent and smaller changes in both of these parameters. 4 Both doses of MK‐196 brought about significant decreases in body weight at Weeks 3 and 4 of drug treatment. 5 Patients taking MK‐196 reported fewer adverse clinical reactions (10 mg = 15%; 15 mg = 13% than those taking HCT (21%). 6 MK‐196 may offer a therapeutic advantage over HCT as an antihypertensive agent for use in the treatment of mild to moderate, essential hypertension.
Assay of azathioprine, 6‐mercaptopurine and a novel thiopurine metabolite in human plasma.
Authors: Maddocks JL
Published: July 2012

1 A simple, specific assay for 6‐mercaptopurine (6‐MP) in human plasma with a sensitivity of 10 ng/ml (66 nmol/1) has been developed. 2 6‐MP was extracted directly from plasma into toluene using a novel extraction procedure. This involves conversion of 6‐MP into a phenyl mercury derivative by its reaction with phenyl mercuric acetate in alkaline plasma and extracting into toluene. Back‐extraction of the toluene layer with 0.1N HCl regenerates 6‐MP, which is then oxidised to purine‐6‐sulphonate and assayed fluorimetrically. 3 This assay has been modified to measure azathioprine and a new thiopurine metabolite in plasma. 4 In a kidney transplant patient given azathioprine, 50 mg i.v., conversion to 6‐MP was rapid and the plasma half‐life of 6‐MP was 36 min. 5 These assays are suitable for studying the pharmacokinetics of azathioprine in patients with kidney transplants. The 6‐MP assay should also prove useful for studying the pharmacokinetics of the drug in patients with leukaemia.
Gentamicin pharmacokinetics in kwashiorkor.
Authors: Buchanan N , Davis MD , Eyberg C
Published: July 2012

1 Single dose intravenous gentamicin kinetics (2.4 mg/kg) were studied in six children with kwashiorkor. It was observed, that therapeutic drug concentrations were achieved which should be neither oto‐ nor nephrotoxic. 2 Due to the diminished glomerular filtration and renal plasma flow seen in the acute phase of kwashiorkor, gentamicin half‐ life was prolonged (229.0 +/‐ 94.8 min) at this time returning to normal (178.5 +/‐ 99.5 min) with nutritional rehabilitation.
Pharmacokinetics of metoclopramide intravenously and orally determined by liquid chromatography.
Authors: Graffner C , Lagerstrom PO , Lundborg P , Ronn O
Published: July 2012

1 A rapid and sensitive method, based on liquid chromatography, has been developed for determination of metoclopramide concentrations in plasma and urine samples. Concentrations down to 15 nmol/1 (5 ng/ml) of plasma and 100 nmol/1 (30 ng/ml) of urine could be determined with a relative standard deviation of less than or equal to 10%. The method was used to study disposition of metoclopramide in healthy volunteers following single doses intravenously and orally as aqueous solution and a slow release tablet. 2 The initial distribution after intravenous administration was very rapid. The elimination half‐life postdistribution was 4.9 h. The apparent volume of distribution, Vd, was 3.0 1/kg body weight. On average 19% was excreted unchanged after intravenous administration of 5 and 10 mg (15 and 30 mumol) of drug. The rate of absorption of metoclopramide was delayed after administration of a slow release tablet and the maximum plasma concentration was about 50% lower than after a solution. The extent of bioavailability was the same following the two different formulations suggesting a first‐pass elimination of 25‐40%.
The [14C]‐aminopyrine breath test. A comparison of different forms of analysis.
Authors: Henry DA , Sharpe G , Chaplain S , Cartwright S , Kitchingman G , Bell GD , Langman MJ
Published: July 2012

