bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered adrenoceptor responsiveness during adrenaline infusion but not during mental stress: differences between receptor subtypes and tissues.
Authors: Larsson PT , Martinsson A , Olsson G , Hjemdahl P
Published: July 2012

1. Effects of 3 h infusions of adrenaline (0.4 nmol kg‐1 min‐1) or placebo and of mental stress evoked by a colour word test (CWT) on adrenergic receptor function were investigated in healthy men. Responses of heart rate, blood pressure, plasma catecholamines, plasma cyclic AMP and plasma free fatty acids (FFA) were evaluated during infusions and CWT. In vitro beta 2‐adrenoceptor numbers [(125I]‐HYP binding) and function (isoprenaline induced cyclic AMP accumulation) were studied on lymphocytes in all experiments. alpha 2‐adrenoceptor binding [(3H]‐yohimbine and adrenaline) to intact platelets was evaluated in the infusion experiments only. 2. Placebo infusion evoked no major alterations of any parameter. 3. Adrenaline infusion raised venous plasma adrenaline levels to 4‐5 nmol l‐1, increased heart rate by 14 +/‐ 3 beats min‐1 and plasma cyclic AMP by 17 +/‐ 3 nmol l‐1, and decreased diastolic blood pressure by 15 +/‐ 5 mm Hg. These responses persisted throughout the infusion. Plasma FFA levels, on the other hand, increased at 30 min of infusion (from 236 +/‐ 44 to 717 +/‐ 92 mumol l‐1) and returned to basal levels after 3 h of infusion. 4. In vitro, lymphocytes showed increased beta 2‐responsiveness after 30 min of adrenaline infusion (delta cyclic AMP increased from 1.86 +/‐ 0.24 to 3.06 +/‐ 0.58 pmol/10(6) cells), but a decreased response (0.47 +/‐ 0.10 pmol/10(6) cells) after 3 h of infusion. [125I]‐HYP binding to lymphocyte membranes showed a three‐fold increase of Bmax at 30 min of adrenaline infusion followed by a return to basal values after 3 h of infusion. [125I]‐HYP binding reflected the functional responsiveness of the lymphocytes in vitro poorly. alpha 2‐adrenoceptors on platelets were not altered with regard to Bmax or Kd for [3H]‐yohimbine binding or Ki for adrenaline displacement of [3H]‐yohimbine binding. 5. CWT evoked marked circulatory changes, a four‐fold increase in plasma adrenaline and a 60% increase in beta 2‐adrenoceptor binding sites without changes in functional responsiveness of the lymphocytes. 6. We conclude that exposure to high physiological levels of adrenaline in vivo alters lymphocyte beta‐adrenoceptor responsiveness in a biphasic manner, with an early increase followed by a later decrease, but that most beta‐adrenoceptor mediated responses to adrenaline in vivo remain intact. Lymphocyte alterations may reflect recruitment of cells into the circulation during sympathoadrenal stimulation. Platelet alpha 2‐ adrenoceptors are apparently not easily subjected to agonist induced dynamic receptor regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Bronchodilator action of inhaled fenoterol and ipratropium in normal subjects: a teaching exercise for medical students.
Authors: Taylor RG , Maclagan J , Cook DG
Published: July 2012

1. A pharmacology practical class for preclinical medical students was designed as a placebo‐controlled, double‐blind trial of two bronchodilator drugs. 2. Fenoterol hydrobromide (800 micrograms), ipratropium bromide (80 micrograms) and placebo (propellant only) were given by metered dose inhaler to 79 non‐asthmatic volunteers. Their effects on FEV1, heart rate and tremor (assessed by the time taken to thread five sewing needles) were compared. 3. Both drugs caused a significant increase in FEV1: the largest group mean increase was 77 ml, recorded 15 min after fenoterol, and 103 ml, recorded 60 min after ipratropium. 4. Fenoterol also caused a mean increase of 8.7 beats min‐ 1 in heart rate, 5 min after inhalation. This effect was still apparent after 60 min. 5. Fenoterol appeared to prolong needle threading time in some individuals. 6. In subjects who inhaled fenoterol, there were no correlations between the increase in FEV1, the increase in heart rate, or the development of tremor. 7. It is concluded that inhaled fenoterol and ipratropium both cause bronchodilation in normal subjects. Systemic absorption of fenoterol is indicated by the rapid increase in heart rate. The bronchodilator effect of ipratropium suggests that resting airway calibre is governed partly by parasympathetic tone in normal subjects. 8. The bronchodilator and systemic effects of these drugs can be used to demonstrate pharmacological, therapeutic and statistical principles to medical students.
Lithium inhibits human sperm motility in vitro.
Authors: Raoof NT , Pearson RM , Turner P
Published: July 2012

Lithium is a widely prescribed drug used for the treatment of bipolar affective illness. Previous reports on its effects on sperm motility and male fertility are conflicting. The effect of lithium on human sperm motility was examined in vitro using the modified transmembrane migration method. This technique takes account of the dilution of lithium that occurs during the incubation. Lithium inhibits human sperm motility in vitro in concentrations comparable with those reported to be achieved in semen after oral administration.
The pharmacokinetics of xamoterol in liver disease.
Authors: Nicholls DP , Taggart AJ , McCann JP , Bastain W , Shanks RG
Published: July 2012

