bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of some extra‐renal effects of spironolactone and canrenone.
Authors: Huston GJ , Al‐Dujaili EA
Published: July 2012

1 Measurement of changes in trans‐mural rectal potential difference (t.m.r.p.d.) and plasma aldosterone levels have been used in a comparison of the extra‐renal activities of spironolactone and its major metabolite canrenone. 2 A characteristic pressure artifact was observed during measurement of t.m.r.p.d. When pressure artifacts were eliminated, there was a log‐linear relationship between increasing doses of intravenous aldosterone and maximum increase in t.m.r.p.d. 3 Pre‐treatment for 5 days with spironolactone or canrenone produced a similar attenuation of the increase in t.m.r.p.d. produced by infused aldosterone, suggesting that canrenone is the active metabolite of spironolactone in the rectum. This is in contrast to the significantly greater renal activity of spironolactone that has been demonstrated after a similar treatment period. Neither antagonist treatment produced significant changes in pre‐infusion plasma aldosterone concentrations. 4 The need for assay of the extra‐renal activities of aldosterone antagonists in the assessment of their therapeutic potential is discussed.
The activity of aryl hydrocarbon hydroxylase in adult human skin.
Authors: Chapman PH , Rawlins MD , Shuster S
Published: July 2012

1 Aryl hydrocarbon hydroxylase (AHH), a mixed‐function oxidase system, has been identified in microsomal preparations of adult breast skin and foreskin. 2 Separation of dermis from epidermis by stretching, showed that AHH activity in human skin is almost exclusively located within the epidermis. 3 Preincubation of whole chopped skin with benzanthracene (5 muM to 100 muM) using a tissue culture system was accompanied by a concentration dependent increase in AHH activity. 4 Although there was no significant difference in AHH activity between the two sites, individuals differed markedly from one another in activity at any one site. Activity was observed to be positively correlated with age.
Changes in the molecular composition of circulating hydroxyethyl starch following consecutive daily infusions in man.
Authors: Mishler JM , Ricketts CR , Parkhouse EJ
Published: July 2012

1 Changes in the circulating molecular composition of hydroxyethyl starch (HES) were determined in four normal men following three consecutive daily 500 ml infusions (total 1,500 ml), by passage of trichloroacetic acid filtrates of plasma through a Sepharose CL4B gel filtration column. 2 The HES recovered from the intravascular space 10 min following the injection on Days 1, 2 and 3, was of a narrower molecular size distribution than the injected material, with a noticeable shift to molecules of a low molecular weight (LMW) size. 3 The HES in the sampled plasma 24 h post‐injection on Days 1, 2 and 3 consisted of molecules possessing a LMW distribution, concomitantly with a slight shift to molecules of a larger molecule size. 4 The HES recovered from the bloodstream 480 h after the third and final injection consisted of molecules possessing an intermediate size distribution, between LMW and high molecular weight (HMW) size material. 5 The results indicate that large HES molecules contained in the injected material are eliminated from the bloodstream; the HMW fraction at least partially by a alpha‐amylase mediated catabolism, and the resulting LMW fraction by excretion.
Phenytoin absorption in patients with ileojejunal bypass.
Authors: Kennedy MC , Wade DN
Published: July 2012

1 The absorption and elimination of phenytoin was studied after a 200 mg oral dose was administered to seven patients with ileojejunal bypass and nine control patients. 2 Analysis of the area under the plasma concentration time curve showed the absorption of phenytoin was decreased in the subjects with ileojejunal bypass (P less than 0.005). 3 The half life of elimination of the drug was shorter in the bypass group (15.1 h) than in the controls (17.8 h, P less than 0.05). 4 Subjects with an ileojejunal bypass receiving phenytoin are likely to require increased oral dosages to achieve an optimal plasma concentration. There is probably malabsorption of other poorly soluble drugs and parenteral therapy may be necessary to ensure adequate bioavailability.
Effect of aluminum hydroxide on diflunisal absorption.
Authors: Verbeeck R , Tjandramaga TB , Mullie A , Verbesselt R , de Schepper PJ
Published: July 2012

1 The effect of aluminum hydroxide on the oral absorption of diflunisal was studied in healthy subjects. 2 Relative bioavailability of the oral diflunisal dose (500 mg) was estimated by comparison of the areas under plasma concentration versus time curves, and comparison of the amount of drug (unchanged + glucuronides) excreted in the urine. 3 From the AUC‐method, a relative bioavailability of 0.60 was calculated. A similar value (F = 0.63) was obtained from the urinary excretion data. 4 The results indicate that co‐administration of aluminum hydroxide reduces the bioavailability of oral diflusinal by about 40%.
The effect of food and tablet formulation on plasma prednisolone levels following administration of enteric‐coated tablets.
Authors: Lee DA , Taylor GM , Walker JG , James VH
Published: July 2012

1 Plasma prednisolone levels have been compared following the administration of enteric‐coated prednisolone to fasted and non‐fasted subjects. The effect on plasma levels of altering the formulation of the enteric‐coating has also been studied. 2 The presence of food in the stomach at the time of administration does not affect the absorption of enteric‐coated prednisolone tablets. 3 There was considerable inter‐subject variation in plasma prednisolone levels after administration of shellac based enteric‐coated tablets. However, plasma levels were more consistent when a preparation whose formulation was based upon cellulose acetate phthalate (CAP) was given. 4 It is concluded that the pattern of absorption and plasma prednisolone levels depend on the formulation of the enteric coating. The bioavailability of the CAP based preparation is similar to that of plain prednisolone.
Effects of oral H1 and H2 receptor antagonists in asthma.
Authors: Leopold JD , Hartley JP , Smith AP
Published: July 2012