1 Following ingestion of [14C]‐aminopyrine, breath 14CO2 data were analysed from normal individuals, patients with hepatic disease, epileptics receiving anticonvulsant therapy and volunteers before and after treatment with glutethimide. 2 The ‘standard’ 2 h [14C]‐ aminopyrine breath test discriminated successfully between the main groups but failed to detect the change in microsomal enzyme function produced by glutethimide. 3 A ‘modified’ form of the 2 h breath test calculated from the area under the breath specific activity curve detected the increase in demethylation following glutethimide. 4 The breath elimination constant (Kb) derived from the breath 14CO2 disappearance curve was as sensitive as the ‘modified’ 2 h breath test and was simpler to compute. 5 Glutethimide 500 mg/day for 14 days resulted in a 42% increase in the metabolic clearance of antipyrine and a 26% increase in demethylation of [14C]‐aminopyrine.
Pharmacokinetics of methylphenidate in hyperkinetic children.
Authors: Hungund BL , Perel JM , Hurwic MJ , Sverd J , Winsberg BG
Published: July 2012

1 Pharmacokinetic study has been carried out following oral administration of 10‐20 mg of methylphenidate hydrochloride to four behaviorally disorders children. 2 It is indicated that the drug is metabolized to ritalinic acid with an apparent plasma half life of 2.5 h. 3 The variability in magnitude of plasma concentration seems to be due not to its metabolism to ritalinic acid but due to the variability in the apparent volume of distribution. 4 The brief half life of methylphenidate which parallels the short duration of action of methylphenidate in behaviorally disordered children may be explained in part by its low protein binding which results in high percentage of free drug being made available for metabolism to pharmacologically inactive metabolites.
Serum morphine concentration after oral administration of diamorphine hydrochloride and morphine sulphate.
Authors: Aherne GW , Piall EM , Twycross RG
Published: July 2012

1 Venous blood was obtained from patients with far‐advanced cancer receiving either diamorphine (diacetylmorphine, heroin) hydrochloride (65 samples) or morphine sulphate (24 samples) regularly by mouth in doses from 2.5 mg to 90 mg every 4 h. 2 Samples were obtained within 30 min of the 09.00 h drug round. 3 Serial samples were also obtained over a 4 h period from three patients receiving diamorphine hydrochloride. 4 Assay of serum ‘morphine equivalents’ was by radioimmunoassay using an antibody that cross reacts almost equally with diamorphine, 6‐0 monoacetylmorphine and morphine. 5 The serum concentration of opiates expressed as ‘morphine equivalents’ ranged from 11 ng/ml to 1440 ng/ml. 6 A highly significant positive linear correlation exists between the dose administered and the serum concentration (P less than 0.001) with respect to both drugs. 7 There was no difference between the two drugs in relation to the serum concentration achieved per 10 mg of opiate administered. 8 Higher oral doses of both diamorphine and morphine are now being used when indicated rather than, as before, resorting to injections when an oral dose in excess of 40 mg is indicated.
Pharmacokinetics, pharmacology of atenolol and effect of renal disease.
Authors: Wan SH , Koda RT , Maronde RF
Published: July 2012

1. The pharmacokinetics of intravenous and oral atenolol (50 mg) in six healthy volunteers was studied. Plasma, saliva and urine were collected up to 24 h after each dose. 2. There was no significant difference in atenolol half‐life when administered by the two routes. Bioavailability of the orally administered atenolol was 50%. 3. Atenolol levels in saliva required about 2 h to reach equilibrium with plasma drug levels. 4. A comparison between the pharmacokinetics and pharmacology of atenolol was made in twelve healthy subjects. 5. Dose‐independent pharmacokinetics were observed. Reductions in resting heart rate and arterial blood pressure were proportional to either the logarithm of dose or area under the plasma concentration time curve or cumulative urinary atenolol excretion. 6. Plasma elimination half‐life in five subjects with renal failure was prolonged.
Interaction of atenolol and adrenaline with respect to intraocular pressure.
Authors: Rushton A
Published: July 2012

