bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial blood gas tensions and pH.
Authors: Flenley DC
Published: July 2012

1 The definition of PO2 and its relationship to the oxygen saturation (SO2) by the oxygen dissociation curve (ODC) is described with details of the ligands of the ODC and the effects of haemoglobinopathies on P50 (the position of the ODC) and the slope of the ODC (Hill's 'n'). 2 The definition of PCO2 and description of CO2 transport by blood leads to consideration of the basis of acid base balance. 3 Acid base balance is expressed in terms of arterial blood (H+) (or pH) PCO2 relationship using a non‐logarithmic diagram. 4 The measurement of arterial blood gas tensions is described with comments on arterial puncture and available modern automated blood gas electrodes and their calibration. 5 Non‐invasive indirect measurements of blood gas tensions, by ear oximetry are described, with calibration figures on the Hewlett‐Packard 47021A ear oximeter. End‐tidal PO2 and PCO2 measurements by mass spectrometer or infra‐red CO2 analyser, and of transcutaneous PO2 measurements by a heated polarographic electrode are described. 6 These measurements are necessary to study the effects of pharmacological agents on the chemical control of breathing, on pulmonary gas exchange, and on acid base balance in humans. The measurements are in everyday use in clinical practice, both to aid diagnosis of respiratory diseases, assess their severity, and to quantiate the effects of therapeutic agents.
The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients.
Authors: Skellern GG , Knight BI , Low CK , Alexander WD , McLarty DG , Kalk WJ
Published: July 2012

1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3‐methyl‐2‐ thiohydantoin in one patient. 3 Large interindividual differences were observed, especially within the carbimazole group. 4 Incomplete absorption of carbimazole could explain particular high apparent volumes of distribution and apparent clearances.
Enhanced metabolism and diminished efficacy of disopyramide by enzyme induction?
Authors: Aitio ML , Vuorenmaa T.
Published: July 2012

1 Monitoring plasma levels of mono‐N‐dealkyldisopyramide (MND), the most important metabolite of disopyramide, has been considered unnecessary. 2 We measured plasma levels of both disopyramide and MND in 64 consecutive patients receiving long term oral therapy with disopyramide. 3 Six patients were found with high plasma levels of MND, and simultaneously low levels of disopyramide. 4 Three of these patients were taking simultaneously phenytoin. The other three had a relatively high dose of disopyramide with regard to their renal function. One patient had terminal uremia, three had less severe renal dysfunction. 5 The underlying mechanism and clinical significance of the findings are discussed.
Response of pathological ischaemic muscle pain to analgesics.
Authors: Sacchetti G. , Lampugnani R. , Battistini C. , Mandelli V.
Published: July 2012

1 Twenty‐four patients suffering from severe pain due to chronic occlusive arterial disease of the legs were given oral doses of indoprofen (200 mg), ibuprofen (300 mg) and placebo. 2 Differences in pain intensity scored on a five‐point scale were taken as measurement of pain relief. 3 This double‐blind, cross‐over trial showed that indoprofen had significantly greater analgesic effect than placebo and reference drug. 4 From a methodological point of view there are many arguments on favour of pathological ischaemic pain as a test for clinical assessment of analgesics.
The effect of oral prednisolone on gas exchange in chronic bronchial asthma.
Authors: Ellul‐Micallef R. , Borthwick RC , McHardy GJ
Published: July 2012

Patients with bronchial asthma frequently have a fall in arterial oxygen tension following bronchodilator treatment in spite of a reduction in airway resistance. Administration of 0.11 mM (40 mg) prednisolone in a single dose resulted in an improvement of both airway obstruction and hypoxaemia in chronic asthmatic patients. The arterial oxygen tension, alveolar‐arterial oxygen tension difference and venous admixture effect all showed a statistically significant improvement as did the dynamic lung volumes and specific airway conductance.
Failure of propranolol and metoprolol to alter ventilatory responses to carbon dioxide and exercise.
Authors: Leitch AG , Hopkin JM , Ellis DA , Clarkson DM , Merchant S. , McHardy GJ
Published: July 2012

Neither propranolol (80 mg) nor metoprolol (100 mg) give orally to eight normal subjects altered mean ventilatory responses to carbon dioxide or to moderate graded exercise. Incremental doses of the drugs to totals of 320 mg propranolol and 400 mg metoprolol also did not effect these ventilatory responses. Both drugs markedly decreased the heart rate response to exercise. Neither propranolol nor metoprolol are likely to cause CO2 retention by an effect on the ventilatory responses to inhaled carbon dioxide or to exercise.
Acute effects of acebutolol on cardiovascular function in man.
Authors: Dalal JJ , Ross PJ , Wong K , Sheridan DJ , Ruttley MS , Lewis MJ , Henderson AH
Published: July 2012

1 The acute cardiovascular effects of acebutolol were measured at constant paced heart rate in thirteen patients investigated for possible coronary artery disease, six of whom showed significant coronary stenosis with regional myocardial dysfunction, seven of whom proved normal. Acebutolol 0.75 mg/kg i.v. was given to three patients with coronary artery disease and three normals, and 1 mg/kg i.v. to the other patients.2 Measurements were made of cardiac output, left ventricular and arterial pressures, and left ventricular angiography. Isovolumic and ejection phase parameters of left ventricular function, and systemic vascular resistance were derived. Plasma levels of acebutolol were measured. 3 The acute effects of acebutolol were a slight fall in cardiac output, LV dp/dt and dP/dt/P. There was no change in LV or arterial pressures, no consistent change in LVEDP or EDV, and no consistent change in ejection fraction or mean VCF. These changes imply a small negative inotropic effect, more marked at the higher dose. 4 The effects of acebutolol differed in patients with ischaemic heart disease compared with normals in that LVEDP and EDV increased, mean VCF decreased and cardiac output was lowered more. 5 These data are consistent with myocardial and vascular effects of beta‐ adrenoceptor blockade more marked at the higher dose and more marked in patients with ischaemic heart disease.
The in vitro metabolism of ethinyloestradiol, mestranol and levonorgestrel by human jejunal mucosa.
Authors: Back DJ , Bates M , Breckenridge AM , Ellis A , Hall JM , Maciver M , Orme ML , Rowe PH
Published: July 2012