1 There is evidence that H2 receptors are present in the lung, both on bronchial smooth muscle and mast cells. In animal studies, stimulation of H2 receptors causes a diminution, and conversely H2 receptor blockade can increase, smooth muscle contraction and mediator release. 2 The effects of H2 receptor blockade in ten patients with asthma has been studied using oral cimetidine in a dose of 1 g daily for 1 week. Treatment was compared with placebo and the H1 receptor antagonist chlorpheniramine. 3 There was no alteration in the severity of naturally‐occurring or exercise‐induced asthma with cimetidine or chlorpheniramine. 4 H2 receptor blockade with oral cimetidine in conventional doses is without ill effect in asthma. The use of larger parenteral doses is discussed.
A pharmacokinetic comparison of two sustained‐release oral procainamide preparations.
Authors: Hore P , Bones P , Rollinson T , Ikram H
Published: July 2012

1 The pharmacokinetics of two different sustained‐release oral procainamide preparations were studied in ten hospital patients with normal blood ureas and no clinical evidence of heart failure. Each patient received either one or other preparation at 12 hourly intervals for four doses. Frequent blood sampling enabled close monitoring of blood levels. 2 Results showed that both preparations were essentially similar in their pharmacokinetics. Both effectively double the half‐ life of conventional oral procainamide to 6.5 h and are suitable as prophylactic preparations. One patient developed toxic levels, thought to be related to her metabolic status of being a very slow acetylator. To avoid toxicity pre‐therapy assessment of a patient's cardiac and renal function and acetylator status is advised.
A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.
Authors: Jones HM , Cummings AJ , Setchell KD , Lawson AM
Published: July 2012

1 The nine infants participating in this study were born to mothers who received continuous therapy with alpha‐methyldopa (0.75‐2.0 g/day) for several weeks extending to the time of delivery. 2 The concentration of free and total (free plus conjugated) alpha‐methyldopa was determined by gas chromatography‐mass spectrometry in amniotic fluid, umbilical cord plasma and maternal plasma at delivery; also in urine collected over time intervals from neonates during the first days after birth. 3 The results indicate that alpha‐methyldopa administered to the mother is present in the infant at birth at a level comparable to the maternal level and persists for some days. The ratio of conjugated to free drug increases with time after birth. 4 The excretion of free and conjugated alpha‐methyldopa in the urine indicated that the drug is slowly eliminated in the neonate by excretion in the urine and apparently by metabolism, mainly to the sulphate conjugate. 5 The concentration of free and conjugated alpha‐methyldopa in amniotic fluid tended to be higher than in umbilical cord plasma but lower than in neonatal urine, conjugated drug predominated.
The kinetics of salivary elimination of cyclophosphamide in man.
Authors: Juma FD , Rogers HJ , Trounce JR
Published: July 2012

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/‐ 0.24 (s.d.) and showed no time‐ dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/‐ 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/‐ 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/‐ 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non‐specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.
Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.
Authors: Vermeulen NP , Teunissen MW , Breimer DD
Published: July 2012

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half‐live of 11.0 +/‐ 1.2 h (n=4). Peak levels were reached at 2.7 +/‐ 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/‐ 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/‐ 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half‐lives were slightly shorter than the corresponding plasma half‐lives.
Kinetics of placentally transferred phenytoin and its p‐hydroxylated metabolites in newborn infants.
Authors: Rane A , Hoppel C , Hojer B
Published: July 2012

1 The kinetics of phenytoin and its main metabolites, unconjugated and conjugated 4‐hydroxy‐phenytoin were studied in newborn infants of epileptic mothers that were treated with phenytoin during the pregnancy. 2 In two of the infants phenytoin was eliminated by an apparent zero‐order process followed by an apparent first‐order process. In the other two infants the mode of elimination could not be characterized. 3 The decline of plasma conjugated 4‐hydroxy‐phenytoin was parallel to that of phenytoin. In contrast, the plasma concentration of unconjugated 4‐hydroxy‐phenytoin remained grossly constant during the first 3 to 4 days.
Comparative effects of imipramine and dothiepin on salivary rate in normal volunteers.
Authors: Sheth UK , Paul T , Desai NK , Pispati PK
Published: July 2012

1 Imipramine induced significant reduction in salivary rate compared to placebo in a cross‐over, double‐blind study of twelve normal volunteers. In contrast, there was no significant difference between the reduction in salivary rate induced by dothiepin and placebo. 2 Comparison of salivary rates showed no significant difference between the drugs in the initial and cross‐over treatment periods. However, pooled observations from the initial and cross‐over treatment periods indicated that imipramine produced a significantly greater reduction in salivary rate than dothiepin. 3 The results suggest that dothiepin would cause far less dryness of mouth compared to imipramine. This feature might ensure greater therapeutic compliance.
Fenamates may antagonize the actions of prostaglandin endoperoxides in human myometrium.
Authors: Sanger GJ , Bennett A
Published: July 2012