1. The effects of topically administered atenolol 4% and adrenaline 1% on intraocular pressure (IOP) were investigated in fourteen healthy male human volunteers. Both the sole and combined effects of single doses of the formulations were recorded over a 7 h period. 2. Adrenaline and atenolol both produced significant reductions in IOP when compared to the placebo control, although the pattern of response differed. 3. Adrenaline had a rapid onset of action, resulting in a significant pressure reduction by 45 min post drug administration. A small upswing in IOP then occurred between 45 and 90 min, followed by a prolonged secondary reduction phase. 4. Atenolol produced a gradual reduction in IOP which reached a maximum at 180 min post drug administration and subsequently declined between 300 and 420 min. 5. Combined treatment with atenolol and adrenaline resulted in additive effects up to 180 min, and the early pressure upswing recorded with adrenaline was completely abolished. 6. The results are compatible with the hypothesis that beta 1‐adrenoceptor stimulation elevates intraocular pressure. The correlation of these results with relevant animal and human pharmacological data is discussed.
Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure.
Authors: Beermann B , Groschinsky‐Grind M
Published: July 2012

1. Hydrochlorothiazide (HCT, 50‐75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma halflife of HCT was correlated with endogenous creatinine clearance. 5. Pharmacokinetics of HCT are considerably changed in cardiac failure.
Plasma levels of 5‐fluorouracil after oral and intravenous administration in cancer patients.
Authors: Finch RE , Bending MR , Lant AF
Published: July 2012

1. Plasma levels of 5‐fluorouracil (5FU) have been determined in eleven cancer patients after 0.5 g and 1.0 g intravenous doses, and in one patient after paired 1.0 g oral and intravenous doses. 2. The plasma half‐life after the 0.5 g intravenous dose was relatively constant, irrespective of the stage and spread of the disease. 3. Plasma kinetics of the drug were dose dependent. Doubling of the intravenous dose produced a 1.5‐fold increase in plasma half life, a two‐fold increase in initial plasma drug concentration, and a three‐fold increase in area under the concentration/time curve. 4. In one patient receiving paired 1.0 g intravenous and oral doses nine weeks apart, an increase in the bioavailability of the drug coincided with a marked clinical regression in palpable intra‐abdominal metastases. 5. The significance of measuring plasma drug kinetics and their relationship to drug efficacy and toxicity are discussed.
Effect of the antihistamines, brompheniramine maleate and triprolidine hydrochloride, on performance in man.
Authors: Nicholson AN
Published: July 2012

1 Effects of brompheniramine maleate (4 and 12 mg) and triprolidine hydrochloride (2.5 and 10 mg) on visuo‐motor coordination, and on subjective assessments of performance, well‐being and sleep were each studied in six subjects at 0.5, 1.5, 3.0, 5.0 and 7.0 h after ingestion. The doses refer to immediate and sustained release preparations respectively. 2. Triprolidine hydrochloride (2.5 mg) had an immediate effect on performance which persisted to 3.0 h, and the sustained release preparation (10 mg) impaired performance from 1.5 to 5.0 h. Brompheniramine maleate (4 mg) impaired performance from 1.5 to 3.0 h, and the sustained release preparation (12 mg) impaired performance at 1.5 h. There were no consistent changes in the subjective assessments of performance, or of well‐being and sleep. 3. The studies emphasize the variable effects of antihistamines on performance, and suggest that effects on performance of sustained release preparations may be similar to those of the usual form. Sustained release preparations may provide an advantage in clinical practice if the antihistaminic activity is prolonged.
The effects of repeated nocturnal doses of clobazam, dipotassium chlorazepate and placebo on subjective ratings of sleep and early morning behaviour and objective measures of arousal, psychomotor performance and anxiety.
Authors: Hindmarch I , Parrott AC
Published: July 2012

1. Repeated nocturnal doses of 30 mg clobazam and dipotassium chlorazepate 15 mg showed no significant effects compared to matching placebo on tests of psychomotor performance and serial subtraction of numbers given in the morning and afternoon of the day following treatment. 2. Both active preparations improved the perceived quality of sleep compared to placebo. 3. A reduction in rated anxiety scores was found with clobazam on the afternoon of the day following treatment together with an elevation of critical flicker fusion thresholds. 4. Dipotassium chlorazepate was found to impair performance of a low level conceptual task but not to influence performance at a more difficult level.
The influence of food on the bioavailability of new formulations of erythromycin stearate and base.
Authors: Rutland J , Berend N , Marlin GE
Published: July 2012