1 Ethinyloestradiol was extensively metabolised in vitro by human jejunal mucosa to form ethinyloestradiol sulphate. 2 The amount of conjugation was directly related to the weight of biopsy tissue. 3 The degree of conjugation of mestranol and levonorgestrel was much lower than for ethinyloestradiol suggesting that the 17‐position of the steroid nucleus is relatively inaccessible for conjugation. 4 No Phase I metabolism of ethinyloestradiol or levonorgestrel was apparent in the conditions used in these experiments.
Clinical trials, reviews, and the Journal of Negative Results.
Authors: Maxwell C
Published: July 2012

1 Eighteen our of twenty non‐significant placebo controlled trials are shown to have trends favouring imipramine and are consistent with a further ten significant at 0.05. 2 The problems of falsely positive and falsely negative results are discussed. A plea is made to medical journal editors to publish 'negative' or null difference trials by title only; rather than not at all.
Does the frequency of daily dosage influence compliance with digoxin therapy?
Authors: Taggart AJ , Johnston GD , McDevitt DG
Published: July 2012

1 The influence of daily dosage frequency on drug compliance has been studied in 80 outpatients for whom maintenance digoxin 0.25 mg daily had been prescribed. 2 Each patient took one tablet (0.25 mg) daily, two tablets (0.125 mg) daily and four tablets (0.0625 mg) daily in randomised order for 2 month periods. 3 Compliance was assessed by tablet counting and by serial measurement of the plasma digoxin concentration. 4 Of the 67 patients (100%) who could have completed the study, 19 (28.4%) were withdrawal for a variety of reasons; in the majority these were consistent with gross non‐compliance. 5 The remaining 48 patients (71.6%) took significantly more tablets when prescribed once daily (98.5 +/− 1.0% of the total) or twice daily (96.4 +/− 1.6%) than when given four times daily (92.2 +/− 1.9%). However, there were no significant differences between the plasma digoxin levels obtained at the three dosage frequencies. 6 We conclude that the small improvement in compliance with once or twice daily dosage was clinically unimportant. Dosage frequency did not appear to have a major influence on the grossly non‐compliant patients.
Acute effect of high dose (48 mg) of piretanide in advanced renal insufficiency.
Authors: Aissa Hadj A , Pozet N , Labeeuw M , Pellet M , Traeger J
Published: July 2012

1 The acute effects of a high dose of piretanide, a new potent diuretic were studied in eight patients with severely impaired renal function (GFR between 0.09 and 0.17 ml s‐1 1.73 m‐2). 2 After hydration and following two control periods, a single dose of 48 mg piretanide was ingested. Thereafter, urine was collected every 30 min for 2 h and every hour for the next 4 h. Urinary fluid losses were replaced orally (100 ml of water ever hour) and intravenously (isotonic saline + glucose infusion). 3 The following measurements were made: urine flow rate, clearances of inulin, PAH, urea, creatinine, uric acid, osmolar and free water clearances, excretion rates of sodium, chloride, potassium, calcium, phosphate, bicarbonate, ammonium, titratable acidity and urine pH. 4 Piretanide (48 mg) appeared to be effective in advanced renal insufficiency, producing a significant increase in urine flow rate, in sodium, chloride, potassium and calcium excretion and in Cosm. 5 There was no significant change in GFR, as measured by inulin clearance, or in the other measured parameters.
Ibopamine (SB 7505) in normal subjects and in chronic renal failure: a preliminary report.
Authors: Stefoni S , Coli L , Mosconi G , Prandini R
Published: July 2012

1 Pharmacological and experimental studies have shown that ibopamine (SB 7505, di‐isobutyric ester of N‐methyldopamine) is capable of increasing renal blood flow, diuresis, urinary sodium, potassium and creatinine excretion. 2 SB 7505 was given to twelve volunteer patients, six of whom had normal renal function and six with various degrees of chronic renal impairment. 3 In both groups the drug yielded a prompt increase in urinary excretion of water, sodium and potassium, while creatinine clearance was also seen to increase. 4 Heart rate and arterial pressure were unaffected by SB 7505 in all patients. 5 Results seen encouraging and call for further study on the proper use of the drug in clinical nephrology.
Radioimmunoassay for perphenazine in human plasma.
Authors: Midha KK , Mackonka C , Cooper JK , Hubbard JW , Yeung PK
Published: July 2012

1 A new sensitive, specific and rapid radioimmunoassay procedure for the determination of plasma concentrations of the neuroleptic drug perphenazine is described. 2 The antiserum developed for perphenazine did not cross‐react with most of the major metabolites of perphenazine nor the tricyclic antidepressants and antianxiety agents commonly co‐ administered with the drug. 3 The assay, based on the above antiserum, enabled the quantitation of 50 pg of the drug in 200 microliters of plasma with a coefficient of variation of about 8% and therefore should be applicable for single dose pharmacokinetic studies, as well as therapeutic monitoring of the drug in patients.
Further evidence for an acetylator phenotype difference in the metabolism of hydralazine in man.
Authors: Facchini V , Timbrell JA
Published: July 2012