1 The prostaglandin endoperoxide analogue U‐46619 potently contracted human isolated myometrium, suggesting that prostaglandin H2 (PGH2) may be a major stimulant of myometrial contractions. 2 Sodium mefenamate, flufenamate or meclofenamate 2 microgram/ml greatly reduced contractions of the myometrium induced by the PGH2 analogue. 3 Flufenamate, but not the other two drugs, also significantly inhibited contractions to acetylcholine. 4 Sodium meclofenamate 2 microgram/ml did not consistently antagonize contractions to PGF2alpha. 5 The relief of dysmenorrhoea by fenamates may be explained both by inhibition of PG synthesis, and by antagonism of contractions to PGH2 produced by incompletely blocked PG synthesis.
Reduction of circulating 25‐hydroxyvitamin D by antipyrine.
Authors: Wilmana PF , Brodie MJ , Mucklow JC , Fraser HS , Toverud EL , Davies DS , Dollery CT , Hillyard CJ , Macintyre I , Park BK
Published: July 2012

1 Twenty‐four Asian vegetarians had significantly lower 25‐ hydroxyvitamin D (25‐OHD) levels and longer antipyrine half‐lives than twenty white non‐vegetarians (P less than 0.001). 2 Treatment with oral antipyrine over 4 or 5 weeks in seven vegetarian Asians and five racially different non‐vegetarians increased drug oxidation significantly in both groups as measured by a fall in antipyrine half‐ lives and a rise in serum gamma‐glutamyltranspeptidase levels and urinary 6 beta‐hydroxycortisol/17‐hydroxycorticosteroid ratios. 3 Antipyrine treatment produced a fall in circulating 25‐hydroxyvitamin D of around 60% in all subjects in whom pretreatment levels could be measured, independent of race and diet. 4. In the Caucasian non‐ vegetarian group 1,25 dihidroxyvitamin D levels, the most active metabolite of vitamin D, were also measured and remained unaltered despite a substantial fall in 25‐hydroxy substrate. 5 The acute fall in 25‐hydroxyvitamin D concentration with a maintained level of 1,25 dihidroxyvitamin D may represent the early changes of drug‐induced osteomalacia.
Modification of phenytoin clearance by valproic acid in normal subjects.
Authors: Frigo GM , Lecchini S , Gatti G , Perucca E , Crema A
Published: July 2012

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/‐ 0.17 v 0.38 +/‐ 0.11 ml min‐1 kg‐1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.
Plasma fluphenazine levels by radioimmunoassay in schizophrenic patients treated with depot injections of fluphenazine decanoate.
Authors: Wiles DH , Gelder MG
Published: July 2012

1 Using a radioimmunoassay, plasma fluphenazine (FPZ) concentrations were examined in 33 schizophrenic patients during 38 intervals between injections of FPZ decanoate. Doses ranged from 12.5 to 150 mg and intervals from 1 to 5 weeks. At least three blood samples were taken between injections from each subject; also in 26 subjects additional samples were taken during the first 24 h post‐injection. 2 FPZ was measurable in all plasma samples. 3 Each injection was followed by a rapid rise in plasma FPZ concentration to a maximum at 1‐8 h. The height of this peak varied considerably. Within the next 12‐36 h plasma FPZ fell to a level slightly above that found before injection and then remained stable until the next injection, thus confirming the steady release of FPZ from the depot over this period. 4 For the group, dose and mean plasma FPZ levels correlated strongly. 5 Despite this, there was a four‐fold variation in plasma FPZ concentration among subjects receiving the same dose. 6 The FPZ level on the last day of an interval between injections was a satisfactory estimate of the mean FPZ level for the interval. 7 In one subject examined in this way, a positive correlation was found (r = 0.76) between plasma FPZ (by radioimmunoassay) and plasma prolactin levels.
Absorption and excretion of rapid and slow release oxprenolol and their effects on heart rate and blood pressure during exercise.
Authors: Bobik A , Jennings GL , Korner PI , Ashley P , Jackman G
Published: July 2012

1. Plasma concentrations and heart rate and blood pressure effects of 160 mg oxprenolol as standard rapid release (RR) and slow release (SR) tablets were compared in healthy volunteers. Peak plasma concentrations were lower with SR tablets than with RR tablets and the peak was delayed. 2. Absorption of oxprenolol was described adequately by first order kinetics with both preparations. The apparent half‐life of absorption was 0.40 h with RR and 2.4 h for the SR formulation. The apparent elimination half‐life of oxprenolol was about 2 h. Relative bioavailabilities of the two formulations were similar. 3. The effectiveness of oxprenolol RR and SR were assessed by their effects on heart rate in severe exercise (EHR) and also by their effects on blood pressure at rest and during exercise. 4. Maximum reductions in these variables coincided with peak oxprenolol concentrations. The effects on EHR and blood pressure parameters had a distinct time course but there was no difference between the time course of inhibition of each variable for the two formulations over 24 h.
Effects of aspirin and dimenhydrinate (Dramamine) on visual processes.
Authors: Luria SM , Kinney JA , McKay CL , Paulson HM , Ryan AP
Published: July 2012

