bluuebunny/crossref_metadata_2025 huggingface dataset:
Double‐blind randomized controlled trial of isoxicam vs piroxicam in elderly patients with osteoarthritis of the hip and knee.
Authors: Bellamy N , Buchanan WW , Grace E
Published: July 2012

1 Fifty‐seven elderly patients with primary osteoarthritis of the hip and knee were entered into a double‐blind, randomized, controlled parallel group trail to compare the efficacy and tolerability of isoxicam (maximum = 200 mg day‐1) and piroxicam (maximum = 20 mg day‐ 1). 2 Clinical assessments were made following a 1 week NSAID‐free washout period and at biweekly intervals during the next 6 weeks of active treatment. 3 The majority of patients in both groups experienced a clinically important and statistically significant therapeutic response. 4 No statistically significant between‐group differences were noted with respect to drug efficacy. 5 One patient was withdrawn from the piroxicam group because of lack of effect, but there were no such withdrawals from the isoxicam group. 6 Five patients were withdrawn from the piroxicam group because of adverse reactions compared to only one withdrawal from the isoxicam group. 7 This study indicates that isoxicam is an efficacious and well‐tolerated once‐daily NSAID for elderly patients with osteoarthritis.
Isoxicam vs ketoprofen in ankylosing spondylitis.
Authors: Doury P , Roux H
Published: July 2012

1 Isoxicam, 200 mg once daily, was compared to ketoprofen, 100 mg three times daily, in 19 patients (16 males, three females) with ankylosing spondylitis in a 30‐day, double‐blind study conducted in two centres. 2 Improvements from baseline to final assessment were noted after both isoxicam and ketoprofen in most clinical variables, with isoxicam, in general, being more effective than ketoprofen. 3 Isoxicam was significantly superior to ketoprofen in reducing pain and was judged by both patients and physicians to be superior overall to ketoprofen. 4 Of the 13 patients who expressed a preference, 10 preferred isoxicam. 5 Typical NSAID side effects were encountered with both drugs.
Double‐blind multicentre UK hospital studies of isoxicam vs naproxen.
Authors: Cardoe N , Hart FD
Published: July 2012

1 Two multicentre, parallel group, randomised, double‐blind, double‐ dummy comparison studies were conducted between isoxicam in the usual dose of 200 mg once daily and naproxen 500 mg twice daily. 2 The drugs were administered for 4 weeks to 230 patients suffering from osteoarthritis of the hip and/or knee in the first trial and to 249 patients suffering from rheumatoid arthritis in the second. 3 The studies compared treatments for both safety and overall effectiveness in the relief of pain. 4 In the osteoarthritis trial, overall pain was reduced by both drugs after 2 weeks of therapy but only isoxicam produced further improvement after 4 weeks. 5 Isoxicam produced reductions comparable to those produced by naproxen in pain on standing from the sitting position, pain on walking, and pain on movement of the affected joint, after 2 and 4 weeks. 6 After 4 weeks, isoxicam given once daily in the morning was significantly more effective than naproxen given in the morning and the evening in relieving not only total pain as assessed by a visual analogue scale but, as importantly, night pain. 7 Compared to naproxen therapy, isoxicam therapy was associated with significantly more patients whose disease state was improved at 2 weeks, as assessed by physicians. 8 In the rheumatoid arthritis trial, isoxicam was equally as effective as naproxen in reducing joint tenderness, joint swelling, and pain; at 4 weeks there was a trend in favour of isoxicam in reduction of joint swelling and pain. 9 Isoxicam reduced morning stiffness significantly more than naproxen after 4 weeks; this trend was apparent at 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of captopril on bradykinin inactivation by human foetal placental circulation.
Authors: Soares de Moura R. , Solano Vale N.
Published: July 2012

The inactivation of bradykinin on passage across the human foetal placental circulation was investigated in six full‐term human placentas. The placentas were perfused with a modified Krebs‐Henseleit solution and placenta perfusion pressure was recorded. Samples collected at the arterial inflow and at the venous effluent were assayed on the isolated guinea‐pig ileum as an estimation of bradykinin activity. Bradykinin (100 ng ml‐1) was infused through the foetal placental vessels before and during captopril 4 X 10(‐7) M. Bradykinin produced a transient increase in placental vascular resistance that was not potentiated by captopril. Bradykinin activity was completely abolished after passage through the foetal placental circulation, and the inactivation was blocked by captopril. These data suggest that angiotensin I converting enzyme (kininase II) might occur in the foetal placental vessels.
Plasma and synovial fluid kinetics of flurbiprofen in rheumatoid arthritis.
Authors: Aarons L. , Salisbury R. , Alam‐Siddiqi M. , Taylor L. , Grennan DM
Published: July 2012

Clinical assessment, plasma and synovial fluid kinetics were studied in 29 rheumatoid patients receiving 100 mg flurbiprofen twice daily. Clinical assessment and pharmacokinetic measurements varied widely within the group of patients. The average values for plasma clearance, volume of distribution and elimination halflife of flurbiprofen were 0.65 +/‐ 0.24 ml min‐1 kg‐1, 0.160 +/‐ 0.093 l kg‐1 and 3.1 +/‐ 1.7 h, respectively. Synovial fluid drug concentrations peaked later and were lower than corresponding plasma concentrations: 5.2 h and 4.4 mg l‐1 as against 1.49 h and 12.5 mg l‐1, respectively. At 48 h after an oral dose of flurbiprofen, all the drug had been cleared from the synovial fluid. Synovial fluid drug concentrations were not related to synovial fluid albumin concentration or pH. There was a weak relationship between synovial fluid drug concentration and the thermographic measurements of disease activity. The fractions of flurbiprofen not bound to protein in synovial fluid and plasma were not significantly different. A simple model is proposed to account for the plasma and synovial fluid pharmacokinetics.
Intra‐ and inter‐individual variation in pharmacokinetics of intravenously infused amoxycillin and ampicillin to elderly volunteers.
Authors: Sjovall J. , Alvan G. , Huitfeldt B.
Published: July 2012