The pharmacokinetics of xamoterol, a beta 1‐adrenoceptor partial agonist, have been studied in patients with liver disease and a group of age‐ and sex‐matched normal controls. No significant differences were observed after the oral administration of xamoterol 200 mg. The low bioavailability of xamoterol was confirmed (6.1% in patients, 6.9% in controls). After i.v. xamoterol 0.2 mg kg‐1, no significant differences between the groups were observed. A small increase in the terminal plasma elimination half‐life (t1/2) was observed in patients when compared with controls (15.3 +/‐ 6.4 vs 8.4 +/‐ 2.8 h, mean +/‐ s.d., P = 0.08). Renal clearance accounted for about 50% of total clearance in patients and about 30% in controls. It is suggested that in patients with heart failure, hepatic dysfunction would probably not influence xamoterol disposition.
The bioavailability of intranasal lignocaine.
Authors: Scavone JM , Greenblatt DJ , Fraser DG
Published: July 2012

Six healthy males participated in a single‐dose two‐way crossover study of the bioavailability of intranasal vs intravenous administration of lignocaine (lidocaine) hydrochloride. Subjects received a single 100 mg dose of lignocaine HCl intranasally from a gel preparation on one occasion and intravenously by a 3 min infusion on another occasion. Multiple plasma samples drawn during 8 h following each dose were analysed for lignocaine by gas chromatography using nitrogen phosphorous detection. The mean (+/‐ s.e. mean) peak plasma concentration of lignocaine following intranasal administration was 144 +/‐ 48 ng ml‐1, and the time to peak was 0.92 +/‐ 0.12 h. The mean AUC values for intranasal and intravenous routes were 421 +/‐ 121 vs 1616 +/‐ 30 ng ml‐1 h, respectively, and the mean bioavailability of the intranasal formulation (AUC ratio) was 0.26 +/‐ 0.08. In all subjects, intranasal absorption was less than 50% complete, and bioavailability varied from 0.05 to 0.48 between individuals. Thus lignocaine is variably and incompletely absorbed when administered by the intranasal route, in the dosage formulation and according to the method used in this study.
The pharmacology of xamoterol: a basis for modulation of the autonomic control of the heart.
Authors: Snow HM
Published: July 2012

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta‐ adrenoceptor partial agonist which is of benefit in the chronic treatment of heart failure (e.g. The German and Austrian Xamoterol Study Group, 1988). These results contrast with those obtained with other beta‐adrenoceptor drugs, prenalterol and pirbuterol which were unsuccessful on chronic dosing (Currie et al., 1984; Glover et al., 1985). 2. Unlike prenalterol and pirbuterol, xamoterol has no significant agonist activity at the beta 2‐adrenoceptor and has shown no tachyphylaxis in animals or man. 3. The overall action of xamoterol is to modulate sympathetic control of the heart such that at rest and at low levels of exercise the heart receives inotropic support whilst during more severe exercise, heart rate is reduced. In patients with left ventricular dysfunction these effects lead to an improvement in the relation between filling pressure and cardiac output at all levels of activity such that a given cardiac output is achieved with a lower filling pressure. It is suggested that this alteration in the pattern of cardiac activity over a long period of time results in a beneficial adaptation of the myocardium and is a possible explanation of the observed clinical improvement.
Xamoterol, a beta 1‐adrenoceptor partial agonist: review of the clinical efficacy in heart failure.
Authors: Marlow HF
Published: July 2012

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587), a beta 1‐ adrenoceptor partial agonist, improves both systolic and diastolic function in heart failure patients. 2. Double‐blind, randomised studies comparing xamoterol with placebo showed that the beneficial haemodynamic effects of xamoterol produced significant improvements in exercise capacity and symptoms in patients with mild to moderate heart failure. These studies formed the basis for a large European multicentre study programme which recruited over 1000 patients, randomised to xamoterol (200 mg twice daily, n = 617), digoxin (0.125 mg twice daily, n = 135) or placebo (n = 300) for 3 months. 3. Efficacy was assessed by measuring exercise capacity and symptoms. The xamoterol group improved exercise capacity by 37% compared with an 18% improvement in the placebo group. Differences in the symptom scores measured by visual analogue scales and Likert scores indicated significant improvements by xamoterol in the cardinal symptoms of heart failure, dyspnoea and fatigue. 4. Analyses of data from subsets of patients in the study showed that elderly patients, patients on no other heart failure therapy and patients with cardiomegaly all had similar improvements in exercise and symptoms to those seen in the whole study population. In the subset which included digoxin treatment, xamoterol produced significantly greater improvements in exercise capacity than digoxin (33% vs 17%, P less than 0.05) and was associated with fewer side‐effects. 5. Xamoterol is therefore a promising addition to heart failure therapies currently available.
Focus on diastolic dysfunction: a new approach to heart failure therapy.
Authors: Pouleur H , Hanet C , Gurne O , Rousseau MF
Published: July 2012