1 The 0‐24 h urine from hypertensive patients treated with hydralazine (100 mg twice daily) has been analysed by gas chromatography and high pressure liquid chromatography. 2 4‐N‐Acetylhydrazinophthalazine‐1‐one (NAcHPZ), s‐triazolo [3, 4‐a] phthalazine (TP), phthalazinone (PZ) and hydralazine (free, H; acid‐labile hydrazones, HH) were detected and assayed. 3 The results indicate that slow acetylators excrete less NAcHPZ and TP than rapid acetylators but more PZ and HH. 4 Free hydralazine was present in low levels and was only detected in some urine samples. 5 The ratios of the metabolites NAcHPZ/HH; TP/HH; NAcHPZ/PZ and PZ/TP are different in the two acetylator phenotypes. 6 It is possible the ratio PZ/TP may be used for determination of acetylator phenotype. 7 It is concluded that hydralazine metabolism is dependent on the acetylator phenotype.
Circadian variations in the signs and symptoms of rheumatoid arthritis and in the therapeutic effectiveness of flurbiprofen at different times of day.
Authors: Kowanko IC , Pownall R , Knapp MS , Swannell AJ , Mahoney PG
Published: July 2012

1 Seventeen patients with rheumatoid arthritis were studied in a double‐ blind crossover trial contrasting three different times of administration of twice‐daily flurbiprofen. 2 Twelve of these patients were also studied when taking the same dose of flurbiprofen as a split dose four times a day. 3 Symptoms and signs of the disease were self‐ assessed throughout the day for several days on each regimen and the information was analysed for rhythmicity. 4 Twice a day flurbiprofen may be more effective than four times daily flurbiprofen, and the regimen without an evening dose was the least effective of three twice‐ daily treatments tested. 5 Circadian rhythms of grip strength and finger joint size were demonstrated, and were similar on all treatment regimens. 6 These rhythms have a similar pattern to those detected during studies of immune responses, and it is suggested that morning stiffness in rheumatoid arthritis is not only the result of nocturnal inactivity, and may respond to appropriately timed medication given to decrease inflammation or to suppress other aspects of the immune response.
Trazodone‐a new assay procedure and some pharmacokinetic parameters.
Authors: Ankier SI , Martin BK , Rogers MS , Carpenter PK , Graham C
Published: July 2012

1 A simple and specific procedure is described for the determination of the new anti‐depressant trazodone in human plasma utilising reverse‐ phase HPLC which is sensitive to 20 ng ml‐1. 2 Following oral administration of single 50 mg doses of two formulations of trazodone on separate occasions to healthy fasted volunteers, the peak plasma concentration, time to peak concentration, area under the curve, elimination rate constant and half‐life were determined. 3 The two formulations are closely similar and they are considered to have comparable bioavailability.
Comparison of four different β‐adrenoceptor blocking drugs on lymphocyte isoprenaline‐stimulated cyclic AMP production
Authors: Lima DRA , Kilfeather S , Hedges A , Turner P
Published: July 2012

1 The influence of acebutolol, atenolol, pindolol and timolol on human lymphocyte cyclic AMP (cAMP) and its stimulation by isoprenaline in vitro has been studied. 2 Acebutolol and atenolol (10−8 ∐ 10−6M) had no significant influence on lymphocyte cAMP levels or on isoprenaline‐stimulated increase in cAMP. 3 Pindolol and timolol significantly antagonised the effect of isoprenaline, and pA2 values were calculated to be 8.12 and 8.04 respectively. This suggests that β2‐adrenoceptors are involved in this phenomenon. 4 Only pindolol produced a significant increase in lymphocyte cAMP, which is consistent with its partial agonist activity.
Pharmacokinetics of cephradine given intravenously with and without probenecid
Authors: Roberts DH , Kendall MJ , Jack DB , Welling PG
Published: July 2012

1 In the light of questions raised by an earlier oral study (Welling, Dean, Selen, Kendall & Wise, 1979) the influence of probenecid on the pharmacokinetics of intravenously administered cephradine has been investigated. 2 Intravenous administration of cephradine resulted in a bi‐exponential curve and the level of antibiotic after 15 min was significantly greater when subjects received probenecid than when they did not. The influence of probenecid on urinary excretion of cephradine was similar to that observed previously. 3 The increase in serum of cephradine due to probenecid could be accounted for by the decrease in the elimination rate of the antibiotic. These results are discussed in the light of other observations.
The early and late effects of digoxin treatment on the sodium transport, sodium content and Na+K+‐ATPase of erythrocytes
Authors: Cumberbatch M , Zareian K , Davidson C , Morgan DB , Swaminathan R
Published: July 2012