The purpose of this study was to investigate the disposition of two aminopenicillins and their intra‐ and inter‐individual variation in pharmacokinetic parameters in healthy, elderly volunteers. Two groups, each of 12 active, community‐dwelling volunteers between 69 and 83 years of age participated. One group was given 500 mg of amoxycillin, the other group 500 mg of ampicillin as single i.v. infusions. Within the drug groups each volunteer was given the infusion at two different occasions separated by a time‐period of 1 week. Amoxycillin and ampicillin were determined in plasma and urine by modern column liquid chromatographic methods. The mean plasma clearance was about 200 ml min‐ 1 1.73 m‐2 for both drugs and renal clearance accounted for approximately 80% of this. As expected, drug clearance was correlated to renal function as determined by 51Cr‐EDTA. The volume of distribution at steady‐state (Vss) was about 0.3 l kg‐1 for both drugs. Compared to our previous results in younger subjects, plasma and renal clearances were essentially similar in this study, but slightly longer half‐lives and higher Vss were seen for amoxycillin and ampicillin. The intra‐individual variation, expressed as the error of a single determination (CV), was small, for plasma clearance 3.7% and 6.4% after amoxycillin and ampicillin. The corresponding inter‐individual variation in clearance was higher, 14.4% after amoxycillin, and 11.9% after ampicillin. The results confirm a higher relative efficiency of a crossover vs a completely randomized parallel groups design in parenteral studies of these penicillins. In our elderly subjects there was only an approximately 30% decrease in renal function. This was not enough to reduce the drug clearance and offers an explanation for the similarity between our present results in the elderly and our previous results in younger subjects. Elderly volunteers may be different from patients with disease as a confounding factor. Studies on elderly active and community‐dwelling volunteers, as in this study, may therefore be more representative as to the effect of age per se on drug kinetics.
Hypnotic activity of an imidazo‐pyridine (zolpidem).
Authors: Nicholson AN , Pascoe PA
Published: July 2012

Effects of an imidazo‐pyridine (zolpidem: 10, 20 and 30 mg) on overnight sleep and on performance the next day were studied in young adults and in middle aged individuals. The young adults were used particularly as an homogenous group to establish any possible adverse effects of the drug on sleep and on performance the next day, and the middle aged subjects with their less restful sleep were used to study efficacy. In the young adults zolpidem led to a marked increase in slow wave sleep with a reduction in stage 2 sleep. There were no significant changes in REM sleep, though there was a tendency for REM sleep to be delayed. In the middle aged there was a reduction in awake activity and drowsy sleep with an increase in stage 2 sleep. The latency to REM sleep was increased but the duration of REM sleep over the whole night was not reduced. Digit symbol substitution and a complex reaction time task were used to study performance, but there were no residual effects with zolpidem (9 h after ingestion). Zolpidem is likely to prove useful in the management of transient and short‐term insomnia in healthy middle aged individuals when impaired performance the next day is to be avoided.
Plasma concentrations of sodium cromoglycate given by nebulisation and metered dose inhalers in patients with exercise‐induced asthma: relationship to protective effect.
Authors: Patel KR , Tullett WM , Neale MG , Wall RT , Tan KM
Published: July 2012

Plasma sodium cromoglycate (SCG) concentrations were measured in 11 patients at regular intervals before and after exercise in a double‐ blind study to assess the protective effect in exercise‐induced asthma (EIA) of 2, 10 and 20 mg SCG aerosol and placebo, and (on an open basis) nebulised SCG (10 g l‐1). There was a dose related increase in plasma concentration and AUC (0‐1 h) with the aerosol formulations; values with nebulised SCG were significantly higher than with any aerosol dose. Protection from EIA increased to a maximum of 66% at plasma concentrations of 4 ng ml‐1 and above. Thus measurement of plasma concentration can allow a comparison to be made between the protective effects of SCG following different methods of inhalation. It is important to note, however, that plasma concentration per se is almost certainly not related directly to protective effect.
Abnormal vitamin K metabolism in the presence of normal clotting factor activity in factory workers exposed to 4‐hydroxycoumarins.
Authors: Park BK , Choonara IA , Haynes BP , Breckenridge AM , Malia RG , Preston FE
Published: July 2012

The case histories of two patients exposed to the novel anticoagulants brodifacoum and difenacoum are reported. Abnormal vitamin K1 metabolism, as indicated by elevated vitamin K1 2,3‐epoxide plasma concentrations after i.v. administration of vitamin K1, could be detected for more than 18 months after exposure to the anticoagulants. There was a marked prolongation of prothrombin time (greater than 50 s) in both cases, at the time of exposure. However, subsequent haematological investigations (prothrombin time and vitamin K‐dependent clotting factor activity) have been shown to be normal in both cases for at least 18 months. These cases confirm the long‐acting nature of brodifacoum and difenacoum and present an apparent dissociation between the effect of coumarin anticoagulants on vitamin K1 metabolism and clotting factor activity.
Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man.
Authors: Rosenkranz B. , Fischer C. , Meese CO , Frolich JC
Published: July 2012