1. The effect of three doses of either aspirin (1280 mg each) or dimenhydrinate (Dramamine) (100 mg each) in an 8 h period on visual processes was investigated double‐blind on sixteen volunteer subjects. 2. Tests included night‐vision, colour‐discrimination, stereoacuity and stereopsis, reaction‐time, pupil size, eye‐movements, visual evoked cortical potentials, electroencephalographs, a dial‐reading task, and a test of texture discrimination. 3. Both drugs affected colour discrimination, and dimenhydrinate degraded night‐vision, reaction‐ time, and stereopsis. 4. The effect of aspirin was minor, but the impairments produced by dimenhydrinate appear to be of practical importance.
Clofibrate and diabetes control in patients treated with oral hypoglycaemic agents.
Authors: Daubresse JC , Daigneux D , Bruwier M , Luyckx A , Lefebvre PJ
Published: July 2012

1. Twenty‐two maturity‐onset type diabetics treated with oral hypoglycaemic agents entered a single‐blind crossover study using placebo (periods A and C, 2 months each) and clofibrate (2 g/day; period B; 2 months). 2. In thirteen patients, under reasonably good control, clofibrate did not reduce fasting or post‐prandial blood glucose, nor 24 h glycosuria; no improvement was noted in the M‐value, an index of diabetes control. 3. In contrast, in nine patients, with poor diabetes control, clofibrate reduced 24 h glycosuria and significantly improved the M‐value. 4. In all patients, clofibrate therapy was associated with a significant 19‐23% reduction in plasma fibrinogen. 5. It is suggested that addition of clofibrate may be useful in maturity‐onset diabetics not adequately controlled by diet combined with oral hypoglycaemic agents.
Impairment of drug metabolism in polycystic non‐parasitic liver disease.
Authors: Sotaniemi EA , Luoma PV , Jarvensivu PM , Sotaniemi KA
Published: July 2012

1. Drug‐metabolizing capacity in cases of polycystic non‐parasitic liver disease was investigated using plasma antipyrine clearance as an index. 2. The four subjects with maternally inherited polycystic liver metabolized antipyrine at a significantly slower rate than the six other members of the family. 3. This reduction in antipyrine metabolism is due to the loss of active liver parenchyma, and is probably also influenced by alterations in the vascular bed due to compression by the enlarged cysts.
The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers.
Authors: Johnston A , Burgess CD , Warrington SJ , Wadsworth J , Hamer NA
Published: July 2012

1. The effect of spontaneous changes in urinary pH on renal excretion and plasma concentration of mexiletine has been examined during chronic administration of subtherapeutic doses of the drug to healthy volunteers. 2. Significant correlations were found between urinary pH and the plasma concentration and renal excretion of mexiletine. 3. Prediction of plasma mexiletine concentrations from our data suggests that the amount of mexiletine in plasma would increase by more than 50% following a rise in urinary pH similar to that which occurred spontaneously in our subjects. 4. Factors which influence urinary pH should be considered when the dosage of mexiletine is chosen. Extremes of urinary pH may account for some cases of inefficacy of the drug, and for the occurrence of unwanted effects at conventional doses.
Blood pressure reduction by incremental infusion of labetalol in patients with severe hypertension.
Authors: Cummings AM , Brown JJ , Fraser R , Lever AF , Morton JJ , Richards DA , Robertson JI
Published: July 2012

1. Labetalol was given by incremental intravenous infusion to nineteen severely hypertensive patients, of whom nine were refractory to previous oral antihypertensive therapy. 2. Smooth reduction of arterial pressure was achieved in twelve subjects; one remained resistant to labetalol up to 160 mg/h; a sudden fall in pressure occurred in the remaining six. No serious complications were encountered. Blood pressure control was accompanied by slight byt significant reduction in heart rate and in plasma angiotensin II and aldosterone concentrations. 3. The administration of labetalol in this way appears to be a useful technique in patients requiring rapid reduction of arterial pressure, although close and continuous supervision is necessary.
The effects of alpha‐ and beta‐adrenergic receptor blockers on the pressure responses to isometric exercise in hypertensive patients.
Authors: Reuben SR , Gale EV , Blake P
Published: July 2012

1. The cardiovascular responses to handgrip exercise have been studied in ten patients with uncomplicated essential hypertension in a randomized crossover study of propranolol and prazosin. 2. Isometric handgrip exercise was performed with a calibrated strain gauge dynamometer at 30% of maximum voluntary contraction for 3 min. 3. Blood pressure and heart rate were measured in the supine position at rest and in the last 10 s of the exercise period. 4. These exercise studies were undertaken at the end of a run‐in period and at the end of 1 month's optimal therapy with the two drugs. 5. The active treatment periods were separated by a 2 weeks placebo washout period. 6. Both drugs lowered the supine and standing systolic and diastolic pressures and there was no difference between these drugs in their effect on these variables. 7. Propranolol lowered the resting heart rate and neither drug suppressed the pressor response to isometric exercise. 8. The degree of pressure rise was similar with both drugs but propranolol suppressed isometric exercise‐induced tachycardia.
The acute changes seen in cardiac glycoside receptor sites, 86rubidium uptake and intracellular sodium concentrations in the erythrocytes of patients during the early phases of digoxin therapy are not found during chronic therapy: pharmacological and therapeutic implications for chronic digoxin therapy.
Authors: Ford AR , Aronson JK , Grahame‐Smith DG , Carver JG
Published: July 2012