1. The effect of food on the bioavailability of two new formulations of erythromycin, 1) erythromycin stearate, 500 mg (Erythrocin, 250 mg capsule‐shaped tablets) and 2) erythromycin base, 500 mg (Eryc, 250 mg capsules containing enteric‐coated pellets) was studied in 16 healthy subjects. 2. The study was a balanced, randomized Latin square design and was conducted on 4 days. The four treatments were erythromycin stearate immediately before (EB) and after EA) breakfast and erythromycin base immediately before (eB) and after (eA) breakfast. 3. The mean +/‐ s.d. maximal plasma erythromycin concentrations were 2.09 +/‐ 1.06, 0.37 +/‐ 0.40, 1.8+ +/‐ 1.15 and 1.91 +/‐ 1.57 micrograms/ml and the mean +/‐ s.d. times at which these occurred were 1.3 +/‐ 0.7, 2.3 +/‐ 0.9, 4.4 +/‐ 1.9 and 4.3 +/‐ 1.1 h for EB, EA, eB and eA respectively. 4. The mean +/‐ s.d. areas under the curves (0 to 8 h) were 4.99 +/‐ 2.41, 1.04 +/‐ 1.57, 4.93 +/‐ 2.98 and 4.98 +/‐ 3.14 for EB, EA, eB and eA respectively. 5. The bioavailability of erythromycin stearate was significantly reduced by the prior administration of food, whereas the absorption of the base was not inhibited by food.
Changes in cardiac glycoside receptor sites, 86rubidium uptake and intracellular sodium concentrations in the erythrocytes of patients receiving digoxin during the early phases of treatment of cardiac failure in regular rhythm and of atrial fibrillation.
Authors: Ford AR , Aronson JK , Grahame‐Smith DG , Carver JG
Published: July 2012

1 Measurements of the binding of 12‐alpha‐[3H]‐digoxin to the membranes of intact erythrocytes, erythrocytic 86rubidium uptake and intraerythrocytic sodium concentrations have been made in the red cells of patients receiving digoxin in the short‐term for atrial fibrillation or cardiac failure in regular rhythm. 2 During the first few days of treatment [3H]‐digoxin binding and 86rubidium uptake fall and intraerythrocytic sodium concentrations rise. 3 Subsequently parallel fluctuations occur in [3H]‐digoxin binding and 86rubidium uptake but not in intraerythrocytic sodium concentrations and the significance of the fluctuations is discussed. 4 The values of all three measurements correlate significantly with the response of the heart in sinus rhythm as measured by QS2I. 5 Plasma digoxin concentrations do not correlate with QS2I.
The effect of beta‐adrenoceptor blockade on factors affecting exercise tolerance in normal man.
Authors: Pearson SB , Banks DC , Patrick JM
Published: July 2012

1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg metoprolol on the cardiovascular and respiratory responses to progressive exercise in nine healthy men in double‐blind, placebo‐ controlled experiment. As judged by their effects on exercise heart rate and cardiac output the doses of the two drugs used were equivalent. 2 Beta‐adrenoceptor blockade reduced oxygen consumption by 3.5% over the whole work range with an increase in the respiratory exchange ratio of 0.056 units. Carbon dioxide production and exercise ventilation were unchanged. The two drugs had similar effects. Possible mechanisms for these observations are discussed. 3 Perceived exertion during exercise was increased by both the beta‐adrenoceptor blocking drugs and this may be of relevance to the symptom of fatigue reported by patients on these drugs. Endurance, assessed as either total work done or maximal work achieved, was reduced by 15%.
A comparison of the effects of labetalol, bendrofluazide and their combination in hypertension.
Authors: Dawson A. , Johnson BF , Smith IK , Munro‐Faure AD
Published: July 2012