The present study was designed to investigate the effects of salicylate on the antiplatelet action of acetylsalicylic acid as well as on in vivo prostanoid formation and platelet function in healthy volunteers. In the first study six female volunteers received 350 mg acetylsalicylic acid intravenously, with and without previous oral administration of sodium salicylate (1200 mg daily for 3 days). Urinary prostanoid excretion as well as platelet aggregation and thromboxane formation were measured before and during salicylate and after acetylsalicylic acid. In the second study seven female volunteers received sodium salicylate (52.6 mg kg‐1) or acetylsalicylic acid (60.7 mg kg‐1) for 8 days in a randomized cross‐over protocol. Urinary prostanoid excretion, platelet aggregation and thromboxane formation as well as salicylate plasma concentrations were determined before, during and after administration of each drug. Sodium salicylate did not impair the complete suppression of arachidonic acid‐induced platelet thromboxane formation and aggregation obtained by the single intravenous dose of acetylsalicylic acid in the first study. Sodium salicylate in the second study did not affect urinary excretion of prostaglandin E2, its major urinary metabolite (7 alpha‐hydroxy‐5,11‐ diketo‐tetranor‐prostane‐1,16‐dioic acid), and 2,3‐dinor‐6‐keto‐ prostaglandin F1 alpha, the main urinary metabolite of epoprostenol (prostacyclin, PGI2). In contrast, acetylsalicylic acid significantly decreased excretion rates of these prostanoids by 64, 59 and 61%, respectively. In both studies platelet aggregation and thromboxane formation induced by collagen, thrombin or arachidonic acid were not significantly affected by salicylate administration, whereas acetylsalicylic acid inhibited platelet aggregation induced by all three agents as well as thrombin‐ and arachidonic acid induced thromboxane formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Tobramycin pharmacokinetics in very low birth weight infants.
Authors: Nahata MC , Powell DA , Durrell DE , Miller MA
Published: July 2012

Tobramycin is commonly used at a dose of 2.5 mg kg‐1 12h‐1, but this regimen often results in trough serum concentrations exceeding 2 mg l‐ 1. Because of limited data in infants weighing less than 1,000 g at birth, we studied eight newborn infants (gestational age 24‐30 weeks; postnatal age 3 X 4 days; birth weight 0.60‐0.97 kg) at a modified dosing regimen of 2.5 mg kg‐1 18 h‐1 or 3.0 mg kg‐1 24 h‐1. Tobramycin peak and trough serum concentrations ranged from 6.0‐10.8 (7.8 +/‐ 1.5) mg l‐1 and 1.2‐2.4 (1.7 +/‐ 0.4) mg l‐1, respectively. Serum concentration exceeded 2 mg l‐1 in seven of eight patients at 12 h and two of eight at 18 h; none had a trough serum concentration above 2 mg l‐1 at 24 h. Total body clearance ranged from 0.55 to 0.82 (0.69 +/‐ 0.10) ml min‐1 kg‐1; apparent volume of distribution ranged from 0.44 to 0.71 (0.59 +/‐ 0.10) 1 kg‐1; and elimination half‐life ranged from 7.7 to 12.6 (9.9 +/‐ 1.5) h. These data indicate that the modified dosage regimen of 2.5 mg kg‐1 18 h‐1 or 3.0 mg kg‐1 24 h‐1 appears to be more acceptable than the current regimen in achieving effective and safe peak and trough serum concentration of tobramycin in newborn infants weighing less than 1 kg at birth.
The effect of vehicle on the oral absorption of cyclosporin.
Authors: Johnston A. , Marsden JT , Hla KK , Henry JA , Holt DW
Published: July 2012

Twelve healthy volunteers received four separate doses of cyclosporin (5 mg kg‐1). On three occasions the neat oil suspension (Sandimmun) was given dispersed in a different liquid vehicle and on one occasion the suspension was taken directly. Measurement of whole blood cyclosporin concentrations by radioimmunoassay showed no significant difference in the pharmacokinetic parameters of absorption between the neat preparation and the three dispersants used (milk, milk + chocolate flavouring and orange juice).
Comparison of the acute vascular effects of frusemide and bumetanide.
Authors: Johnston GD , Nicholls DP , Kondowe GB , Finch MB
Published: July 2012

The acute peripheral vascular and diuretic effects of intravenous frusemide 10 mg and 20 mg were compared with those of bumetanide 250 micrograms and 500 micrograms in a group of 10 salt depleted volunteers. Significant reductions in forearm blood flow (FBF) were observed after frusemide 10 mg (‐0.77 ml 100 ml‐1 min‐1 P less than 0.05) and 20 mg (‐0.75 ml 100 ml‐1 min‐1 P less than 0.01 at 15 min). No changes were observed after bumetanide. The reductions in blood flow produced by frusemide were significantly different from those of bumetanide (P less than 0.05) at 15 min. Increases in venous capacitance (VC) and mean arterial blood pressure (MAP) were observed after frusemide but these differences were not statistically different from placebo or bumetanide. No increases were seen after bumetanide. Plasma aldosterone concentrations were unchanged after either drug but plasma renin activity (PRA) was increased after frusemide 10 mg (4.42 +/‐ 1.01–8.50 +/‐ 1.90 ng A I ml‐1 h‐1 P less than 0.01) and 20 mg (4.01 +/‐ 0.72–7.81 +/‐ 2.27 ng A I ml‐1 h‐1 P less than 0.05). No increases were observed after bumetanide and significant differences between bumetanide and frusemide were observed (P less than 0.01). This study demonstrates that the acute peripheral arterial effects of frusemide are not observed after comparable diuretic doses of bumetanide. The differences appear to be related to the ability of the drugs to stimulate acute renin release from the kidney.
Comparison of pharmacokinetic profiles of single and multiple doses of a slow release Oros oxprenolol delivery system in young normotensive and elderly hypertensive subjects.
Authors: Bradbrook ID , Babiker M. , Crome P. , Gillies HC , Morrison PJ , Rogers HJ , Shotton P.
Published: July 2012