1 Erythrocyte sodium content, sodium transport (ouabain sensitive sodium flux Eos, and ouabain sensitive efflux rate constant ERCos) sodium, potassium activated ouabain sensitive adenosine triphosphatase (Na+K+ATPase) and plasma digoxin were measured in patients during acute digitalisation and in patients who were on long‐term digoxin treatment. 2 In the six patients who were studied during digitalisation, the ERCos and Na+K+ATPase activity decreased and erythrocyte sodium content increased during days 2‐4 of treatment, but there was no change in Eos. 3 In 39 patients on long term digoxin therapy (2‐119 months) the erythrocyte sodium content was normal, but the erythrocyte Na+K+ATPase activity was higher than the control group. When the results from these 39 patients were divided according to the duration of treatment it was found that the erythrocyte sodium content was higher in patients treated for 2‐4 months than in patients treated for longer periods and the erythrocyte Na+K+ATPase activity increased with duration of treatment. In eight patients (duration of treatment > 29 months) in whom ERCos and Eos were measured, ERCos and Eos were higher than the control group. 4 The results suggest that the effects of digoxin on erythrocytes which occur during acute digoxin treatment do not persist in the long term. 5 The possible explanation for the higher ERCos, Eos and Na+K+ATPase activity in patients treated with digoxin for more than 2 months is discussed.
Bioavailability of quinidine in congestive heart failure
Authors: Ueda CT , Dzindzio BS
Published: July 2012

1 The oral bioavailability of quinidine was evaluated in eight patients with moderate to severe congestive heart failure. Each patient was given a 400 mg dose of quinidine gluconate by intravenous infusion and orally in solution. Serial plasma samples and total urine for drug analysis were collected for 24 and 48 h after drug administration, respectively. 2 When compared to control cardiac patients, the rate of quinidine absorption was slower in the heart failure patients. The mean value for the apparent absorption half‐life and time to achieve peak plasma quinidine concentration was 38 ± 18 min and 2.4 ± 1.5 h, respectively. The corresponding values observed in the control subjects were 18 ± 6 min and 1.0 ± 0.6 h. 3 The extent of quinidine absorption when evaluated by the AUC and urinary excretion methods was about 72% of the administered dose in the congestive heart failure patients. This value was similar to the extent of quinidine absorption (approximately 73%) observed in the control subjects. 4 A reduction in the plasma clearance rate and apparent volume of distribution for quinidine was observed in the congestive heart failure patients. 5 When compared with non‐heart failure cardiac patients, the results of this study suggest that patients with congestive heart failure may require smaller oral quinidine dosages to achieve therapeutic drug concentrations in the plasma or serum.
Kinetics of isosorbide dinitrate and relationships to pharmacological effects
Authors: Fung HL , McNiff EF , Ruggirello D , Darke A , Thadani U , Parker JO
Published: July 2012

1 The inter‐relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), from 0‐6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose‐response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.
Direct measurement of chlormethiazole extraction by liver, lung and kidney in man.
Authors: Mather LE , Runciman WB , Ilsley AH , Thomson KR , Goldin AR
Published: July 2012

1 Chlormethiazole was used as a basal sedative for patients undergoing angiographic procedures. 2 Blood samples were drawn opportunistically to examine chlormethiazole extraction across liver, lungs and kidney. 3 Extraction across liver was typically 70‐80% and apparently unrelated to input concentrations. Evidence for extraction across lung and kidney was inconclusive but these could each be approximately 20%. 4 Pharmacokinetics of chlormethiazole derived from compartment models were in accord with previous reports and were characterised by a high total body clearance (1‐1.5 l/min). 5 Postural changes associated with the radiological procedures caused fluctuating blood concentrations which appear as noise in curve fitting procedures. 6 Pharmacokinetic properties derived from compartment theory cannot cope with these perturbations because of the restriction imposed by time averaging (i.e. mean clearances, half‐lives and volumes are produced). Systematic studies of pharmacokinetic properties of perfusion‐limited drugs such as chlormethiazole must be developed in such a way as to allow for independent variation of flow and extraction.
Effect of beta‐adrenergic receptor blockade with propranolol on the response of plasma catecholamines and renin activity to upright tilting in normal subjects.
Authors: Vandongen R , Davidson L , Beilin LJ , Barden AE
Published: July 2012

1 Relationship between plasma catecholamines (measured as noradrenaline and adrenaline) and plasma renin activity (PRA) were examined at rest and during passive head‐up tilting for 30 min in nine normal subjects, before and after treatment with propranolol 160 mg daily for 7 days. 2 Noradrenaline (NA) and adrenaline (A) increased substantially after tilting for 15 min. There were no changes in PRA. After 30 min tilting, NA remained elevated, whereas A had returned to resting levels. A significant increase in PRA was apparent at 30 min. Pulse rate and diastolic blood pressure increased progressively during tilting. Systolic pressure did not change. 3 Treatment with propranolol reduced pulse rate and systolic blood pressure at rest and during tilting. Resting catecholamine concentrations and the response of NA to tilting were unaffected. In contrast, treatment prolonged the A response leading to significantly higher levels after 30 min tilting. Propranolol reduced PRA in six of the nine subjects and prevented the increase with tilting observed before treatment.
A study of the antihypertensive action of xipamide using ambulatory intra‐arterial monitoring.
Authors: Raftery EB , Melville DI , Gould BA , Mann S , Whittington JR
Published: July 2012

1 The antihypertensive activity of the diuretic xipamide has been studied in 18 patients with mild/moderate essential hypertension using the technique of continuous ambulatory intra‐arterial blood pressure recording. Full data from 48 h blood pressure recordings before and after treatment were available from 13 patients. 2 After a mean period of 3 months' treatment with xipamide 20 mg once daily, both systolic and diastolic blood pressure were markedly reduced throughout the whole 24 h day, the reductions of systolic being statistically significant throughout the whole period, and of diastolic for 19 out of the 24 hourly periods measured. There was no postural hypotension seen during treatment and there was a conspicuous lack of side effects. 3 Xipamide would appear to be as effective as many beta‐adrenoceptor blockers but without their side effects and produces a better control of blood pressure throughout the whole day and night.
Nadolol in human serum and breast milk.
Authors: Devlin RG , Duchin KL , Fleiss PM
Published: July 2012