1 Measurements of the binding of 12‐alpha‐[3H]‐digoxin to the membranes of intact erythrocytes, erythrocyte 86rubidium uptake and intraerythrocytic sodium concentrations have been made in the red cells of various groups of patients‐those who have not received digoxin, those during the early phases of treatment, those during chronic (greater than 2 months) treatment, and those toxic. 2 The values of those measurements in the patients in the early phases of therapy and in the toxic patients differed significantly from those of the untreated patients. 3 However, the values in the chronically treated patients were not different from those of the untreated patients. 4 The results suggest that the biochemical pharmacological effects of digoxin which occur during the early phases of therapy do not persist in the long‐term. 5 The possible clinical significance of these observations is discussed.
Determination of viloxazine in plasma by GLC.
Authors: Norman TR , Burrows GD , Davies BM , Wurm JM
Published: July 2012

1 A gas chromatographic procedure for the determination of viloxazine in therapeutic concentrations in human plasma, with use of a flame ionization detector, is described. 2 The drug is extracted at pH 12 into hexane, back extracted into HCl, re‐extracted into hexane after alkalinization of the HCl and derivatized with acetic anhydride. 3 An imipramine‐butriptyline mixture is used as an internal standard. The coefficients of variation for a concentration of 0.75 microgram/ml are 9.4% and 13.1% for within day and day to day precision respectively. For a 1.75 micrograms/ml solution the within day precision was 5.7%. 4 The method has been applied to a patient receiving 300 mg/day viloxazine treatment.
Plasma propranolol concentrations and the erythrocyte sedimentation rate.
Authors: Schneider RE , Bishop H. , Hawkins CF
Published: July 2012

1. The plasma propranolol concentrations after a single oral dose of 40 mg were measured in 25 patients with rheumatoid arthritis and compared with those of 16 patients with Crohn's disease from a previous study. Thirteen healthy volunteers were used as controls. 2. In both diseases some high and some low values occurred. This scatter did not correlate with any symptoms or biochemical or haematological data other than with the erythrocyte sedimentation rate (ESR). 3. Both sets of patients were therefore separated into two groups depending on whether or not their ESRs were above or below 20 mm/l h. In both diseases the plasma propranolol concentrations of the patients with a raised ESR were significantly higher than the controls as well as those of the low ESR group. 4. In rheumatoid arthritis the plasma propranolol concentrations of the patients with a low ESR did not differ from those of the controls, but in Crohn's disease they remained significantly higher. 5. In one patient with Crohn's disease there was a dramatic rise in propranolol concentrations during an exacerbation (ESR 91 mm/l h) compared with those during a remission (ESR 20 mm/l h). 6. A difference in smoking habits did not seem to have been responsible for the difference in plasma propranolol concentrations.
Sympathetic reflex responses during treatment of essential hypertension with hydrallazine and oxprenolol.
Authors: Davies IB , Sever PS , Rosenthal T.
Published: July 2012

1. The short term effects of hydrallazine, oxprenolol and oxprenolol plus hydrallazine were studied in five patients with essential hypertension. 2. The increase in pulse rate caused by hydrallazine was prevented by combined treatment with oxprenolol, which also lowered the high plasma noradrenaline levels, associated with the use of hydrallazine. 3. Plasma renin activity was higher in the supine and standing positions with hydrallazine than with oxprenolol alone and with the patients standing this high renin level was prevented by simultaneous treatment with oxprenolol. With the patients supine, combination of oxprenolol with hydrallazine resulted in a mean plasma renin activity which was less than half that with hydrallazine alone, although this difference was not statistically significant. 4. The combination of oxprenolol with hydrallazine did not lower the blood pressure further, but reduced the increased sympathetic activity which occurred with hydrallazine alone.
Promoting rational prescribing: an international perspective.
Authors: Hogerzeil HV
Published: July 2012

Irrational prescribing is a global problem. Rational prescribing cannot be defined without a method of measurement and a reference standard. The former is now available but the latter needs further development. Proven effective interventions to promote rational prescribing in developed countries are treatment protocols based on wide consultation and consensus, properly introduced and with a possibility of feedback; face‐to‐face education focussed on a particular prescribing problem in selected individuals; structured order forms; and focussed educational campaigns. Essential drugs lists are probably effective when based on consensus and used within a comprehensive educational programme. Printed materials alone are not effective. In most cases the usefulness of such strategies in developing countries has not been proven and should be studied. Medical education in clinical pharmacology and pharmacotherapy should be based on the practical needs of future prescribes, should include the principles of rational therapeutics and problem solving, and should immunize the students against the influences they are likely to encounter in their professional life, such as patient pressure, drug promotion and irrational prescribing by peers. Within the scope of a national formulary, specialist departments in teaching hospitals should define prescribing policies as the basis for prescribing, teaching, examinations and medical audit.
A comparison of the neuro‐endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers.
Authors: de Koning P , de Vries MH
Published: July 2012