Oxprenolol in an Oros 8/130 sustained release osmotic pump system (equivalent to 120 mg oxprenolol hydrochloride in a conventional formulation and releasing 8 mg h‐1) was given to eight normal young subjects (mean age 23 years) and eight elderly hypertensive patients (mean age 77 years). The plasma concentration‐time profiles of oxprenolol were determined over 32 h using gas liquid chromatography after the initial dose and following seven doses. The elderly patients had a significantly higher AUC and maximum plasma oxprenolol concentration following both the first and final doses studied. It is unlikely that this difference is due to a prolonged absorption phase in the elderly patients. Reduced drug clearance seems the most probable explanation.
Slow release nifedipine and atenolol as initial treatment in blacks with malignant hypertension.
Authors: Isles CG , Johnson AO , Milne FJ
Published: July 2012

We have compared the efficacy and safety of slow release nifedipine and atenolol given orally as initial treatment for malignant hypertension. Twenty consecutive black patients with untreated malignant hypertension, whose diastolic pressure remained greater than 120 mm Hg after 3 h bed rest, were randomized to receive either slow release nifedipine 40 mg at 1 and 12 h, or atenolol 100 mg at 0 h only. Patients remained supine throughout the study. Blood pressure was measured using a semi‐automatic recorder (Omega 1000) at 15 min intervals from ‐3 to 24 h. Baseline blood pressure was similar in the nifedipine (233/142 mm Hg) and atenolol (226/141 mm Hg) groups. The rate of fall of pressure was greater after nifedipine whose maximum hypotensive effect occurred 4‐5 h after each dose. Blood pressure decreased more slowly and more enduringly after atenolol, although the extent of fall was the same (delta BP 5 h after first dose nifedipine = 67/41 mm Hg; delta BP 16 h after atenolol = 64/40 mm Hg). There were no precipitous falls in pressure. No patient developed focal neurological signs, nor was heart failure precipitated by either form of treatment. These results support recommendations that most patients with malignant hypertension can be managed without recourse to parenteral therapy.
The effect of verapamil on antipyrine pharmacokinetics and metabolism in man.
Authors: Bach D. , Blevins R. , Kerner N. , Rubenfire M. , Edwards DJ
Published: July 2012

The effect of verapamil pre‐treatment on the pharmacokinetics and metabolism of antipyrine was studied in eight healthy male volunteers. The oral clearance of antipyrine was decreased from 2.18 to 1.95 l h‐1 (P less than 0.01) by verapamil (80 mg three times daily for 2 days prior to antipyrine administration and 2 days following) while half‐ life was increased from 13.2 to 15.6 h (P less than 0.01). The urinary excretion of norantipyrine, 4‐hydroxyantipyrine and 3‐ hydroxymethylantipyrine was decreased by 19.2%, 23.1% and 16.7% respectively (P less than 0.05) in the presence of verapamil. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 30%. These results suggest that verapamil is capable of inhibiting oxidative metabolism, a finding which could be of clinical significance for drugs highly dependent upon pathways such as those inhibited in this study for elimination.
Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid.
Authors: Miners JO , Grgurinovich N. , Whitehead AG , Robson RA , Birkett DJ
Published: July 2012

Salicylic acid and acetylsalicylic acid (aspirin) disposition after an oral dose of aspirin, 900 mg (equivalent to 689.7 mg of salicylic acid) was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Salicylic acid clearance was 61% higher in males compared to the control female group, an effect due largely to enhanced activity of the glycine conjugation pathway (salicyluric acid formation) in males. Salicylic acid clearance was 41% higher in OCS‐users compared to the control female group due to increases in both the glycine and glucuronic acid conjugation pathways in the pill users. There was no difference in any salicylic acid disposition parameter between males and OCS‐users. Area under the plasma concentration‐time curve (AUC) and elimination half‐life of aspirin was significantly greater and aspirin plasma hydrolysis rate was significantly lower in both female groups compared to males. There was no difference between OCS‐users and the control female group in any of these parameters. Aspirin AUC and elimination half‐life were significantly correlated with aspirin plasma hydrolysis rate. These data confirm the importance of hormonal factors in the regulation of drug conjugation reactions in humans and suggest that sex‐related differences in salicylic acid and aspirin disposition may be of clinical importance.
Dose determinants of rebound insomnia.
Authors: Roehrs TA , Zorick FJ , Wittig RM , Roth T.
Published: July 2012

A polysomnographic assessment in healthy normal sleepers of possible dose relations for rebound insomnia was conducted. As an additional measure of rebound the study included a direct test of sleep/wake tendency during the night of drug discontinuation. Twelve, healthy men (21‐30 years) each received placebo, 0.25 mg and 0.50 mg triazolam for 6 consecutive nights followed by a discontinuation night and 14 nights of recovery at home. The three conditions were presented, double‐blind, in a latin square design. On night 6 of drug administration both doses increased total sleep time compared to placebo, but 0.50 mg did not improve sleep beyond 0.25 mg. On drug discontinuation (night 7) wake time over the 8 h recording and sleep latency after an experimental awakening (02.30 h) were increased with 0.50 mg compared to placebo and 0.25 mg. On these measures of rebound 0.25 mg did not differ from placebo. Thus rebound insomnia occurred only at a dose (0.50 mg) which produced no additional hypnotic efficacy in these normal sleepers. Whether tests of sleep/wake tendency make a useful measure of rebound insomnia needs further clarification.
Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin.
Authors: Kirch W. , Stenzel J. , Dylewicz P. , Hutt HJ , Santos SR , Ohnhaus EE
Published: July 2012