1 Simultaneous serum and milk samples were collected over a 10‐day period from twelve normotensive, lactating subjects who ingested 80 mg nadolol once daily for a period of 5 days. For comparative purposes, serum samples were also collected from seven patients with a history of mild essential hypertension who ingested the same dose of nadolol for a period of 13 days. 2 In lactating subjects, steady‐state serum concentrations of nadolol were attained in 3 days. Milk concentrations of nadolol were much higher than serum concentrations starting on Day 3 and throughout the remainder of the study. The mean (+/‐ s.e. mean) steady‐state levels of nadolol in milk (356.9 +/‐ 40.4 ng/ml) were 4.6 times higher than the mean steady‐state levels in serum (77.3 +/‐ 6.9 ng/ml). 3 In hypertensive patients, the mean serum concentration of nadolol 24 h after the twelfth dose was 40.3 +/‐ 8.2 ng/ml as compared to a mean serum concentration in lactating subjects of 40.7 +/‐ 3.4 ng/ml, 24 h after the fifth dose. Mean serum concentrations in hypertensive patients at 1 and 4 h after the final daily dose were not significantly different from those in lactating subjects. 4 It can be estimated that a 5 kg nursing infant would consume about 2‐7% of the daily adult therapeutic dose of nadolol. The data suggest that caution should be exercised in the use of nadolol in lactating patients.
Metabolism and pharmacokinetics of dothiepin.
Authors: Maguire KP , Burrows GD , Norman TR , Scoggins BA
Published: July 2012

1 Seven healthy volunteers received a single oral dose of 75 mg dothiepin. Plasma concentrations of dothiepin were measured by gas chromatography‐mass fragmentography. 2 The plasma concentrations obtained were fitted to the equation Ct = Ae‐a(t‐tau) + Be‐beta(t‐tau) ‐ Ce‐ka(t‐tau). The mean peak concentration was 47(33‐71) microgram/l at 3(2‐5) h. Mean estimates were as follows: absorption half life 1.2(0.07‐ 3.0) h, distribution half‐life 2.6(1.1‐3.8) h, elimination half‐life 22(14‐40) h, apparent volume of distribution 45(20‐92) l/kg, and oral clearance 1.36(0.88‐1.8) l kg‐1 h‐1. 3 Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7(0.6‐0.8). 4 Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S‐ oxide, two metabolites of dothiepin, were also measured. Dothiepin S‐ oxide was the major metabolic reaching a peak level of 81(34‐150) microgram/l at 5(4‐6) h. In comparison, northiaden reached a peak concentration of only 10 (3‐21) microgram/l at 5 (4‐9) h. The mean half‐ life of elimination of dothiepin S‐oxide was 19 (13‐35) h while that for northiaden was 33 (22‐60) h.
Is the measurement of blood cimetidine levels useful?
Authors: Festen HP , Diemel J , Lamers CB , Van Schaik A , Tangerman A , Van Tongeren JH
Published: July 2012

1 Blood cimetidine levels were measured up to 5 h after oral intake of 200 mg cimetidine with breakfast in 13 duodenal, 5 gastric and 15 anastomotic ulcer patients. 2 There were larger inter individual differences in results. The mean peak blood concentrations was 1.14 +/‐ 0.07 microgram/ml (range 0.54‐1.94 microgram/ml), the mean period during which the blood concentration exceeded 0.5 microgram/ml was 141 +/‐ 11 min (range 23‐306 min) and the mean area under the cimetidine blood concentration curve (AUC) was 166 +/‐ 8 microgram ml‐1 min (range 96‐280 microgram ml‐1 min). Coefficient of variation of these parameters was 33%, 43% and 29% respectively. 3 There were no significant differences in these parameters between non‐operated patients and patients with a partial gastrectomy. 4 In 11 patients restudied after 2 to 5 months blood cimetidine levels proved well reproducible; mean coefficient of variation of peak blood levels was 8.5 +/‐ 2.4%, of time during which blood levels exceeded 0.5 microgram/ml 7.6 +/‐ 2.5% and of the AUC 5.0 +/‐ 1.0%. 5 There was no difference in peak blood levels, duration of blood level exceeding 0.5 microgram/ml and blood cimetidine AUC between 24 patients healed after 4 weeks cimetidine therapy and 9 in whom healing took longer. Likewise, there was no evidence of lower blood cimetidine concentrations in 9 patients who relapsed during maintenance cimetidine treatment compared with 24 who did not relapse.
Long‐term cyclophosphamide treatment in rheumatoid patients: effects on serum sulphydryl levels, technetium index, ESR and clinical response.
Authors: Grimaldi MG
Published: July 2012

1 After 12 months cyclophosphamide administration the serum sulphydryl concentrations increased in all of twelve rheumatoid patients treated, and returned towards the normal range in eleven. 2 A decrease was observed in the technetium index, the erythrocyte sedimentation rate, and joint count. 3 Long‐term cyclophosphamide‐induced serum SH increase may represent a specific change in the process of the rheumatoid disease activity, possibly involving the pathogenic B cells.
Human platelet function as a model for investigating the clinical efficacy of chlorpromazine.
Authors: Youdim MB , Hefez A , Oppenheim B
Published: July 2012