1. Although heart failure is commonly associated with depressed systolic function, there is increasing evidence that impaired diastolic performance is also universally present and might be a key determinant of symptoms, physical capacity and even survival in some subsets of patients. 2. Reduced diastolic distensibility increases cardiac filling pressure not only at rest, but even more during exercise when diastolic filling time is reduced. The increases in filling pressure and diastolic wall stress lead to pulmonary congestion and subendocardial ischaemia, it also triggers myocardial hypertrophy and a detrimental remodelling of the ventricular cavity. Perhaps even more importantly, impaired ventricular distensibility limits the use of the Frank‐ Starling mechanism, impairing systolic pump function and cardiac output adaptation during exercise. Therapies able to improve the distensibility of the ventricle are, therefore, desirable in heart failure. 3. Nitrates, angiotensin converting enzyme (ACE) inhibitors and diuretics may indirectly increase left ventricular chamber compliance by their effects on the right side of the heart. Cardiac glycosides do not improve myocardial relaxation and may even cause diastolic contracture at toxic doses. The new beta 1‐adrenoceptor partial agonist, xamoterol, on the other hand, consistently lowers left ventricular filling pressure at rest and during exercise, and produces an increase in left ventricular dynamic compliance through the direct lusitropic effect of beta 1‐adrenoceptor stimulation. These beneficial effects are maintained during prolonged therapy and also appear sufficient to slow the remodelling of the ventricular cavity. The improvement in symptoms and in exercise tolerance observed during xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) therapy might, therefore, be related to the improvement in left ventricular diastolic distensibility induced by this drug.
Long‐term studies with xamoterol in heart failure.
Authors: Waller DG
Published: July 2012

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta 1‐ adrenoceptor partial agonist which, unlike full beta‐adrenoceptor agonists, does not down‐regulate beta‐adrenoceptors in the rat ventricle during chronic administration. 2. Improvements in myocardial performance have been demonstrated following acute administration of xamoterol to patients with mild or moderate heart failure, and these are sustained during at least 1 year of continued treatment. 3. Exercise duration is increased by xamoterol in patients with left ventricular dysfunction and benefit is still apparent after at least 1 year of therapy. 4. Despite sustained cardiac stimulation, xamoterol does not appear to affect adversely mortality in patients with mild or moderate heart failure. 5. Few adverse events directly attributable to xamoterol were reported during 3 month efficacy studies in more than 600 patients, and the laboratory safety profile over 1 year of treatment is good. 6. Xamoterol is a promising, well‐tolerated addition to established therapies for chronic mild or moderate heart failure.
The effect of age and renal impairment on the pharmacokinetics of xamoterol.
Authors: Bastain W , Marlow HF
Published: July 2012

The effects of age and renal function on the pharmacokinetics and plasma concentrations of xamoterol were examined. Peak and steady state concentrations were higher in older patients, but this was due to deterioration of renal function rather than to age itself. The dose of xamoterol only need be reduced in the elderly if there is evidence of impaired renal function.
Xamoterol in mild to moderate heart failure: a subgroup analysis of patients with cardiomegaly but no concomitant angina pectoris. The European 'Corwin' Study Group.
Authors: Bastain W , Marlow HF
Published: July 2012

Xamoterol has been shown in large, double‐blind studies to produce benefit in patients with heart failure. Ischaemic heart disease is the commonest cause of heart failure in the Western World and many patients with heart failure also have angina pectoris (Califf et al., 1982). In view of the known anti‐ischaemic effects of xamoterol, we analysed the results of a subgroup of 269 patients with heart failure but without chest pain as a limiting factor on exercise to compare the efficacy of xamoterol in such patients with that of the total group. There were no differences in exercise heart rate, exercise tolerance and symptoms in patients without chest pain compared with the total group. Xamoterol is probably, therefore, acting through myocardial mechanisms other than an anti‐ischaemic effect.
Effect of beta‐adrenoceptor agents on the blood flow in carotid arteries in normal volunteers.
Authors: Fitzgerald DE , Harry JD
Published: July 2012

The effects on carotid artery blood flow of atenolol (a selective beta 1‐adrenoceptor antagonist) and xamoterol (a beta 1‐adrenoceptor partial agonist with 43% agonist activity) were measured using a Doppler technique in eight healthy volunteers. Atenolol produced a decrease in blood pressure and blood velocity flow, and tended to reduce volume flow. In contrast, there were no changes with xamoterol or placebo. Beta 1‐adrenoceptor blockade may reduce cerebral blood flow but the partial agonist xamoterol does not appear to reduce carotid blood flow.
The effects of age, sex and treatment with xamoterol on exercise capacity in patients with heart failure.
Authors: France LA , Green FL , Snow HM
Published: July 2012

The influence of age, sex and xamoterol treatment on exercise capacity has been investigated in 705 heart failure patients who took part in a multicentre, placebo‐controlled study. Regression analysis suggests that although less than 20% of the total variation in exercise capacity between patients is explained by these factors, useful information may be gained by taking them into account. Exercise capacity declines with age, more rapidly in males than in females; the benefits of xamoterol are independent of age and sex. This approach demonstrates that exercise testing is a sensitive indicator of physical performance and allows the effects of treatment to be seen in context.
The cardiovascular pharmacology of xamoterol, cicloprolol, prenalterol and pindolol in the anaesthetised dog.
Authors: Hadfield SE , Slee SJ , Snow HM
Published: July 2012

