bluuebunny/crossref_metadata_2025 huggingface dataset:
A population study of the pharmacokinetics of felodipine.
Authors: Blychert E , Edgar B , Elmfeldt D , Hedner T
Published: July 2012

1. The pharmacokinetics of felodipine was studied after continuous oral administration of 5 or 10 mg conventional tablets to a population of 140 male and female Caucasian subjects, of which 67 were hypertensive patients and 73 were healthy volunteers. In addition, 42 of these individuals received felodipine intravenously. 2. With increasing age the area under the felodipine plasma concentration vs time curve (AUC), the maximum plasma concentration (Cmax), and the terminal elimination half‐life of felodipine increased, while the plasma clearance of felodipine decreased. The bioavailability and steady state volume of distribution and the time to Cmax were not consistently influenced by age. 3. The ratio of the AUC of the primary pyridine metabolite of felodipine and that of unchanged drug decreased with increasing age. 4. Neither Cmax, AUC nor the half‐life of felodipine were related to body mass index. 5. The distribution of AUC for felodipine, as well as the ratio of the AUC of this first metabolite to that of unchanged felodipine, was unimodal. Thus, the presence of a sizable group of individuals, with a clinically significant different metabolism of 1,4‐ dihydropyridine due to genetic factors is unlikely. 6. The pharmacokinetics of felodipine did not seem to differ between hypertensive patients and healthy volunteers, when adjusted for age. Neither was there a difference between patients taking beta‐ adrenoceptor antagonists and those who did not. 7. As a group the elderly had higher total concentrations of unchanged felodipine in plasma compared with younger individuals. The variation in plasma concentrations of felodipine between individuals is, however, only partially explained by age. In clinical practice this emphasizes the need for dose titration of felodipine.
Which vasodilator drug in patients with chronic heart failure? A randomised comparison of captopril and hydralazine.
Authors: Schofield PM , Brooks NH , Lawrence GP , Testa HJ , Ward C
Published: July 2012

1. Fifty patients with symptoms due to chronic heart failure despite diuretic therapy were randomised to receive additional treatment with either hydralazine or captopril. The dose was titrated; 24 received hydralazine and 26 captopril up to a maximum daily dosage of 225 mg and 75 mg respectively. Forty‐three patients had coronary heart disease and seven dilated cardiomyopathy. 2. Dyspnoea and tiredness were assessed using a visual analogue scale (0‐100) before and during 12 weeks' treatment. Captopril produced a significantly greater reduction in breathlessness (F = 31.6, P less than 0.001) and tiredness (F = 65.8, P less than 0.001) compared with hydralazine. 3. There was an increase in treadmill exercise time during treatment with both hydralazine (from 5.5 (3.47‐7.53) min to 6.9 (4.87‐8.93) min), and captopril (from 5.0 (3.05‐6.95) min to 7.8 (5.85‐9.75) min), but the degree of improvement was significantly greater in the patients treated with captopril (F = 7.4, P less than 0.001). 4. There was no significant change in right ventricular ejection fraction (from 27.9 (19.3‐36.5)% to 28.7 (20.1‐ 37.3)%) or left ventricular ejection fraction (from 22.2 (14.2‐30.2)% to 23.9 (15.9‐31.9)%) during treatment with hydralazine. However, both right and left ventricular ejection fraction increased significantly during treatment with captopril (from 27.1 (18.9‐35.3)% to 32.0 (23.8‐ 40.2)%, P less than 0.05; and from 25.0 (17.2‐32.8)% to 29.6 (21.8‐ 37.4)%, P less than 0.05 respectively). 5. These results suggest that in patients with symptoms due to chronic heart failure despite diuretic therapy, treatment with captopril produces a greater symptomatic and haemodynamic improvement than treatment with hydralazine.
The effects of flosequinan on regional blood flow in normal man.
Authors: Scott RA , Woods KL , Barnett DB
Published: July 2012