1 Enhancement of platelet aggregation response (PAR) to 5‐ hydroxytryptamine (5‐HT) in some schizophrenic patients receiving chlorpromazine (CPZ) may provide a biological index for the efficacy of this drug. 2 In a double‐blind study 33 schizophrenic patients hospitalized following their first psychotic breakdown were followed up clinically with concurrent assessment of their PAR to 5‐HT. The patients followed a standardized treatment schedule with (CPZ) as the sole antipsychotic medication. 3 Twelve patients (Group A) developed an enhanced biphasic 5‐HT PAR, within 2‐3 weeks and improved clinically by the sixth week. In most cases, the appearance of the enhanced biphasic PAR preceded clinical improvement. Twenty‐one patients (Group B) did not have enhanced biphasic PAR to 5‐HT by the sixteenth week of treatment. However, twelve subjects from this group showed clinical response to CPZ by the end of this period, while the remaining patients did not improve. 4 The enhanced PAR to 5‐HT in Group A discriminated best between good and bad outcome cases when Feighner's research diagnostic criteria were used. We could not confirm the previous reports of platelet aggregation response to dopamine in pre‐ or post‐ chlorpromazine treatment.
Effect of propranolol on the airway response to prostaglandin E2 in normal man.
Authors: Seth RV , Clarke VS , Lewis RA , Tattersfield AE
Published: July 2012

1 The airway response to inhaled prostaglandin E2 (PGE2) and the effect of oral propranolol on this response was studied in eight normal subjects in a double‐blind randomised trial. The airway response was measured as specific airway conductance (sGaw). 2 Inhalation of PGE2 caused retrosternal soreness, coughing and an awareness of mucus production. Despite this, PGE2 caused bronchodilatation and reproducible dose‐response curves were obtained, with a maximum increase in sGaw of 53%. 3 Inhalation of the diluent of PGE2, an ethanol/saline mixture, did not cause irritation nor did it alter sGaw. 4 Prior administration of propranolol 80 mg did not alter baseline sGAW, nor the response to PGE2, indicating that the action of PGE2 in vivo is unaffected by bronchial beta‐adrenoceptor blockade. 5 This technique should be of value in studying bronchodilator prostaglandins and their interaction with other drugs.
Comparison of the in vivo and in vitro rates of formation of the three main oxidative metabolites of antipyrine in man.
Authors: Boobis AR , Brodie MJ , Kahn GC , Toverud EL , Blair IA , Murray S , Davies DS
Published: July 2012

1 The metabolism of antipyrine to its three main oxidative metabolites, 4‐hydroxyantipyrine, 3‐hydroxymethylantipyrine and norphenazone was investigated in vivo and in vitro in separate groups of subjects with normal hepatic function and in the same group of patients with suspected liver disease. 2 The rank order for the rate of formation of the three metabolites of antipyrine was similar in vivo and in vitro. 3 There was no significant correlation between the rates of formation of any pair of antipyrine metabolites either in vivo or in vitro. 4 Despite this there was a significant correlation between the in vivo and in vitro rates for formation of each of the three metabolites in the same group of patients. 5 It is concluded that determination of rates of formation of antipyrine metabolites from their excretion in urine provides an indication of the activity of the enzymes involved in their formation.
Inhibition of antipyrine metabolism by beta‐adrenoceptor antagonists.
Authors: Bax ND , Lennard MS , Tucker GT
Published: July 2012

1 The effects of two beta‐adrenoceptor antagonists (propranolol and metoprolol), and of the beta‐adrenoceptor agonist, terbutaline, on the plasma kinetics of antipyrine were studied in five normal subjects. In addition, the influence of propranolol on the clearance of antipyrine to three of its major metabolites was investigated. 2 At the same level of beta‐adrenoceptor blockade, assessed by lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 37.3 +/‐ 9.9 s.d. % (P less than 0.001) and metoprolol decreased it by 18.0 +/‐ 4.7 s.d. % (P less than 0.01). Terbutaline had no effect on antipyrine clearance. The volume of distribution of antipyrine was unchanged following treatment with all three drugs. 3 Only the metabolic clearance of antipyrine to its 3‐hydroxymethyl product was impaired to a statistically significant degree by propranolol. However, four of the five subjects also showed impaired clearance to 4‐hydroxyantipyrine and three of the five to norantipyrine after propranolol treatment. In four of the five subjects propranolol lowered the renal clearance of antipyrine. 4 Inhibition of the metabolism of antipyrine by beta‐ adrenoceptor antagonists may be related to their lipid‐solubility and extent of metabolism and is independent of their effect on beta‐ adrenoreceptors.
Cimetidine increases steady state plasma levels of propranolol.
Authors: Reimann IW , Klotz U , Siems B , Frolich J
Published: July 2012

1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the study) the mean (Css) and minimal (Css min) propranolol steady state plasma levels increased significantly from 24.1 +/‐ 14.9 ng/ml (mean +/‐ s.d.) to 39.2 +/‐ 27.7 ng/ml (P = 0.01) and from 14.8 +/‐ 9.3 ng/ml to 27.1 +/‐ 21.2 ng/ml (P = 0.03), respectively. The apparent oral clearance (Clo) was reduced from 6.7 +/‐ 4.3 l/min to 4.6 +/‐ 3.11/min (P = 0.006). 3 A prolongation of cimetidine administration to 5 days (day 13 of the study) intensified this effect significantly (P = 0.02): Css of propranolol was elevated from 23.2 +/‐ 14.4 ng/ml to 44.9 +/‐ 26.7 ng/ml (P = 0.003); Css min was increased from 14.1 +/‐ 10.2 ng/ml to 28.4 +/‐ 17.9 ng/ml (P = 0.02) while Clo decreased from 6.9 +/‐ 4.1 1/min to 3.3 +/‐ 1.61/min (P = 0.006). 4 We conclude that the drug interaction between propranolol and cimetidine leads to significant elevations of propranolol steady state plasma concentrations which may cause a clinically relevant enhancement of the effect of a given dosage. This requires careful observation of patients under concomitant treatment with propranolol and cimetidine.
Lack of effect of ranitidine on warfarin action.
Authors: Serlin MJ , Sibeon RG , Breckenridge AM
Published: July 2012