In a placebo controlled double‐blind study including 10 patients with heart failure the nisoldipine/digoxin interaction was studied. Nisoldipine was shown to elevate digoxin plasma concentrations significantly by about 15% (trough levels). During chronic combination therapy with nisoldipine trough levels and plasma concentrations 4 h after the morning dose of digoxin were 1.35 +/‐ 0.14 and 1.92 +/‐ 0.16 ng ml‐1 respectively, whereas they averaged to 1.16 +/‐ 0.14 and 1.52 +/‐ 0.16 ng ml‐1 with digoxin and placebo (P less than 0.05; mean +/‐ s.e. mean). Systolic time intervals were significantly altered by nisoldipine co‐administration compared with digoxin plus placebo. In certain patients the elevation of digoxin plasma levels due to nisoldipine co‐administration could be of clinical relevance.
Effect of oral verapamil on glibenclamide stimulated insulin secretion.
Authors: Semple CG , Omile C. , Buchanan KD , Beastall GH , Paterson KR
Published: July 2012

In order to study the effect of the calcium antagonist, verapamil, on glibenclamide stimulated insulin release, nine healthy fasted male volunteers were given 5 mg oral glibenclamide with either 120 mg oral verapamil or placebo in a double‐blind crossover manner 1 week apart. Blood was withdrawn at intervals for drug, hormonal and glucose estimations. Concomitant administration of verapamil resulted in higher levels of glibenclamide at each time point (P less than 0.01) suggesting that verapamil interferes with glibenclamide metabolism. However, levels of plasma glucose, C‐peptide, insulin and glucagon did not differ between the verapamil and placebo studies.
The disposition of amodiaquine in man after oral administration.
Authors: Winstanley P , Edwards G , Orme M , Breckenridge A
Published: July 2012

A method is described for the simultaneous determination of amodiaquine (AQ) and desethylamodiaquine (AQm) in plasma, urine, whole blood and packed red cells. After oral administration of AQ (600 mg) to seven healthy subjects, absorption of AQ was rapid, reaching peak concentrations in plasma, whole blood, and packed cells at 0.5 +/‐ 0.03, 0.5 +/‐ 0.1 and 0.5 +/‐ 0.1 h respectively (mean +/‐ s.e. mean). The apparent terminal half‐life of AQ was 5.2 +/‐ 1.7 h. AQ was detectable for no longer than 8 h. AQ underwent rapid conversion to AQm, which reached peak concentrations in plasma, whole blood and packed cells at 3.4 +/‐ 0.8, 2.3 +/‐ 0.5 and 3.6 +/‐ 1.1 h respectively. AQm was still detectable at the end of the sampling period (96 h) when the plasma concentration was 29 +/‐ 8 ng ml‐1. The area under the plasma concentration vs time curve (AUC(0, infinity] for AQ was 154 +/‐ 38 ng ml‐1 h; the corresponding value for AQm was 8037 +/‐ 1383 ng ml‐1 h. There were no significant differences in the values for AUC of AQ between plasma, whole blood, or packed cells. The whole blood to plasma concentration ratio for AQm was 3.1 +/‐ 0.2, and the AUC (0.24) for AQm in whole blood (6811 +/‐ 752 ng ml‐1 h) was significantly greater than that in plasma (2304 +/‐ 371 ng ml‐1 h), P less than 0.001. The recovery of AQm from urine collected 0‐24 h was 6.8 +/‐ 0.8 mg (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of sputum eicosanoids in cystic fibrosis and in normal saliva by bioassay and radioimmunoassay.
Authors: Zakrzewski JT , Barnes NC , Piper PJ , Costello JF
Published: July 2012

We have measured arachidonic acid (AA) metabolites, leukotrienes (LTs) and prostanoids (Ps), in sputum of patients with cystic fibrosis (CF) and in normal saliva using bioassay and radioimmunoassay (RIA). Almost three times as much LTB4 is present in CF extracts compared with slow reacting substances (SRSs). Leukotrienes were not detected in normal saliva. In CF sputum there is a three‐fold increase in the level of the vasodilator prostanoid prostaglandin E2 (PGE2) and the stable metabolite of prostacyclin, 6‐oxo PGF1 alpha compared with the vasoconstrictor prostaglandin F2 alpha (PGF2 alpha) and thromboxane B2 (TxB2), a hydrolysis product of thromboxane A2. Experiments with BW755c (25 micrograms ml‐1, n = 3) indicated that the majority of this activity was not produced during the extraction procedure. The detection of LTs and Ps in sputum of CF patients shows that these substances are present at biologically active concentrations and may contribute to the pathophysiology of this disease.
Nimodipine disposition and haemodynamic effects in patients with cirrhosis and age‐matched controls.
Authors: Gengo FM , Fagan SC , Krol G , Bernhard H
Published: July 2012

Six biopsy proven cirrhotics and five age‐matched controls (mean 55.3 vs 52.4 years) were randomly given single 60 mg p.o. and 30 mg s.l. doses of nimodipine. Serum concentrations and blood pressure were measured regularly over the subsequent 24 h period. The clearance of nimodipine was reduced in the patients with cirrhosis. Apparent oral clearance of nimodipine in the cirrhotic group was significantly lower than that observed in the normal group (187 +/‐ 163 l h‐1 vs 469.6 +/‐ 198.4 l h‐1, P less than 0.01). There were no significant changes in mean arterial pressure (MAP) in the normal subjects. There were, however, significant reductions in MAP following oral nimodipine in the cirrhotics. These reductions were significantly related to nimodipine concentrations in individual patients (P less than 0.05).
The mechanism of salbutamol‐induced hypokalaemia.
Authors: Whyte KF , Addis GJ , Whitesmith R , Reid JL
Published: July 2012