An anaesthetised dog preparation was used to examine the pharmacological profiles of xamoterol, cicloprolol, prenalterol and pindolol. The effects of these agents on heart rate and hind limb perfusion pressure revealed that xamoterol is highly cardioselective and has no significant agonist activity at beta 2‐receptors and no membrane stabilising effect. These pharmacological properties are not complicated by the formation of active metabolites and may explain the clinical benefits in the long‐term treatment of heart failure.
Estimation of regional metabolism and production of angiotensins in hypertensive subjects.
Authors: Schalekamp MA , Admiraal PJ , Derkx FH
Published: July 2012

1. We attempted to collect information on the metabolism and production of angiotensins (ANG) in different vascular beds in humans by constant i.v. infusion of mono‐iodinated [125I]‐ANG I into subjects with essential hypertension, at the time of renal vein catheterization as part of the diagnostic work‐up for renovascular hypertension. 2. Blood samples were taken from the aorta and the renal, antecubital, femoral and hepatic veins. ANG I, ANG II, [125I]‐ANG I and [125I]‐ANG II were extracted from plasma, separated by h.p.l.c. and quantitated by radio‐ immunoassay or gamma counting. 3. Our studies so far are restricted to subjects on captopril 50 mg twice daily. Under ACE inhibition (4‐6 h after dosing of captopril) no differences in elimination half‐life and regional extraction were found between infused [125I]‐ANG and unlabelled ANG I. Extraction of arterially delivered [125I]‐ANG I was 80% in the kidney, 45% in the forearm, 58% in the leg and 95% in the hepato‐mesenteric vascular bed. 4. Measurements of arterial and venous [125I]‐ANG II levels indicated that [125I]‐ANG I‐II conversion had occurred in the cardio‐pulmonary vascular bed. 5. ANG I production in the hepato‐mesenteric region could be largely accounted for by the renin activity of circulating plasma, but in kidney and limbs only 20‐ 30% of regionally produced ANG I could be accounted for by plasma renin activity. 6. Thus, a major fraction of regionally produced ANG I appears to be formed locally, i.e. not in circulating plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of angiotensin converting enzyme inhibitors.
Authors: Burnier M , Waeber B , Nussberger J , Brunner HR
Published: July 2012

1. The pharmacokinetics of most ACE inhibitors have been evaluated indirectly by the measurements of plasma ACE activity and circulating levels of angiotensin I and II. 2. Although plasma ACE activity is very useful to study the degree and the time‐course of ACE inhibition, one has to be aware that very different results can be obtained depending on the substrate employed in the assay. It is therefore impossible to compare the results of different inhibitors unless an identical methodology is used. 3. A clear dissociation between plasma angiotensin II levels and the antihypertensive effects of ACE inhibitors has been reported. This observation is in part linked to problems with the measurement of angiotensin II. New methods of determination of plasma angiotensin II have now allowed demonstration of the complete disappearance of plasma angiotensin II following acute ACE inhibition. During chronic treatment, however, angiotensin II generation is effectively blocked only during part of the day, but blood pressure remains controlled permanently. 4. Among the different pharmacokinetic characteristics of ACE inhibitors presently available, the route of excretion and to a lesser degree the half‐life appear to be the most clinically relevant. However, the importance of the ability of ACE inhibitors to inhibit tissue renin‐angiotensin systems remains to be defined.
Angiotensin converting enzyme inhibition and cerebral circulation‐a review.
Authors: Waldemar G , Paulson OB
Published: July 2012

1. The identification of a vascular wall renin angiotensin system and of angiotensin converting enzyme on the luminal surface of the endothelium in many tissues, including the brain, has stimulated research on the influence of the renin angiotensin system on regional blood flows. 2. In experimental studies inhibition of the angiotensin converting enzyme shifts the limits of cerebral blood flow autoregulation towards lower blood pressure values. 3. In patients with chronic arterial hypertension and in patients with chronic heart failure cerebral blood flow is not changed by acute or chronic angiotensin converting enzyme inhibition, despite in some cases pronounced reductions in the mean arterial blood pressure. Angiotensin converting enzyme inhibition does not change ischaemic regional cerebral blood flow in acute stroke. 4. It is concluded that following angiotensin converting inhibition cerebral blood flow is maintained at an unchanged level. The mechanism may include inhibition of locally produced angiotensin II leading to a selective dilation of larger cerebral arteries with a compensatory constriction of the smaller cerebral arteries.
The effect of roxatidine acetate and cimetidine on hepatic drug clearance assessed by simultaneous administration of three model substrates.
Authors: Tanaka E. , Nakamura K.
Published: July 2012

The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half‐life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3‐hydroxymethyl‐3‐nor‐antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance.
Divided‐dose kinetics of mefloquine in man.
Authors: Franssen G. , Rouveix B. , Lebras J. , Bauchet J. , Verdier F. , Michon C. , Bricaire F.
Published: July 2012