1. The effects of 100 mg and 200 mg flosequinan on limb, hepatic and renal blood flow were investigated in 14 healthy male volunteers in a placebo controlled double‐blind randomised three‐way crossover study. 2. Heart rate, blood pressure, forearm blood flow and venous capacitance measured by volume plethysmography, were recorded sequentially over 4 h, after oral dosing. 3. Apparent hepatic and renal blood flows were estimated 2 h post‐dose by indocyanine green dye clearance and clearance of 125‐iodohippuran respectively. 4. Flosequinan produced dose‐dependent reductions in resting diastolic blood pressure, accompanied by a rise in heart rate. 5. Forearm blood flow increased to a maximum 4 h after 200 mg and this was accompanied by a fall in forearm vascular resistance. 6. Hepatic blood flow increased, compared with placebo, after 200 mg flosequinan, accompanied by a fall in hepatic vascular resistance. Renal blood flow remained unchanged but renal vascular resistance fell significantly, compared with placebo, following both doses of the drug. 7. In normal man blood flow to the limb, hepatic and renal vascular beds is preserved despite dose‐dependent reductions in blood pressure following single doses of flosequinan.
Metabolism of almitrine in extensive and poor metabolisers of debrisoquine/sparteine.
Authors: Herchuelz A , Gangji D , Derenne F , Jeanniot JP , Douchamps J
Published: July 2012

1. Almitrine bismesylate displays wide inter‐subject variation in peak plasma concentrations and can induce peripheral polyneuropathy. 2. The phenotyped volunteer panel approach was used to examine whether almitrine oxidation displayed a genetic polymorphism of the debrisoquine/sparteine type. 3. There was no difference between poor and extensive metabolisers of debrisoquine with respect to the pharmacokinetics and metabolism of almitrine.
The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.
Authors: Lewis LD , Fitzgerald DL , Mohan P , Thatcher N , Harper PG , Rogers HJ
Published: July 2012

1. We investigated the pharmacokinetics of ifosfamide 5 g m‐2 given by two regimens. Six patients (one female), median age 55 (range 40‐71) years, all with lung cancer received 5 g m‐2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23‐72) years were studied on seven treatment occasions with 5 g m‐2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2. After ifosfamide 5 g m‐2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t1/2,z of 5.4 h (3.6‐10.4 h). The median clearance was 60 ml min‐1 (47‐104) and the median volume of distribution was 388 (329‐783) ml kg‐1. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24‐177) nmol nor nitrogen mustard eq h ml‐1. 3. When ifosfamide 5 g m‐2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t1/2,z was 4.5 (3.4‐6.1), the median volume of distribution was 563 (292‐818) ml kg‐1 and the median clearance was 79 (59‐116) ml min‐1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45‐131) nmol nor nitrogen mustard eq ml‐1 h.(ABSTRACT TRUNCATED AT 250 WORDS)
An evaluation of different ibuprofen preparations in the control of postoperative pain after third molar surgery.
Authors: Seymour RA , Hawkesford JE , Weldon M , Brewster D
Published: July 2012

1. Two separate placebo‐controlled studies of parallel design were carried out to evaluate the efficacy of single doses (400 mg) of soluble ibuprofen, ibuprofen liquid in a gelatin capsule and ibuprofen tablets (Nurofen), in patients with postoperative pain after third molar surgery. 2. All ibuprofen preparations provided significant pain relief (P less than 0.05) over a 6 h investigation period. 3. Mean pain scores after ibuprofen tablets and ibuprofen liquid in a gelatin capsule were similar. 4. Soluble ibuprofen 400 mg provided an earlier onset of pain relief (20 min) than ibuprofen tablets (30 min). 5. No unwanted effects were reported in the various ibuprofen treatment groups. 6. The ibuprofen preparations evaluated in this study are effective up to 4 h for controlling postoperative pain after third molar surgery. The soluble form is more efficacious with regard to onset of action.
The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.
Authors: Young MA , Aarons L , Toon S
Published: July 2012