1. Nineteen healthy male volunteers participated in a double‐blind, six‐ way, crossover study. With a separation of 1 week between sessions, volunteers received randomly one oral dose of each of the following compounds: 3 or 10 mg of the dopamine (DA2) receptor antagonist and serotonin (5HT1A) agonist DU 29894, 1 mg flesinoxan, 400 mg sulpiride, 3 mg haloperidol or placebo. 2. To assess the dopamine (DA2) antagonistic activity of the different compounds, plasma levels of prolactin were assessed at pre‐dose, 0.5, 1, 2, 3, 4, 6 and 24 h post‐ dose. To assess the serotonin (5HT1A) agonistic activity, plasma levels of ACTH, cortisol and growth hormone were assessed at the same time‐ points as well as body temperature; the latter was also assessed 8 h post‐dose. Plasma levels of DU 29894 were assessed at pre‐dose and 2, 3, 4 and 24 h post‐dose. 3. Sulpiride, haloperidol and both doses of 3 mg and 10 mg DU 29894 produced statistically significant increases in prolactin levels. The increase produced by 3 mg was roughly equivalent to that produced by 3 mg haloperidol whereas the increase produced by 10 mg DU 29894 was significantly larger. 4. Only 10 mg DU 29894 and 1 mg flesinoxan produced statistically significant increases in ACTH, cortisol and growth hormone. All compounds either showed a significant attenuation of the normal day time increase of body temperature (3 mg DU 29894, haloperidol and sulpiride) or a true significant decrease in body temperature (10 mg DU 29894 and flesinoxan).(ABSTRACT TRUNCATED AT 250 WORDS)
Lack of interaction between a new antihistamine, mizolastine, and lorazepam on psychomotor performance and memory in healthy volunteers.
Authors: Patat A , Perault MC , Vandel B , Ulliac N , Zieleniuk I , Rosenzweig P
Published: July 2012

1. The possible interaction between a new H1 antihistamine, mizolastine, and lorazepam was assessed in a randomised, double‐blind, cross‐over, placebo‐controlled study involving 16 healthy young male volunteers who received mizolastine 10 mg or placebo once daily for 8 days with a 1 week wash‐out interval. The interaction of mizolastine, at steady‐state, with a single oral dose of lorazepam or placebo was assessed on days 6 or 8 of each treatment period. 2. Psychomotor performance and cognitive function were evaluated using objective tests (critical flicker fusion threshold, choice reaction time, tapping, arithmetic calculation, body sway) and self‐ratings (visual analogue scale, ARCI) before and at 2, 4, 6 and 8 h after dosing. Short‐term memory (Sternberg memory scanning immediate free recall of a word list) and long‐term memory (delayed free recall and recognition of words and pictures) were assessed before and at 3 h after dosing. Pharmacodynamic interactions were evaluated by repeated measures ANOVA in a 2 × 2 factorial interaction model. 3. Mizolastine, 10 mg once daily, at steady‐state, was devoid of sedation and detrimental effect on skilled performance and memory. 4. In contrast, a single 2 mg dose of lorazepam produced marked impairment of psychomotor performance, cognitive functions (significant reduction in flicker fusion threshold, tapping and arithmetic calculation and increase in reaction times and body sway) and subjective sedation from 2 to 8 h after dosing. In addition, lorazepam induced an anterograde amnesia, characterised by a decrease in delayed free recall and recognition, and a deficit in short term memory.(ABSTRACT TRUNCATED AT 250 WORDS)
Concentration‐effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.
Authors: Harder S , Baas H , Bergemann N , Demisch L , Rietbrock S
Published: July 2012

1. The relationship between plasma concentration of levodopa and motor‐ response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double‐blind, randomized, cross‐over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax‐model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose‐corrected AUC of levodopa after the IR‐formulation was 27.5 (+/‐ 9.1 s.d.) ng ml‐1 h per mg and 23.2 (+/‐ 4.6 s.d.) ng ml‐1 h per mg after the CR‐formulation. Cmax was 1714 (+/‐ 1027 s.d.) ng ml‐1 after the IR‐formulation and 1494 (+/‐ 383 s.d.) ng ml‐1 after the CR‐ formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/‐ 144 s.d.) ng ml‐ 1 (IR) and 1024 (+/‐ 502 s.d.) ng ml‐1 (CR), respectively (95%‐CI: 1.51‐ 2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/‐ 0.5 s.d.) h (IR) and 2.8 (+/‐ 0.7 s.d.) h (CR), respectively (95%‐CI: 1.12‐2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)
Amlodipine and haemodynamic effects of cyclo‐oxygenase inhibition.
Authors: Minuz P , Pancera P , Ribul M , Priante F , Degan M , Campedelli A , Arosio E , Lechi A
Published: July 2012