The following four intravenous treatments were administered in a balanced, randomized Latin square design to eight healthy volunteers: (‐)‐adrenaline (0.06 microgram kg‐1 min‐1 for 90 min) + vehicle control (+)‐glucose infusion (60 min), salbutamol (120 ng kg‐1 min‐1 for 30 min) + vehicle control (+)‐glucose infusion (90 min), (‐)‐adrenaline (0.06 microgram kg‐1 min‐1 for 90 min) + salbutamol (120 ng kg‐1 min‐1 for 30 min) and two vehicle control infusions of (+)‐glucose. All active solutions were preceded by a 1 h control infusion and the control infusion was continued for 1 h following the active solutions. Both the active solutions, (‐)‐adrenaline and salbutamol were increased stepwise to the above doses. Heart rate and blood pressure were recorded at frequent intervals throughout and venous blood was taken for the estimation of potassium, insulin, glucose, catecholamine and salbutamol levels. Adrenaline levels similar to those seen in acute illness were achieved using this infusion protocol. Salbutamol levels rose throughout the period of the salbutamol infusions and steady‐state was not achieved. Potassium levels were unchanged on the control + control study day and fell on all active treatments (0.45 mmol l‐1 following (‐)‐adrenaline + control; 0.48 mmol l‐1 following salbutamol + control; 0.93 mmol l‐1 following (‐)‐adrenaline + salbutamol). Insulin levels rose insignificantly after salbutamol alone and fell slightly on all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of enalapril on the skin response to bradykinin in man.
Authors: Fuller RW , Warren JB , McCusker M , Dollery CT
Published: July 2012

We tested the effect of oral enalapril on intradermal bradykinin to determine if kininase II inhibition occurs with therapeutic doses in vivo. Six normal male volunteers took either 5 mg enalapril orally or placebo on 2 days. Three hours later bradykinin was injected into the skin of the back in doses increasing from 10(‐11) to 10(‐9) M. Enalapril increased the bradykinin‐induced wheal. Inhibition of kininase II may cause accumulation of endogenous bradykinin. This could be an important mechanism in the occasionally reported side effect of angioedema with the angiotensin converting enzyme (ACE) inhibiting group of drugs.
The effect of an angiotensin converting enzyme inhibitor, ramipril, on bronchial responses to inhaled histamine and bradykinin in asthmatic subjects.
Authors: Dixon CM , Fuller RW , Barnes PJ
Published: July 2012

The effect of a potent inhibitor of angiotensin‐converting enzyme, ramipril, was studied on both inhaled histamine and bradykinin‐induced bronchoconstriction in six male, normotensive, mild asthmatic subjects. Oral administration of 10 mg ramipril caused no change in lung function or airway reactivity to inhaled histamine or bradykinin despite achieving adequate reduction in angiotensin‐converting enzyme activity.
Pharmacokinetics of imipenem and cilastatin after their simultaneous administration to the elderly.
Authors: Toon S , Hopkins KJ , Garstang FM , Aarons L , Rowland M
Published: July 2012

The pharmacokinetics of imipenem and cilastatin were studied in a group of six healthy elderly male volunteers following the combined intravenous administration of 500 mg imipenem and 500 mg cilastatin sodium as either single or multiple (6 hourly for 6 days) 20 min constant‐rate infusions. The pharmacokinetics of both imipenem and cilastatin in the elderly were similar to those of young individuals with mild renal failure (Verpooten et al., 1984). There was no change in the pharmacokinetics of either species with time following multiple‐ dosing. Correlations existed between total clearance and the glomerular filtration‐rate (51Cr‐EDTA) for both imipenem and cilastatin.
The respiratory effects of oral ethyl loflazepate in volunteers.
Authors: Fazackerley EJ , Randall NP , Pleuvry BJ , Bradbrook I , Mawer GE
Published: July 2012

A volunteer study was undertaken to assess the respiratory effects of ethyl loflazepate, a new benzodiazepine, and to correlate these with plasma concentrations of the active metabolites. Twelve volunteers were given placebo, 2 mg ethyl loflazepate, and 6 mg ethyl loflazepate on separate occasions. Respiration and plasma metabolite levels were assessed hourly for 8 h and at 24 h. The 6 mg ethyl loflazepate treatment produced a significant decrease (P less than 0.02) in the ventilatory response to carbon dioxide at 5 h. However this did not equate with a peak in plasma metabolite concentrations which were maintained at a plateau level from 4 to 24 h.
Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation.
Authors: Van den Ouweland FA , Franssen MJ , Van de Putte LB , Tan Y , Van Ginneken CA , Gribnau FW
Published: July 2012

Patients with rheumatoid arthritis often have hypoalbuminaemia as a sign of disease activity. In view of the extensive binding of naproxen to albumin, the pharmacokinetics of total and unbound drug were studied in eight patients and eight healthy male volunteers during chronic intake of 500 mg twice daily. The area under the serum concentration‐ time curve of total naproxen during a dose interval, AUC (0,12), smaller in patients (641 +/‐ 101 mg l‐1 h) than in volunteers (896 +/‐ 85 mg l‐1 h; P less than 0.0001). The unbound naproxen AUCu (0,12) was larger in patients (1.9 +/‐ 0.9 mg l‐1 h) than in volunteers (0.7 +/‐ 0.2 mg l‐1 h; P less than 0.01). The higher unbound naproxen concentrations in patients were accompanied by an approximately 40% increase in apparent clearance/bioavailability (CL/F) and a 60% increase in volume of distribution (V/F). Both CL/F and V/F were inversely correlated with the individual serum albumin concentration (r = 0.76, P less than 0.001; r = −0.85, P less than 0.001, respectively). The high unbound naproxen concentration in the serum of patients with active rheumatoid arthritis and concomitant hypoalbuminaemia is not known to be accompanied by an increase in side effects and may be beneficial if anti‐inflammatory effects correlate with unbound drug concentration.
Benoxaprofen‐adverse reactions and monitoring in general practice.
Authors: Newrick PG , Bainton D
Published: July 2012