Plasma and synovial fluid concentrations of the enantiomers of flurbiprofen were measured in 15 rheumatoid patients receiving 100 mg racemic flurbiprofen twice daily. Pharmacokinetic parameters showed considerable variability within the group of patients, although differences in S(+)/R(‐) plasma concentration ratios were small. The average values (+/− s.d.) of oral plasma clearance, volume of distribution and elimination half‐life for R(‐)‐flurbiprofen were 0.075 (+/− 0.066) l min‐1, 12.47 (+/− 5.79) l and 138 (+/− 61) min, respectively. The average values (+/− s.d.) of oral plasma clearance, volume of distribution and elimination half‐life for S(+)‐flurbiprofen were 0.057 (+/− 0.035) l min‐1, 12.81 (+/− 4.43) l and 155 (+/− 49) min, respectively. S(+)/R(‐) ratios (+/− s.d.) rose from 1.06 (+/− 0.12) to 1.75 (+/− 0.61) at the end of the 12 h interval in plasma and from 1.18 (+/− 0.13) to 1.47 (+/− 0.24) over the measured time course in synovial fluid. Increases in S(+)/R(‐) ratios may be clinically important as they demonstrate accumulation of the pharmacologically active species.
Interaction between digoxin and indomethacin or ibuprofen.
Authors: Jorgensen HS , Christensen HR , Kampmann JP
Published: July 2012

To study a potential interaction between digoxin and two non‐steroid anti‐inflammatory drugs, indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily) were given for 10 days to 10 and 8 patients, respectively, on chronic digoxin treatment. Serum digoxin measured by fluorescence polarisation immunoassay increased significantly (P less than 0.05) during treatment with indomethacin from pre‐treatment values of 0.73 +/− 0.34 nmol l‐1 (mean +/− s.d.) to a mean value of 1.02 +/− 0.43 nmol l‐1, while administration of ibuprofen did not change the steady state serum concentration of digoxin. The result demonstrates that some non‐steroidal anti‐ inflammatory drugs such as indomethacin increase serum digoxin to levels high in the therapeutic range. This should be taken into consideration when co‐administering other drugs known to increase the serum concentration of digoxin such as several antiarrhythmics.
The effects of enalapril and sulindac on the dermal response to substance P and neurokinin A.
Authors: Ferner RE , Kamali F , Rawlins MD
Published: July 2012

The effects of pretreatment with enalapril, and sulindac, on the weal response to intradermal injections of substance P and neurokinin A were assessed in a randomised, double‐blind, placebo‐controlled study. Weal responses to both substance P and neurokinin A depended significantly on dose. Neither enalapril nor sulindac, nor the combination of these agents influenced the responses to either tachykinin. These results do not suggest any role for substance P or neurokinin A in the clinical effects of angiotensin converting enzyme inhibitors.
Paracetamol poisoning in children and hepatotoxicity.
Authors: Penna A , Buchanan N
Published: July 2012

1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re‐evaluate the safety of paracetamol in the context of chronic therapy in infants and young children.
Disposition and tumour concentrations of platinum in hypoalbuminaemic patients after treatment with cisplatin for cancer of the head and neck.
Authors: Holding JD , Lindup WE , Bowdler DA , Siodlak MZ , Stell PM
Published: July 2012