1. The haemodynamic effects of calcium antagonists could depend at least in part on the activity of vasoactive prostanoids. 2. We set out to study the effect of the cyclo‐oxygenase inhibitor ibuprofen, 400 mg three times daily for 3 days, by a randomised cross‐over study vs placebo in 12 mild to moderate essential hypertensive patients who had been treated for 1 month with amlodipine. 3. Blood pressure, heart rate and vascular resistances in the upper limb (Doppler ultrasound) were measured. Plasma renin activity and urinary aldosterone, as well as indices of renal function, were evaluated. Urinary 2,3‐dinor‐6‐keto‐ PGF1 alpha and 2,3‐dinor‐TXB2, as well as 6‐keto‐PGF1 alpha and TXB2, were measured as indices of systemic and renal PGI2 and TXA2 synthesis. 4. Amlodipine normalised blood pressure and reduced upper limb vascular resistances; it did not affect urinary prostanoid excretion. Short‐term combined administration of ibuprofen resulted in, by comparison with placebo, inhibition of systemic PGI2 (‐80.5 ng 24 h‐1, 95% CI ‐99.2, ‐ 61.4; P < 0.001) and TXA2 (‐216.1 ng 24 h‐1, 95% CI ‐276.5, ‐155.8; P < 0.001), together with an increase in systolic (+7.8 mm Hg, 95% CI +3.1, +12.3; P < 0.01) and diastolic (+3.9 mm Hg, 95% CI +1.2, +6.6; P < 0.01) blood pressure; it had no significant effect on regional vascular resistances (+4.7 mm Hg ml‐1 s, 95% CI ‐5.6, +15.0). Effects of ibuprofen on renal prostanoid synthesis were less marked, and there was no change in indices of renal function or hydro‐electrolytic balance.(ABSTRACT TRUNCATED AT 250 WORDS)
The renin angiotensin aldosterone system and frusemide response in congestive heart failure.
Authors: Reed S , Greene P , Ryan T , Cerimele B , Schwertschlag U , Weinberger M , Voelker J
Published: July 2012

1. To test the hypothesis that basal renin angiotensin aldosterone system (RAAS) activity impairs the acute natriuretic response to frusemide in patients with mild or moderate congestive heart failure (CHF), we studied eight adult volunteers with preserved renal function, stable New York Heart Association Class II or III CHF, and echocardiographic evidence of left ventricular dysfunction due to myocardial infarction, hypertension, or both causes. 2. All patients received three dosing regimens administered in random order: (a) intravenous frusemide: 40 mg bolus then 40 mg h‐1 for 3 h, (b) captopril: two 12.5 mg oral doses separated by 2 h, (c) combined dosing: the first captopril dose preceded the frusemide bolus by 30 min. Sodium balance on an 80 mmol day‐1 sodium diet was documented prior to each dosing regimen. Sodium excretion was quantitated in urine collected at intervals until 3.5 h after initiating drug administration. During this time, urine output was replaced intravenously with an equivalent volume of 0.45% saline. 3. Captopril significantly lowered plasma angiotensin converting enzyme (ACE) activity and plasma aldosterone concentration, and raised inulin clearance. The drug had essentially no effect on the time course of magnitude of frusemide's natriuretic effect. Maximal fractional sodium excretion during frusemide infused by itself and in combination with captopril was 24.7 +/‐ 1.9% vs 28.2 +/‐ 3.8%, respectively (difference 3.5%; 95% CI, ‐4.0 to 11.0%; P > 0.05). Cumulative sodium excretion ending at 3.5 h was 429 +/‐ 53 mmol when frusemide was given alone and 455 +/‐ 69 mmol when captopril was added (difference, 26 mmol; CI, ‐121 to 174 mmol; P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Caffeine as a metabolic probe: a comparison of the metabolic ratios used to assess CYP1A2 activity.
Authors: Notarianni LJ , Oliver SE , Dobrocky P , Bennett PN , Silverman BW
Published: July 2012

1. Caffeine is widely used as an in vivo probe for CYP1A2; the distribution/activity of this enzyme is reported to be reflected by metabolic ratios. 2. Several metabolic ratios using different combinations of urinary metabolites have been used to measure CYP1A2, with varying conclusions on its distribution. 3. A mathematical comparison of five metabolic ratios claiming to reflect CYP1A2 activity was made using data from 237 healthy volunteers. 4. All five metabolic ratios were symmetrically distributed. The five ratios however, measured at least three different parameters, with no one ratio correlating exactly with any other. 5. Data in the literature claiming to measure CYP1A2 using caffeine may reflect other parameters. 6. The complex metabolism of caffeine together with different parameters controlling the renal clearance of each metabolite, makes the use of urinary metabolic ratios an inaccurate probe for assessing the distribution of CYP1A2 activity in populations.
Tolerance with beta 2‐adrenoceptor agonists: time for reappraisal.
Authors: Grove A , Lipworth BJ
Published: July 2012

1. In spite of the widespread use of beta 2‐adrenoceptor agonists in the treatment of asthma controversy continues regarding their possible role in increasing asthma mortality and morbidity. There is however no evidence available to suggest that tolerance to the bronchodilator or anti‐bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. 2. There is no conclusive evidence to suggest that tolerance develops to the bronchodilator effects of short‐acting beta 2‐adrenoceptor agonists. Tolerance does however appear to develop to the anti‐ bronchoconstrictor effects of these drugs. 3. With regard to the long‐ acting beta 2‐adrenoceptor agonists, there is evidence to suggest that tolerance develops both to their anti‐bronchoconstrictor, and bronchodilator effects. Tolerance was however demonstrated in the presence of improved symptom control, therefore the clinical relevance of this phenomenon is uncertain. 4. Systemic corticosteroids can modulate lymphocyte beta 2‐adrenoceptor function both preventing, and reversing tolerance. The situation regarding the effects of systemic or inhaled corticosteroids on modulating bronchodilator responses in asthmatics is less clear. There is some evidence to suggest that inhaled corticosteroids are unable to prevent bronchodilator or systemic tolerance to long‐acting beta 2‐adrenoceptor agonists. 5. On the basis of the current evidence, the British Thoracic Society guidelines for the management of asthma appear appropriate with regard to their recommendations for the use of long‐acting beta 2‐adrenoceptor agonists.
The reproducibility and effect on non‐specific airway responsiveness of inhaled prostaglandin D2 and leukotriene D4 in asthmatic subjects.
Authors: Wood‐Baker R , Town GI , Benning B , Holgate ST
Published: July 2012