1 Bendrofluazide (10 mg/day) or labetalol (300 mg and 600 mg/day) produced significant reductions in lying, standing, and post‐exercise blood pressure in ten hypertensives. 2 Active treatments were approximately equivalent in anti‐hypertensive effect. However, comparing lying and standing determinations, labetalol (600 mg/day) produced significantly greater additional postural falls in systolic blood pressure than during placebo or bendrofluazide treatment. 3 Systolic blood pressure rose after exercise during placebo or bendrofluazide treatment. However, on labetalol, mean changes in systolic blood pressure after exercise were negative and significantly different from those seen on placebo. 4 Greater reductions in lying and post‐exercise systolic blood pressure were produced by combination treatment than by either individual drug. Additional postural and exercise‐related falls in systolic blood pressure tended to be smaller with combination treatment than during treatment with labetalol alone. 5 Labetalol significantly reduced lying, standing, or post‐exercise heart rate by comparison with placebo or bendrofluazide. 6 Labetalol significantly reduced lying, standing, or post‐exercise heart rate by comparison with placebo or bendrofluazide. 6 Labetalol moderately reduced plasma renin activity, whereas bendrofluazide caused marked elevation. The effect of bendrofluazide predominated during combination treatment.
Plasma concentrations of propranolol and 4‐hydroxypropranolol during chronic oral propranolol therapy.
Authors: Wong L. , Nation RL , Chiou WL , Mehta PK
Published: July 2012

1 The plasma levels of propranolol and 4‐hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4‐hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean (+/‐ s.d.) plasma concentration ratio of 4‐ hydroxypropranolol to propranolol was 0.130 (+/‐ 0.005); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4‐hydroxypropranolol and that of propranolol. 5 Propranolol and 4‐hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.
A single dose comparison of piretanide and bumetanide in congestive cardiac failure.
Authors: Homeida M. , Roberts CJ , Dombey SL
Published: July 2012

1 This study has compared the diuresis produced by a single oral administration of 6 mg piretanide, 9 mg piretanide and 1 mg bumetanide in a group of nine patients with cardiac failure using a balanced randomized design. 2 The natriuresis and kaliuresis produced in the first 6 h after administration of piretanide 9 mg and bumetanide 1 mg were similar. Piretanide 6 mg produced a lesser response. 3 There was evidence of sodium and water conservation following the diuresis for up to 48 h with all three treatments. 4 The patterns of urate and calcium excretion were similar for the two diuretics.
Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients.
Authors: Perucca E. , Richens A.
Published: July 2012

1. The pharmacokinetics of lignocaine following single oral and intravenous doses have been investigated in six normal volunteers and in six patients receiving chronic antiepileptic drug therapy. 2. After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean +/‐ s.d.) was slightly higher in the patients (0.85 +/‐ 0.09 v 0.77 +/‐ 0.07 l/min) but the difference was not statistically significant. 3. Lignocaine bioavailability after oral administration was more than two‐ fold in the patients than in the normal subjects (0.15 +/‐ 0.06 v 0.37 +/‐ 0.09, P < 0.001). 4. It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first‐pass metabolism by antiepileptic drugs.
Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out‐patients.
Authors: Neuvonen PJ , Bardy A. , Lehtovaara R.
Published: July 2012

1. The bioavailability of a brand of phenytoin tablets used in Finland was improved in 1976. In the present retrospective study serum concentrations of phenytoin, measured before and after the change of bioavailability, are compared in 50 epileptic out‐patients, who for various reasons used exactly the same dose of phenytoin tablets and of other drugs despite the increased bioavailability of phenytoin. 2. The mean increase of serum phenytoin steady‐state concentration was about 70% after the change of bioavailability but there were considerable interindividual differences in the response. The mean increase in serum phenytoin was only 28% in patients with serum phenytoin concentrations 5 microgram/ml or less but the mean increase was 100% in patients with serum phenytoin between 5 and 10 microgram/ml. In patients with serum phenytoin concentrations more than 10 microgram/ml the mean increase in concentration was 60‐80% after the improvement of bioavailability. However, in these groups of patients some clinically manifested phenytoin intoxications enforced the patients to the control and to dose reduction obviously before the steady‐state concentration of phenytoin was reached. 3. On the basis of our experiences and those reported in the literature some proposals are presented to be considered when the bioavailability of phenytoin or of another drug with a narrow therapeutic range and a dose‐dependent kinetics has to be changed.