1 Platinum concentrations in the tumour reached a peak of 3.8 +/‐ 1.5 micrograms g‐1 wet weight tissue at the end of an 8 h intravenous infusion of cisplatin. The tumour concentrations of platinum were higher than the corresponding plasma concentrations (2.5 +/‐ 0.9 micrograms ml‐1) and declined more slowly. 2 Patients with squamous carcinoma of the head and neck had a significantly shorter median survival time if they had low plasma albumin concentrations (less than 40 g l(‐1) compared with patients in the normal range, 133 days and 768 days respectively (P less than 0.05) after treatment with cisplatin. 3 No changes in the pharmacokinetics of platinum were detected to account for this poor response of hypoalbuminaemic patients, but plasma albumin concentration was found to be negatively correlated with the first order elimination rate constant. 4 The cumulative urinary excretion of platinum in the first 24 h was not altered by lowered plasma albumin. 5 The concentration of platinum in the tumour did not correlate with the survival time of the patient, but was found to be correlated with the volume of distribution in the post‐distributive phase.
The pharmacodynamics and pharmacokinetics of a novel thromboxane receptor blocking drug vapiprost (GR32191) after single intravenous doses in healthy subjects.
Authors: Thomas M , Keery RJ , Charter MK , Scully NL , Chilton JE , Lumley P
Published: July 2012

1 The effect of single, serially increasing, intravenous doses of a specific thromboxane receptor blocking drug, vapiprost, upon platelet aggregation induced ex vivo by the thromboxane A2 mimetic, U‐46619, was examined in 12 healthy males. 2 Subjects received either 1 (n = 1 subject), 2 (n = 6), 3 (n = 2), or 4 (n = 3) administrations of vapiprost within the dose range 0.125 to 16 mg and, in random order, placebo on separate study days at intervals of at least 48 h. 3 All doses of vapiprost produced an immediate antagonism of U‐46619‐induced platelet aggregation in whole blood. Both the magnitude and duration of the rightward displacement of the concentration‐effect curves increased with dose. Although lower doses produced parallel displacements of these curves, with the higher doses the maximum response to U‐46619 was reduced such that 50% platelet aggregation was not achieved. After the 16 mg dose of vapiprost, virtually complete suppression of platelet aggregation (up to a concentration of 30 microM) was seen. This degree of inhibition was maintained for 2 h after dosing, following which there was a gradual return to pre‐dose U‐46619 sensitivity over the next 12 to 24 h. U‐46619‐induced platelet aggregation was unaffected by placebo. 4 Across the dose range, vapiprost was rapidly cleared from plasma, with an elimination half‐life of 69‐84 min and a plasma clearance of 514‐721 ml min‐1.(ABSTRACT TRUNCATED AT 250 WORDS)
Single dose pharmacokinetics of perindopril and its metabolites in hypertensive patients with various degrees of renal insufficiency.
Authors: Verpooten GA , Genissel PM , Thomas JR , de Broe ME
Published: July 2012

1 Perindopril is a prodrug which is hydrolysed in vivo to the active metabolite perindoprilat, an angiotensin‐converting enzyme inhibitor. Perindoprilat glucuronide is also found in plasma. 2 The pharmacokinetics of perindopril and its metabolites were studied after administration of a single 4 mg dose to hypertensive patients with various degrees of renal failure. 3 The absorption and elimination of perindopril were not influenced by the degree of renal failure. 4 The mean area under the serum concentration‐time curve of the active metabolite perindoprilat increased from 93 ng ml‐1 h in subjects with normal renal function to 1106 ng ml‐1 in patients with severe renal failure, whereas its half‐life varied from 5.0 to 27.4 h. 5 In the same subjects, the mean area under the curve of perindoprilat glucuronide increased from 78 to 513 ng ml‐1 h, while its half‐life varied from 1.8 h to 7.7 h. 6 Perindopril, perindoprilat, and perindoprilat glucuronide were dialysable. 7 The extent and duration of serum angiotensin‐ converting enzyme inhibition was augmented in renal failure. The mean area under the inhibition time curve (extrapolated to infinity) increased from 2490%.h in subjects with normal renal function to 42241 %.h in patients with severe renal impairment. The half‐life of inhibition varied from 12.1 h to 100.4 h. This effect of renal failure on the pharmacodynamics of perindoprilat was more pronounced than its influence on perindoprilat kinetics. 8 In view of the important influence of renal impairment on the elimination and action of the active substance perindoprilat, a dosage reduction of perindopril is proposed in in patients with renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of selective beta 2‐adrenoceptor blockade on serum potassium and exercise performance in normal men.
Authors: Gullestad L , Birkeland K , Nordby G , Larsen S , Kjekshus J
Published: July 2012