We report on the pattern of use of benoxaprofen (Opren) in a single group practice for a period which included the complete clinical life of the drug. One hundred and seventy‐two patients of the 6495 practice patients had been prescribed benoxaprofen, but 55% had only a small exposure (less than 20 g). Recorded adverse reactions, of which none was serious, appeared in 25 patients. Most were taking benoxaprofen for osteoarthritis (53%) or non‐specific musculoskeletal pain (39.9%). The issue of a prescription was not recorded in 19.6% of cases and 88% were on additional drugs. Greater precision in record‐keeping is required to avoid problems similar to the experience with benoxaprofen.
N‐desmethylclobazam: a possible alternative to clobazam in the treatment of refractory epilepsy?
Authors: Haigh JR , Pullar T , Gent JP , Dailley C , Feely M
Published: July 2012

The development of anticonvulsant tolerance during 10 days treatment with either clobazam or its principal metabolite, N‐desmethylclobazam (NDMC), was compared in mice using an i.v. infusion of pentylenetetrazole as the convulsive stimulus. Subsequently the anticonvulsant activity of NDMC was assessed in patients with refractory epilepsy. In mice, a highly significant tolerance (P less than 0.001) developed to clobazam (10 mg kg‐1 twice daily). During the same period, there was no significant change (P greater than 0.05) in the protection afforded by NDMC (40 or 80 mg kg‐1 twice daily) although some reduction in anticonvulsant activity was apparent. NDMC (30 mg once daily) was given to nine patients with frequent complex partial and/or grand mal seizures who had become tolerant to the anticonvulsant effect of clobazam. Seven of the patients had been free from benzodiazepine therapy for at least 2 weeks, while the other two patients were switched directly from clobazam. Eight of the nine patients showed a favourable response to NDMC. In the seven who had been given a holiday from clobazam the response to NDMC was similar to the initial response to clobazam and was achieved at plasma NDMC concentrations in the same range as those seen during clobazam administration (1000‐3000 ng ml‐1). It is concluded that NDMC is active as an anticonvulsant in man and there is evidence from the animal studies to suggest that it may be preferable to clobazam.
Acute and subchronic effects of Org 2305 and diazepam on psychomotor performance in man.
Authors: Mattila MJ , Koski J , Stromberg C
Published: July 2012

Three doses (15, 30 and 60 mg) of Org 2305 (O 15, O 30 and O 60 respectively), a novel anxiolytic drug chemically related to mianserin, were compared with placebo and 15 mg diazepam (DZ) on human psychomotor performance in a double‐blind, cross‐over study with 15 healthy volunteers. Objective measurements (choice reaction, tracking, flicker fusion, Maddox wing, digit symbol substitution, memory recall) and subjective assessments (visual analogue scales) were done at baseline and 2 and 13 h after the first dose. This testing procedure was repeated on day 7 when administering the seventh consecutive daily night‐time dose. After the first dose O 15 did not differ from placebo and O 30 rarely differed from placebo. O 60 impaired various objective functions similarly to, or less than DZ. Subjectively, DZ and O 60 were felt as sedative. During subchronic treatment, DZ caused some impairment of baseline due to accumulation of bioassayable benzodiazepines, but significant responses to the last DZ dose were less than those to the first dose. DZ but not O 60 was reported to have caused lethargy and clumsiness during subchronic treatment. In the doses used Org 2305 impaired psychomotor performance less than diazepam did. A dose of 60 mg Org 2305 may offer some advantage over 15 mg diazepam, provided that their anxiolytic effects are about similar.
Metabolism of azathioprine to 6‐thioguanine nucleotides in patients with pemphigus vulgaris.
Authors: Lennard L , Harrington CI , Wood M , Maddocks JL
Published: July 2012

Azathioprine metabolism, to red cell 6‐thioguanine nucleotides (6TGN), was studied in four patients with pemphigus vulgaris. Throughout treatment blood samples were taken for red cell 6TGN assay and differential white cell counts. Metabolite steady‐state occurred in three patients in 2, 2 and 4 months respectively. In the fourth patient red cell 6TGN concentrations increased slowly over 3 years. There was a significant negative correlation between 6TGN concentrations and the white blood cell count (rs = −0.92, P less than 0.0005) in this patient.
The effect of topical dimethindene maleate on weal reactions.
Authors: Humphreys F , Shuster S
Published: July 2012

The topical effect of the histamine H1‐receptor antagonist dimethindene maleate on the wealing response to intradermal histamine, compound 48/80 and house dust mite antigen was studied in 16 subjects using a double‐blind procedure. The mean reduction in weal area +/‐ s.e. mean was 44% +/‐ 13%, 43% +/‐ 13% and 31% +/‐ 13% for histamine, 48/80 and antigen respectively. We conclude that dimethindene maleate is a moderately potent H1‐receptor antagonist, and that the inhibition of the 48/80 and house dust mite induced weals is accounted for by the antihistaminic effect of dimethindene maleate.
Intravenous bumetanide attenuates the rise in plasma vasopressin concentrations during major surgical operations.
Authors: Kaufman L , Bailey PM
Published: July 2012