1. Mast cell mediators PGD2 and LTD4 may play important roles in asthma pathogenesis. There is little information on the repeatability of inhalation challenge with these agonists in the laboratory. 2. We assessed the repeatability of inhalation challenges using PGD2 and LTD4 in two groups of 10 asthmatic volunteers. Non‐specific bronchial responsiveness was assessed by histamine inhalation challenges. 3. Using the Bland‐Altman method, we found the coefficient of repeatability to be 1.2 doubling doses for LTD4 and 2.1 for PGD2 at a 1 week interval. Repeatability for histamine inhalation challenge over the same time period was similar at 1.4 and 2.1 doubling doses respectively. 4. Non‐specific bronchial responsiveness following LTD4 challenge decreased significantly, mean PD20FEV1 increasing from 169 nmol on day 1 to 278 nmol on day 3 (P = 0.001), before returning to baseline levels. 5. A progressive decrease in non‐specific bronchial responsiveness occurred following PGD2 challenge. Baseline PD20FEV1 was 195 nmol, increasing to 238 nmol by day 3 (NS) and 313 nmol by day 8 (P = 0.016). 6. PGD2 inhalation challenges performed a week apart are less reproducible than LTD4 challenges, possibly as a result of significant changes in histamine bronchial responsiveness. Our findings allow accurate power calculations to be made for studies to assess new pharmacological antagonists to these mediators.
Relation between changes in blood pressure and serum ACE activity after a single dose of enalapril and ACE genotype in healthy subjects.
Authors: Todd GP , Chadwick IG , Higgins KS , Yeo WW , Jackson PR , Ramsay LE
Published: July 2012

1. The effects of a single oral dose of enalapril 10 mg on serum ACE activity and blood pressure in relation to the ACE genotype were studied in 27 healthy men, n = 9 each of genotype DD, ID and II, in a parallel group study design. 2. Before treatment serum ACE activity differed significantly between the genotypes, with serum ACE activity 56% higher in DD than II subjects, and the genotype explaining 40% of between‐subject variance in serum ACE activity. 3. After oral enalapril 10 mg the absolute fall in serum ACE activity was significantly larger in DD than II subjects at 2, 4, and 6 h (by 9.0 (95% CI 0.7‐17.2), 10.7 (3.8‐17.6), and 9.7 (2.8‐16.6) nmol ml‐1 min‐1 respectively), but not at 24 h (fall in II > DD by 1.1 (‐8.9 to 6.7) nmol ml‐1 min‐1). 4. Serum ACE activity remained significantly related to the ACE genotype at each time‐point after enalapril, with the genotype explaining 22‐46% of between‐subject variance in serum ACE. 5. Falls in mean arterial pressure in response to enalapril were not significantly related to the ACE genotype, with the average fall over 6 h in DD > II genotype by 0.7 mm Hg (95% CI ‐5.5 to 4.1). 6. Blood pressure responses to enalapril did not correlate significantly with the initial serum ACE, or the absolute or percent reductions in serum ACE activity after enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison of the effects of simvastatin and pravastatin monotherapy on muscle histology and permeability in hypercholesterolaemic patients.
Authors: Contermans J , Smit JW , Bar PR , Erkelens DW
Published: July 2012

1. In this double‐blind, placebo controlled, prospective study, it was assessed whether simvastatin or pravastatin monotherapy have adverse effects on muscle histology and muscle membrane permeability in hypercholesterolaemic patients. 2. Twenty‐four patients, seven females and 17 males, with primary hypercholesterolaemia (LDL cholesterol levels > or = 4.14 mmol l‐1) were selected from the outpatient lipid clinic of a 650 bed academic medical centre. 3. After a 6‐week lipid lowering diet and placebo period, patients were randomized into two groups of 12 subjects with similar characteristics, to receive either simvastatin or pravastatin in dosages of 10‐40 mg day‐1 for three periods of 6 weeks. After each 3‐week period the dose was adjusted to LDL cholesterol to aim for equipotent dosage. 4. All subjects performed a 45 min, lean body mass standardized bicycle ergometer test, before and after 18 weeks of treatment. As parameter for muscle damage, the exercise‐induced rise of the muscle proteins, creatine kinase (CK) and myoglobin (Mb), relative to pre‐exercise levels, were determined 1 and 8 h after the test. Forty‐eight hours after each test a biopsy was taken from the quadriceps muscle and histology was judged by three independent observers. 5. Eighteen weeks of monotherapy with simvastatin and pravastatin did not affect the exercise induced release of CK and Mb, neither were any differences observed in muscle histology before and after treatment with either of the drugs. 6. Although simvastatin doses were lower than pravastatin, reductions in total‐ and LDL‐cholesterol were greater in the simvastatin treated patients than in the pravastatin treated group.(ABSTRACT TRUNCATED AT 250 WORDS)