The kinetics of mefloquine was investigated following oral divided‐ doses in 10 healthy Caucasian volunteers. They received 500 or 750 mg followed by 500 mg 8 h later. Unchanged mefloquine (M) and its carboxylic acid metabolite (MM) were measured in whole blood and plasma for 50 days by h.p.l.c. Maximum blood and plasma M concentrations of 1872 +/‐ 362 ng ml‐1 (mean +/‐ s.d.) and 1900 +/‐ 434 ng ml‐1, respectively, were found within 6‐10 h after the second dose. The terminal plasma elimination half‐life was 20.1 +/‐ 3.7 days (mean +/‐ s.d.) and the oral clearance was 22.3 +/‐ 6.7 ml h‐1 kg‐1 (mean +/‐ s.d.). Plasma concentrations of MM exceeded those of M by 2‐3 fold within 2 days. The whole blood concentration of MM was lower than that in plasma but also exceeded the whole blood concentration of M.
Co‐administration of ciprofloxacin and cyclosporin: lack of evidence for a pharmacokinetic interaction.
Authors: Tan KK , Trull AK , Shawket S.
Published: July 2012

Ciprofloxacin is widely reported to lower theophylline clearance in patients. Since cyclosporin and theophylline are metabolized by cytochrome P‐450 enzymes in the human liver, we investigated whether ciprofloxacin could alter the pharmacokinetics of cyclosporin in healthy volunteers. There was no significant difference (P greater than 0.05) in the pharmacokinetic parameters estimated for cyclosporin without and during ciprofloxacin administration. The results of the present study suggest that ciprofloxacin is unlikely to affect the pharmacokinetics of cyclosporin to a clinically important extent at a dosage of 500 mg twice a day.
Effect of diclofenac on prostaglandin E and hyaluronic acid production by human synovial fibroblasts stimulated with interleukin‐1.
Authors: Meyer FA , Yaron I. , Mashiah V. , Yaron M.
Published: July 2012

Cultured human synovial fibroblasts were stimulated with human recombinant interleukin 1 beta to overproduce prostaglandin E (PGE) and hyaluronic acid (HA). Diclofenac, indomethacin and hydrocortisone inhibited stimulation of PGE production. Half‐maximal inhibition occurred at 1.10 x 10(‐9), 2.79 x 10(‐8) and at 5.52 x 10(‐8) M, respectively. Diclofenac or indomethacin had no effect on HA production, while hydrocortisone had an inhibitory effect (half‐maximal inhibition at 2.76 x 10(‐7) M). This model could be a useful in vitro indicator for the in vivo pharmacological actions of anti‐inflammatory drugs.
Pharmacokinetics of quinine in African children suffering from kwashiorkor.
Authors: Salako LA , Sowunmi A. , Akinbami FO
Published: July 2012

The pharmacokinetics of quinine were studied in seven normal African children and in six African children suffering from kwashiorkor, after an oral dose of 10 mg kg‐1 of quinine hydrochloride. The two groups were similar in age but the children with kwashiorkor weighed significantly less than the control children (P less than 0.001). The children with kwashiorkor further differed from the control children in having significantly lower packed cell volume (P less than 0.001), total plasma protein and plasma albumin (P less than 0.001), and higher serum SGOT (P less than 0.05). The apparent absorption half‐life was significantly longer in kwashiorkor than in controls (P less than 0.05). Similarly, the Cmax was significantly lower (P less than 0.01) in kwashiorkor than in controls. Quinine was eliminated more slowly in children with kwashiorkor, the elimination half‐life being significantly longer (P less than 0.001) and the oral clearance significantly less (P less than 0.001) than in controls. It is concluded that kwashiorkor significantly affects the pharmacokinetics of quinine, and that the effect may be due to the pathological changes in the intestine and liver in this condition.
Prediction of creatinine clearance from plasma creatinine: comparison of five formulae.
Authors: Robertshaw M. , Lai KN , Swaminathan R.
Published: July 2012

1. Glomerular filtration rate is commonly assessed by measurement of endogenous creatinine clearance (CLcr). Several formulae have been described to calculate CLcr from plasma creatinine and we have evaluated the effectiveness of five formulae in 95 healthy subjects (17 F and 78 M, 20‐25 years) and in 72 patients attending a renal clinic (48F and 24 M, 14‐69 years). Endogenous CLcr was measured and the CLcr was also estimated by five formulae. 2. In healthy subjects CLcr calculated by the formulae of Cockcroft & Gault (1976) and Mawer et al. (1972) gave higher correlation coefficients than the other three formulae. 3. When all of the subjects with a wide range of CLcr (3.1‐ 164) were considered all formulae gave good correlations, but the formula of Cockcroft & Gault (1976) gave the best estimate.
Population pharmacokinetics of tobramycin.
Authors: Aarons L. , Vozeh S. , Wenk M. , Weiss P. , Follath F.
Published: July 2012

1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two‐compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h‐1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/‐ 0.002 x CLcr (ml min‐1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/‐ 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half‐life of tobramycin, 26.6 +/‐ 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.
A double‐blind dose ranging study of BRL 24924 and metoclopramide on lower oesophageal sphincter pressure in healthy volunteers.
Authors: Robertson CS , Ledingham SJ , Cooper SM , Evans DF
Published: July 2012