1. The differential effects of beta‐adrenoceptor subtypes on potassium fluxes and exercise capacity were compared in eight healthy young men using single oral doses of the selective beta 2‐adrenoceptor antagonist ICI‐118551, the selective beta 1‐adrenoceptor antagonist atenolol or the non‐selective beta‐adrenoceptor antagonist propranolol. The study was randomized, double‐blind and placebo controlled. 2. Potassium in the venous effluent from the exercising muscles increased progressively with increasing exercise intensity. This response was augmented by propranolol, whereas neither atenolol nor ICI‐118551 modified the response. After exercise potassium concentration fell exponentially with no difference between the treatment regimens. 3. Cumulative work was significantly reduced by ICI‐118551 (6.4%, P = 0.04) and by propranolol (12.4%, P less than 0.01), whereas the reduction with atenolol (5.6%) did not reach statistical significance. 4. Atenolol and propranolol reduced peak heart rate by 23% and 29%, and peak systolic blood pressure by 9% and 11% respectively during maximal exercise. ICI‐ 118551 caused a non‐significant reduction in heart rate during submaximal exercise, with a significant reduction at maximum exercise (6% reduction), whereas systolic blood pressure was not different from placebo. Diastolic blood pressures were similar across all treatment regimens. 5. Similar glucose concentrations were obtained at baseline and at exhaustion during all treatment regimens. Lactate concentrations were comparable for any given exercise intensity irrespective of treatment regimens. Propranolol reduced lactate concentrations from the exercising muscles at maximum exercise in proportion to the reduction of maximal exercise capacity. 6. The subjective perception of fatigue was not affected by either beta 1‐ or beta 2‐adrenoceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
Prolonged effect of CGRP in Raynaud's patients: a double‐blind randomised comparison with prostacyclin.
Authors: Shawket S , Dickerson C , Hazleman B , Brown MJ
Published: July 2012

1. Calcitonin gene related peptide (CGRP) is a potent endogenous vasodilator to which we have previously demonstrated a specific hypersensitivity in skin blood flow in the hands in patients with Raynaud's disease. 2. We have now investigated whether long infusion of CGRP can relieve symptoms of patients with Raynaud's disease using prostacyclin as a control. 3. Six patients were randomised to receive intravenous infusion of either human alpha‐CGRP on one occasion, or prostacyclin (PGI2) on another occasion in a double‐blind and cross‐ over design. The dose of each agent was initially titrated up to 8 ng kg‐1 min‐1 or to a maximum increase in heart rate of 25 beats min‐1. 4. In addition to blood pressure, heart rate and skin blood flow measurements, infrared thermography and cold stress challenge was performed before, immediately after infusion and at 3 and 14 days post‐ infusion. 5. CGRP caused an increase in hand skin blood flow throughout its infusion, whilst PGI2 caused only a short lived increase. The thermographic results showed significant improvement in hand rewarming 3 days after CGRP but not after PGI2. 6. We conclude that 3 h infusion of CGRP was better tolerated than PGI2 and caused objective improvement up to 3 days. CGRP may be an alternative to PGI2 in some patients.
Subcutaneous apomorphine increases regional cerebral blood flow in parkinsonian patients via peripheral mechanisms.
Authors: Sabatini U , Rascol O , Celsis P , Houin G , Rascol A , Marc‐Vergnes JP , Montastruc JL
Published: July 2012