1 In five volunteers taking daily subtherapeutic doses of warfarin the addition of ranitidine 200 mg twice daily for 14 days did not affect prothrombin time or plasma warfarin concentration. 2 Ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat. 3 Ranitidine had no effect on pentobarbitone sleeping time in the rat whereas cimetidine significantly prolonged the sleeping time. 4 The interaction between cimetidine and oral anticoagulants is unrelated to histamine H2‐receptor antagonism.
The effect of frusemide and piretanide on the renal clearance of gentamicin in man.
Authors: Whiting PH , Barber HE , Petersen J
Published: July 2012

1 Gentamicin alone (dose 1 mg/kg) or in combination with frusemide (dose 0.25 mg/kg) or piretanide (dose 0.1 mg/kg) was administered intravenously to six healthy male volunteers. 2 Blood samples were collected at various times for 24 h and urine for up to 48 h. 3 Both diuretics increased the renal clearance of gentamicin during the period of the diuresis, without influencing either the glomerular filtration rate or the distribution of the antibiotic. 4 The results are discussed in relation to gentamicin‐induced nephrotoxicity.
The effect of variations in urinary pH on the pharmacokinetics of diethylcarbamazine.
Authors: Edwards G , Breckenridge AM , Adjepon‐Yamoah KK , Orme ML , Ward SA
Published: July 2012

1 The partitioning of diethylcarbamazine (DEC) between octan‐1‐ol and aqueous buffer was shown to be dependent upon the pH of the buffer. 2 Buccal absorption of DEC in five subjects was shown to increase with increasing pH. 3 In view of these findings, the disposition of DEC was investigated in the same five subjects following the oral administration of 50 mg DEC citrate on two occasions. 4 The elimination half‐life (T1/2) of DEC and the area under the plasma concentration v time curve (AUC) were significantly increased when an alkaline urinary pH was maintained compared with the values of these parameters obtained on a second occasion when an acidic urinary pH was maintained. Renal clearance and total urinary excretion of DEC were significantly less at alkaline urinary pH than under acidic conditions. 5 The clinical significance of these observations is discussed both with respect to dose modification under conditions of changing urinary pH and the possibility of the manipulation of urinary pH in order to produce more effective dosage regimens.
Effect of long‐term treatment with sodium valproate on gonadotrophin and prolactin secretion in paediatric patients.
Authors: Masala A , Meloni T , Alagna S , Rovasio PP , Rassu S , Mele G , Franca V
Published: July 2012

1 Luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin levels were measured in twenty paediatric patients receiving sodium valproate (30 mg/kg body weight daily) and in ten control subjects under control conditions and following LRH‐TRH administration. In addition, baseline GH levels were measured in the two groups. 2 No significant differences were observed between the basal and stimulated hormone levels in the two groups. Although sodium valproate may act as anticonvulsant by increasing GABA levels in the central nervous system, the present data indicate that a central GABAergic pathway is probably not involved in the control of gonadotrophin and prolactin secretion.
Relationship between the transplacental gradients of bupivacaine and alpha 1‐acid glycoprotein.
Authors: Petersen MC , Moore RG , Nation RL , McMeniman W
Published: July 2012

1 The binding of bupivacaine (400 ng/ml) to isolated alpha 1‐acid glycoprotein was studied at two protein concentrations. At 20 mg/100 ml the extent of bupivacaine binding was 31.0 +/‐ 1.8% (mean +/‐ s.d., n = 4), and at a protein concentration of 60 mg/100 ml binding of bupivacaine was 85.8 +/‐ 1.5% (n = 4). 2 Bupivacaine and alpha 1‐acid glycoprotein concentrations were measured in plasma samples collected from a maternal peripheral vein and the umbilical vein at delivery (n = 23). The ratio of the foetal:maternal bupivacaine concentrations ranged from 0.17 to 0.52, while the foetal:maternal ration for alpha 1‐acid glycoprotein concentrations ranged from 0.20 to 0.96. A positive relationship emerged between the two ratios (P less than 0.01). 3 The alpha 1‐acid glycoprotein concentration gradient across the placenta, and interindividual variability in the gradient appear to contribute to the low and variable transplacental bupivacaine concentration ratio observed.
An oral buprenorphine and paracetamol combination compared with paracetamol alone: a single dose double‐blind postoperative study.
Authors: Bullingham RE , McQuay HJ , Moore RA , Weir L
Published: July 2012