1. A double‐blind placebo controlled dose ranging study of the effect of single oral doses of 1 and 2 mg BRL 24924 and 10 mg metoclopramide on lower oesophageal sphincter pressure has been performed in 20 healthy volunteers. 2. The 2 mg dose of BRL 24924 caused a statistically significant increase in mean lower oesophageal sphincter pressure (P less than 0.05) at 30‐45 min post‐dose (20.8 +/‐ 7.1 cm H2O BRL 24924; 16.4 +/‐ 5.7 cm H2O placebo). BRL 24924 1 mg and metoclopramide 10 mg failed to increase lower oesophageal sphincter pressure at any time. However, eight volunteers with a hypotensive resting lower oesophageal sphincter pressure (less than 15 cm H2O) showed a statistically significant rise in pressure at 120 min for both 1 mg, 2 mg (P less than 0.01; P less than 0.001) BRL 24924 and 10 mg metoclopramide (P less than 0.01). No other significant effect was detected on oesophageal manometry. 3. BRL 24924 (2 mg) has statistically significant effects on lower oesophageal sphincter pressure. However, further studies in patients with gastro‐oesophageal reflux disease and oesophagitis are needed to evaluate its clinical efficacy, especially where a hypotensive lower oesophageal sphincter pressure predominates.
Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.
Authors: Tjia JF , Back DJ , Breckenridge AM
Published: July 2012

The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine.
Yohimbine increases human salivary secretion.
Authors: Chatelut E. , Rispail Y. , Berlan M. , Montastruc JL
Published: July 2012

The effect of oral yohimbine (14 mg) on salivary secretion was evaluated in healthy volunteers. Yohimbine significantly increased salivary secretion when compared with placebo. This effect was significant from 60 min until 180 min after administration under our experimental conditions. Yohimbine (or alpha 2‐adrenoceptor blocking agents) could have a potential interest in the treatment of dry mouths.
Amiloride disposition in geriatric patients: importance of renal function.
Authors: Somogyi A , Hewson D , Muirhead M , Bochner F
Published: July 2012

1. The absorption and disposition of the potassium sparing diuretic amiloride were determined in nine elderly patients aged 71 to 87 years and in eight young (25 to 38 years) subjects following oral administration of 5 mg amiloride HCl daily to steady‐state. 2. The maximum and steady‐state plasma amiloride concentrations were significantly (P less than 0.05 and P less than 0.001) higher in the elderly patients. The renal clearance of amiloride was lower in the elderly than in young subjects (102 +/‐ 36 ml min ‐1 vs 300 +/‐ 64 ml min‐1, P less than 0.001) as was the urinary excretion of amiloride (36 +/‐ 13 vs 62 +/‐ 18% of the dose, P less than 0.01). 3. The steady‐ state plasma amiloride concentration correlated significantly (r2 = 0.61, P less than 0.001) with amiloride renal clearance and with creatinine clearance (r2 = 0.59, P less than 0.001). There was a very strong positive correlation between renal amiloride clearance and creatinine clearance (r2 = 0.76, P less than 0.001). The slope of the regression line was 2.5 indicating substantial proximal tubular secretion of amiloride. 4. Sodium and potassium excretion, along with urine volume were significantly (P less than 0.05) lower in the elderly (by 39, 45 and 34% respectively). 5. The disposition of amiloride was highly dependent on renal function, with higher plasma amiloride concentrations in the elderly reflecting diminished renal function. The dose of amiloride should be titrated to individual response, and the lower potassium excretion in the elderly patients suggests that the dose of amiloride could be reduced in this group of patients.
Single dose pharmacokinetics and pharmacodynamics of oral oxazepam during concomitant administration of propranolol and labetalol.
Authors: Sonne J , Dossing M , Loft S , Olesen KL , Vollmer‐Larsen A , Victor MA , Hamberg O , Thyssen H
Published: July 2012

1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta‐adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta‐adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta‐adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta‐adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol.
The influence of levodopa on gastric emptying in man.
Authors: Robertson DR , Renwick AG , Wood ND , Cross N , Macklin BS , Fleming JS , Waller DG , George CF
Published: July 2012

1. Simultaneous radioisotopic (99Tc‐DTPA) gastric emptying measurements and paracetamol pharmacokinetic studies were performed in eight healthy male volunteers with and without levodopa (125 mg orally). 2. In the absence of levodopa gamma camera imaging showed rapid mono or biexponential emptying in all subjects and the plasma concentration‐ time curves for paracetamol displayed a single major peak. 3. In the presence of levodopa the time to 90% emptying was prolonged from 32 +/‐ 24 min to 81 +/‐ 20 min (P less than 0.01). Gastric emptying was interrupted by a plateau phase in six subjects and this pattern of emptying was associated with double peaks in the plasma concentration‐ time curves of both levodopa and paracetamol. The time to the end of the plateau phase of emptying correlated with the time to the trough plasma concentrations of paracetamol and levodopa. 4. There was excellent agreement between the plasma concentration‐time curves of levodopa and paracetamol, i.e. time to initial peak, r = 0.946, P less than 0.001; time to trough concentration r = 0.943, P less than 0.01; time to second peak r = 0.974, P less than 0.001. 5. The results indicate that levodopa inhibits gastric emptying and thus influences its own absorption. Temporary inhibition of gastric emptying by levodopa (or a metabolite) is the cause of the multiple plasma peaks commonly observed following oral levodopa.
Effects of a PAF‐antagonist (BN 52063) on bronchoconstriction and platelet activation during exercise induced asthma.
Authors: Wilkens JH , Wilkens H , Uffmann J , Bovers J , Fabel H , Frolich JC
Published: July 2012