During a study in seven patients on the endocrine response to major surgical procedures under general anaesthesia an incidental finding was that the administration of intravenous bumetanide prior to surgical stimulation led to reduced concentrations of plasma vasopressin (AVP) when compared with a control group of patients.
Decreased plasma concentrations and clinical effects of alprenolol during combined treatment with pentobarbitone in hypertension.
Authors: Seideman P , Borg KO , Haglund K , von Bahr C
Published: July 2012

The antihypertensive effect of alprenolol has been studied before, during and after additional pentobarbitone treatment. The combined alprenolol‐pentobarbitone treatment significantly decreased alprenolol levels by 59% and 4‐hydroxyalprenolol by 24%. The effect was significant after three doses and declined over 4‐5 days after pentobarbitone withdrawal. The decreased alprenolol plasma levels were associated with increased pulse rate (6%), and systolic (8%) and diastolic (9%) blood pressure. The inhibition of exercise tachycardia by alprenolol was reduced by 18% at the end of pentobarbitone treatment compared to initial monotherapy with alprenolol. The interaction is probably clinically important in those patients with hypertension and angina pectoris that are treated with barbiturates and alprenolol.
Intravenous infusion of adenosine but not inosine stimulates respiration in man.
Authors: Reid PG , Watt AH , Routledge PA , Smith AP
Published: July 2012

The effects on respiration of intravenous infusions of the endogenous nucleoside adenosine and its deaminated metabolite, inosine, administered in random order, single‐blind, were compared in six healthy volunteers. The infusion rate of each nucleoside was initially 3.1 mg min‐1 and was increased stepwise every 2 min, as tolerated, up to a possible maximum of 23.4 mg ml‐1. The maximum dose rates received by all subjects were 8.5 mg min‐1 for adenosine and 16.8 mg min‐1 for inosine. Adenosine infusion at rates of 6.1 mg min‐1 and above caused a significant increase in minute ventilation, principally due to an increase in tidal volume, with an associated significant fall in end‐ tidal Pco2. Mean inspiratory flow rate increased and expiratory duration decreased during adenosine infusion, but there was no change in inspiratory duration. Adenosine infusion also caused a significant increase in heart rate and a slight, but significant increase in systolic blood pressure. Infusion of inosine at dose rates up to 16.8 mg min‐1 produced no pharmacological effects. This study shows that adenosine by infusion produces sustained respiratory stimulation in man and demonstrates that it does not depend on prior conversion of adenosine to inosine or related metabolites and that it is not secondary to systemic hypotension.
Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients.
Authors: Edwards DJ , Axelson JE , Visco JP , vanEvery S , Slaughter RL , Lalka D
Published: July 2012

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non‐smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S‐3‐hydroxyquinidine, 2′‐oxoquinidinone or quinidine‐N‐oxide between smokers and non‐smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.
Age‐related changes in trimethadione oxidizing capacity.
Authors: Tanaka E , Ishikawa A , Ono A , Okamura T , Misawa S
Published: July 2012

The metabolism of trimethadione (TMO) following oral administration (4 mg kg‐1) has been studied in 11 young male and 11 elderly male patients. The elimination half‐life (h) of TMO was 11.8 +/‐ 1.4 (mean +/‐ s.e. mean) in the young and 23.5 +/‐ 2.17 in the elderly (P less than 0.01). Total body clearance (1 h‐1 kg‐1) was 41.4 +/‐ 2.8 in the young and 29.0 +/‐ 2.4 in the elderly (P less than 0.01). The apparent volume of distribution (1 kg‐1) was 0.67 +/‐ 0.03 in the young and 0.65 +/‐ 0.04 in the elderly. Serum dimethadione (DMO)/TMO ratios at 4 h were 0.65 +/‐ 0.03 in the young and 0.46 +/‐ 0.03 in the elderly (P less than 0.01). These results suggest that N‐demethylation of TMO is inversely related to age.
Release of 5‐aminosalicylic acid from Pentasa during normal and accelerated intestinal transit time.
Authors: Christensen LA , Slot O , Sanchez G , Boserup J , Rasmussen SN , Bondesen S , Hansen SH , Hvidberg EF
Published: July 2012

The influence of intestinal transit time on the release of 5‐ aminosalicylic acid (5‐ASA) from a peroral, slow‐release preparation (Pentasa) was studied at steady state in seven healthy volunteers. Daily dose was 1500 mg Pentasa, normal transit time (NTT) was 24 h (16‐ 26 h) and accelerated transit time (ATT), caused by a laxative, was 5 h (4‐9 h). Median total recovery (24 h, 5‐ASA + acetyl‐5‐ASA) was 87% (61‐ 129%) (NTT) and 81% (56‐100%) (ATT), respectively, (P greater than 0.10). The total faecal excretion of 5‐ASA (per cent of dose) increased from 16%, (9‐21%) (NTT) to 29%, (16‐38%) (ATT) (P less than 0.02). Free 5‐ASA rose from 12% (4‐19%) to 17% (10‐25%), the retained part (in granules) from 4% (2‐5%) to 12% (4‐24%). Urinary excretion decreased correspondingly from 32% (19‐59%) to 21% (11‐38%), predominantly as Ac‐ 5‐ASA (P less than 0.05). Mean plasma Ac‐5‐ASA concentration decreased from 1.42 micrograms ml‐1 to 0.86 microgram ml‐1 (P less than 0.05). An almost complete release of 5‐ASA from Pentasa takes place during NTT. At ATT conditions about 88% is released, indicating Pentasa to be an acceptable source of 5‐ASA in diarrhoeal states.