1 An oral combination of buprenorphine and paracetamol was compared with paracetamol alone in a single dose, double‐blind postoperative study. One hundred and twenty patients undergoing elective minor orthopaedic operations were allocated to four groups of 30 patients. The four treatments were 1,1.5 or 2 mg of buprenorphine with paracetamol 1,000 mg or paracetamol 1,000 mg alone. 2 There were no significant differences between the groups in analgesia measured by the observer over the 6 h period of direct observations. The oral opiate produced a significant increase in duration of analgesia beyond the 6 h study period. A significant increase in side‐effects was seen only at the highest buprenorphine dose compared with paracetamol. 3 The problems of trial design for analgesic combinations are considered. Drug mixtures create additional complexities which decrease the certainty of the conclusion that no real benefits result from such mixtures.
RHC 3659: a new orally active angiotensin converting enzyme inhibitor in normal volunteers.
Authors: Burnier M , Turini GA , Brunner HR , Porchet M , Kruithof D , Vukovich RA , Gavras H
Published: July 2012

1 The new converting enzyme inhibitor RHC 3659 was tested in 15 male volunteers. The study consisted of two parts: first, the ability of a single oral dose (5, 10, 20, 40 or 80 mg) to inhibit the pressor response to exogenous angiotensin I was tested with blood pressure and heart rate monitored continuously through an intraarterial catheter. A dose‐related shift to the right of the pressor response curve to angiotensin I was observed with a peak occurring within 0.5 to 1 h. The pressor response to angiotensin II was unaffected. 2 In the second part, plasma renin and converting enzyme activity, angiotensin II and aldosterone were measured serially before and up to 8 h after administration of a single oral dose of RHC 3659. As expected. plasma angiotensin II and aldosterone fell within 30 min while plasma renin activity increased. Plasma converting enzyme activity was suppressed at 0.5 h in a dose‐related manner with levels still below 30% of control 4 h following 80 mg of the inhibitor. 3 However, in vitro the enzyme‐ inhibitor complex seemed quited fragile since during storage of the plasma samples at −20 degrees C, converting enzyme activity increased significantly already within days (P less than 0.001, n = 28) and continued to rise for more than 2 months. This fragility may explain the seemingly lower potency of RHC 3659 when compared to captopril. No side effects were observed.
Systolic time interval v heart rate regression equations using atropine: reproducibility studies.
Authors: Kelman AW , Sumner DJ , Whiting B
Published: July 2012

1. Systolic time intervals (STI) were recorded in six normal male subjects over a period of 3 weeks. On one day per week, each subject received incremental doses of atropine intravenously to increase heart rate, allowing the determination of individual STI v HR regression equations. On the other days STI were recorded with the subjects resting, in the supine position. 2. There were highly significant regression relationships between heart rate and both LVET and QS2, but not between heart rate and PEP. 3. The regression relationships showed little intra‐subject variability, but a large degree of inter‐subject variability: they proved adequate to correct the STI for the daily fluctuations in heart rate. 4. Administration of small doses of atropine intravenously provides a satisfactory and convenient method of deriving individual STI v HR regression equations which can be applied over a period of weeks.
Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11‐epoxide in epileptic patients.
Authors: MacKichan JJ , Duffner PK , Cohen ME
Published: July 2012

1. The relationships between saliva, free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine 10,11‐epoxide (CBZ‐EP) were studied in 24 chronically medicated epileptic patients. Four patients were taking CBZ alone, while 20 were taking one or more additional anticonvulsant drugs. 2. The free fraction of CBZ in plasma ranged from 0.19 to 0.33 (mean 0.24) while the saliva:plasma (S:P) concentration ratios ranged from 0.20 to 0.35 (mean 0.27). The free fraction of CBZ‐EP in plasma ranged from 0.16 to 0.50 (mean 0.32), while the S:P ratios ranged from 0.14 to 0.70 (mean, 0.43). The plasma protein binding and S:P ratios of these compounds appeared to be independent of age, sampling time and concurrently administered anticonvulsant drugs. 3. Significant linear relationships between saliva and total plasma concentrations and between saliva and free plasma concentrations were observed for both compounds (P less than 0.001). However, salivary concentrations of CBZ and CBZ‐EP were significantly more reliable as predictors of their respective free plasma concentrations than of their respective total plasma concentrations (P less than 0.01). 4. It is concluded that measurement of CBZ and CBZ‐EP in the saliva of chronically medicated epileptic patients provides a more reliable estimate of the pharmacodynamically active, free concentrations of these compounds in plasma.
Bronchial and cardiac beta‐adrenoceptor blockade‐a comparison of atenolol, acebutolol and labetalol.
Authors: Gribbin HR , Mackay AD , Baldwin CJ , Tattersfield AE
Published: July 2012

Bronchial and cardiac beta‐adrenoceptor blockade have been compared in six normal subjects after three beta‐adrenoceptor antagonists. Single and double doses of atenolol (50 and 100 mg), acebutolol (100 and 200 mg) and labetalolol (150 and 300 mg) were studied on separate occasions. 2 Salbutamol airway dose‐response curves were obtained by measuring the airway response as the change in specific airway conductance (sGaw) after increasing doses of inhaled salbutamol. Bronchial beta‐adrenoceptor blockade was assessed after each drug as the dose of salbutamol needed to cause a 50% increase in sGaw (sGaw D50). 3 Cardiac beta‐adrenoceptor blockade was assessed after the same doses of each beta‐adrenoceptor antagonist, by measuring the percentage reduction in exercise heart rate from control, after exercise for 5 min at 70% of the subject's maximum work rate. 4 Atenolol 50 and 100 mg caused least bronchial beta‐adrenoceptor blockade and the greatest reduction in exercise heart rate. 5 Acebutolol 100 and 200 mg and labetalol 150 and 300 mg produced more bronchial beta‐adrenoceptor blockade than atenolol. 6 With this approach new beta‐adrenoceptor antagonists can be assessed without putting asthmatic patients at risk.