1. The effects of a specific PAF acether antagonist (BN 52063) on the response to isocapnic hyperventilation with dry cold air (ISH study) and exercise (EIA study) were assessed in a single dose and short term treatment study in 10 patients with exercise induced asthma. 2. ISH challenge was performed twice within 1 h after administration of either placebo, 240 mg BN 52063 p.o. or inhalation of 2.4 mg BN 52063. Hyperventilation increased Raw from 0.30 +/‐ 0.02 to 0.89 kPa s l‐1 (P less than 0.001) after the first challenge and from 0.28 +/‐ 0.04 to 0.84 +/‐ 0.06 kPa s l‐1 (P less than 0.001) after the second challenge. Oral pretreatment with BN 52063 did not result in a reduction of bronchoconstriction during both challenges. A significant increase of Raw was noted immediately after inhalation of BN 52063. An inhibition of PAF induced platelet aggregation (by a factor of 2) occurred after oral administration of BN 52063 after both ISH challenges (P less than 0.05). No significant inhibition of PAF induced platelet aggregation was seen after inhalation of BN 52063. At concentrations up to 30 microM in vitro, BN 52063 inhibited PAF induced platelet aggregation in a dose dependent manner. The IC50 of BN 52063 against the aggregating effect of 1 microM PAF was 7.0 +/‐ 2.1 microM. 3. In the EIA study the patients were challenged on the third day of treatment with either placebo or 240 mg BN 52063 p.o. or 5 mg BN 52063 by inhalation. Peak expiratory flow rates (PEFR) fell by 155 +/‐ 37 1 min‐1 after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Ouabain inhibition of the sodium‐potassium pump: estimation of ED50 in different types of human leucocytes in vitro.
Authors: Moller B , Vaag A , Johansen T
Published: July 2012

1. We examined the effect of ouabain on the Na(+)‐K+ pump of intact mononuclear leucocytes and polymorphonuclear leucocytes by using the radioactive potassium analogue, 86rubidium, as a tracer and measuring the cellular uptake of K+ (86Rb+). Na(+)‐K+ pump activity was determined as the cellular uptake of K+ (86Rb+) that is sensitive to ouabain, 10(‐5) mol l‐1. 2. Dose‐response curves for inhibition of the Na(+)‐K+ pump were obtained after exposure of the cells to various concentrations of ouabain for 2.5 h when the level of pump inhibition was considered to be at steady state. 3. The ED50 of ouabain for the effect on the Na(+)‐K+ pump was estimated to be 3 X 10(‐9) mol l‐1 in the absence of potassium. In the presence of potassium, 3 and 6.5 X 10(‐ 3) mol l‐1, it was increased by factors of 10 and 45 respectively. In the presence of potassium, 4 X 10(‐3) mol l‐1, the ED50 was similar but somewhat higher when determined in an artificial medium (Ringer solution) than when determined in autologous plasma. 4. The ED50 values observed in the present study were very similar to KD values reported in the literature on ligand binding of tritiated ouabain to the same types of human leucocytes.
Debrisoquine oxidation phenotype and susceptibility to lung cancer.
Authors: Speirs CJ , Murray S , Davies DS , Mabadeje Biola AF , Boobis AR
Published: July 2012

1. It has been suggested that poor metabolisers of debrisoquine are at reduced risk of developing lung cancer from smoking cigarettes. This has been investigated in 82 patients with established cancer of the lung. 2. The frequency of poor metaboliser subjects was not different from that in the normal population. 3. There was no tendency for subjects with lung cancer to metabolise debrisoquine more rapidly than non‐cancer subjects. 4. It is concluded that debrisoquine metabolic phenotype is not a good predictor of risk of developing lung cancer in the population at large.
Effects of aspirin upon the flushing reaction induced by niceritrol.
Authors: Jay RH , Dickson AC , Betteridge DJ
Published: July 2012

The usefulness of niceritrol as a lipid‐lowering agent is limited by a prostaglandin‐mediated flushing reaction after each dose occurring in the early stages of treatment. We have tested the effect of premedication with aspirin on the reaction to 250 mg niceritrol in 30 healthy male volunteers using both subjective and observed assessments of severity. Both 300 mg and 600 mg of aspirin significantly reduced the severity of flushing when compared with placebo. No significant difference was seen between the two dose levels. Prior dosing with aspirin may increase acceptability of niceritrol and hence improve compliance.
Biliary elimination of non‐steroidal anti‐inflammatory drugs in patients.
Authors: Schneider HT , Nuernberg B , Dietzel K , Brune K
Published: July 2012

In view of evidence in animals that enterohepatic recirculation of non‐ steroidal anti‐inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.
Respiratory and sedative effects of clobazam and clonazepam in volunteers.
Authors: Wildin JD , Pleuvry BJ , Mawer GE , Onon T , Millington L
Published: July 2012

1. The respiratory and psychomotor effects of two benzodiazepines used mainly as anticonvulsants were compared in healthy volunteers, using a double‐blind placebo controlled design. 2. Clobazam (10 and 20 mg) produced significantly fewer psychomotor side effects than clonazepam (0.5 and 1 mg). Neither drug at either dose affected the ventilatory response to CO2. 3. Although clonazepam produced significant effects on psychomotor performance, these did not correlate with plasma drug concentration. 4. Our studies provide further evidence that at the doses chosen clobazam is considerably less sedating than clonazepam. Further investigation is required into the tolerance profile of both drugs in patients.
The measurement of haloperidol and reduced haloperidol in hair as an index of dosage history.
Authors: Matsuno H , Uematsu T , Nakashima M
Published: July 2012

1. We report a method for measuring the concentrations of haloperidol (HL) and its major active metabolite, reduced haloperidol (RHL), in human scalp hair. 2. Hair samples were obtained from 59 patients who had been taking HL at fixed daily doses for more than 4 months and whose compliance was good. A morning pre‐dose plasma sample was also obtained from 48 of these patients. 3. The concentrations of HL and RHL in hair (ng mg‐1 hair) correlated significantly both with the daily dose (micrograms kg‐1 body weight) of HL (r = 0.682, P less than 0.001 for HL and r = 0.813, P less than 0.001 for RHL, n = 59) and with the trough concentration (ng ml‐1) of the corresponding compound in plasma at steady state (r = 0.558, P less than 0.001 for HL and r = 0.563, P less than 0.001 for RHL, n = 48). The correlation coefficients were slightly higher using the sum of the concentrations of both substances in hair (r = 0.829 for the correlation with daily dose and r = 0.609 for that with trough concentration). 4. Hair from other patients, in whom the dosage of HL had been changed within a few months prior to sampling, was sectioned into 1 cm‐long portions successively from the roots and the concentrations of both compounds in each portion were measured. Assuming a growth rate of 1‐1.5 cm/month, a history of individual dosage could be deduced in all patients from the distribution of the drug and metabolite along the single hair length.(ABSTRACT TRUNCATED AT 250 WORDS)
Diuretic effect and diuretic efficiency after intravenous dosage of frusemide [see comments]
Authors: Alvan G , Helleday L , Lindholm A , Sanz E , Villen T
Published: July 2012

1. Frusemide was given intravenously at a dose of 5 mg kg‐1 to five healthy volunteers and the diuresis was assessed by frequent spontaneous voiding over 5 h. Urinary volume and contents of sodium, chloride, potassium and frusemide were measured. 2. Diuretic response was evaluated using the sigmoid Emax model and non linear regression of diuresis vs frusemide excretion rate. The time courses of diuresis (pharmacological effect) and diuretic efficiency were constructed from the fitted parameters of the sigmoid Emax model. 3. The frusemide excretion rate associated with maximum efficiency was found, as predicted theoretically, to be less than the excretion rate associated with 50% of maximum effect in four of the five subjects in whom the slope factor was less than 2. 4. The effect over time is dependent both on the instantaneous drug effect but also on its pharmacokinetic properties and mode of administration. An intravenous bolus is the least efficient mode of administration while a controlled input producing a frusemide excretion at maximum efficiency should yield up to a 2.3 times higher diuretic response.
An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole.
Authors: Toon S , Ross CE , Gokal R , Rowland M
Published: July 2012

1. The oral pharmacokinetics of fluconazole were studied in three groups of volunteers (n = 5) with various degrees of renal function (GFR greater than 70 ml min‐1; 20‐70 ml min‐1; less than 20 ml min‐1) and in a group of patients with chronic end‐stage renal failure requiring regular haemodialysis. 2. The pharmacokinetics of fluconazole were markedly affected by impaired renal function with the elimination of half‐life in Group III (GFR less than 20 ml min‐1) being approximately three times that observed in normal volunteers (Group I). 3. Fluconazole renal clearance was positively correlated with GFR. 4. Non‐renal clearance of fluconazole decreased with decreasing renal function. 5. Approximately 38% of the 50 mg dose of fluconazole was removed by haemodialysis extending over a 3 h period.
Altered sensitivity to amiloride in cystic fibrosis. Observations using cultured sweat glands.
Authors: Cuthbert AW , Brayden DJ , Dunne A , Smyth RL , Wallwork J
Published: July 2012

1. Using cultured epithelia from sweat glands, derived from both cystic fibrosis and normal subjects, the relationship between amiloride concentration and the inhibition of electrogenic sodium transport was measured, under short circuit conditions. 2. The Kd for amiloride in cultures from normal subjects was 0.64 microM (n = 6) while in cultures derived from CF patients the value was 1.07 microM (n = 4). The values were significantly different (P less than 0.02, ANOVA). 3. In cultures from normal sweat glands, bathed in solutions free of permeable anions (chloride/bicarbonate), the Kd for amiloride rose to a value greater than found in CF tissues (2.3 microM). In CF epithelia subject to the same conditions the abnormally high value increased further, so that in solutions without permeable anions normal and CF cultures behaved similarly. 4. In cultures derived from normal and CF tissues lowering the sodium concentration to 10 mM also lowered the Kd for amiloride, however the shift was greater for CF cultures. 5. Several possible explanations for the results are discussed. The most probable is that the relatively more positive apical membrane potential in CF epithelia opposes the interaction of amiloride with the sodium channel, implying that complex formation is potential sensitive.