1. We have measured regional cerebral blood flow (rCBF) and motor function before and after the subcutaneous (s.c.) injection of apomorphine in parkinsonian patients deprived of their usual treatment for at least 48 h. 2. Nineteen patients, pretreated with domperidone (20 mg three times daily for 48 h), received a mean dose of 5.8 mg s.c. apomorphine. All patients switched 'on'. The mean motor score was significantly improved (‐65%, P less than 0.01) but no significant change in rCBF was observed. 3. Seven other patients, not pretreated with domperidone, received a lower dose (0.3 mg) of s.c. apomorphine. No change in motor score was observed while the mean rCBF significantly increased (+12%, P less than 0.05). 4. We conclude that s.c. apomorphine increases rCBF in parkinsonian patients. This effect is independent of the central therapeutic effects of the drug. It is mediated by the stimulation of dopaminergic receptors of the cerebral vessels. These receptors are located outside the cerebral blood brain barrier and can be considered as 'peripheral' ones.
Pharmacokinetics of the anti‐inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.
Authors: Taylor IW , Chasseaud LF , Taylor T , James I , Dorf G , Darragh A
Published: July 2012

The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml‐1 +/‐ 0.83 s.d. occurred at a mean time of 1.95 h +/‐ 1.40 s.d. and, thereafter, concentrations declined monoexponentially with a mean half‐life of 3.8 h +/‐ 1.4 s.d. Comparison of these data with those from younger healthy subjects showed that peak drug concentrations, areas under the curve and half‐lives were about two‐ fold greater in the elderly, these differences probably reflecting a lower systemic drug clearance. Similar results were obtained on comparing data from young healthy subjects and elderly rheumatic patients receiving single and repeated doses of ximoprofen (15 mg twice daily). In patients, the half‐life of ximoprofen was 2.5 h +/‐ 0.7 s.d. Within either group, pharmacokinetic parameters after single or repeated doses were similar: ximoprofen did not accumulate in the plasma of the young or elderly.
The disposition of bupivacaine following a 72 h interpleural infusion in cholecystectomy patients.
Authors: Kastrissios H , Triggs EJ , Mogg GA , Higbie JW
Published: July 2012

The disposition of bupivacaine and degree of analgesia following a 72 h interpleural infusion was investigated in 12 adult patients undergoing elective cholecystectomy. The infusion regimen of an initial interpleural bolus dose of 20 ml of 0.5% bupivacaine HCl with adrenaline (1:200,000) followed by continuous infusion at a rate of 8 ml h‐1 of 0.25% plain bupivacaine HCl was designed to achieve continuous post‐operative pain relief for 72 h. In practice an additional bolus dose (identical to the first) administered 5 h after infusion commencement was required to achieve adequate pain relief on the first postoperative day. The mean measured steady‐state plasma bupivacaine concentration was 2.1 mg l‐1 (s.d. +/‐ 0.54, range 1.3‐3.2 mg l‐1). Disposition parameters for bupivacaine measured for the infusion were calculated by non‐compartmental methods and compared with previous values obtained after single and multiple interpleural bolus dose administration. No statistically significant differences were noted and, in particular, the systemic clearance of bupivacaine (mean 10.2 l h‐1 s.d +/‐ 3.0; range 6.3‐16.0 1 h‐1) remained unchanged following the long‐term interpleural infusion. Analgesia was deemed satisfactory throughout the entire post‐operative period.
Comparison and reproducibility of transthoracic bioimpedance and dual beam Doppler ultrasound measurement of cardiac function in healthy volunteers.
Authors: Ng HW , Walley T , Tsao Y , Breckenridge AM
Published: July 2012

1. We compared the ease of use and reproducibility of two noninvasive methods, transthoracic electrical bioimpedance (TEB) (BoMed NCCOM3‐R7) and non‐imaging dual beam Doppler ultrasound (Quantascope‐Vital Science), in cardiac output (CO) and stroke volume (SV) measurement in healthy volunteers at rest and during physiological stress, both short term and from day to day. 2. The TEB method was easier to use and not dependent on the operator. The TEB method was more reproducible both in the short term and from day to day. Both devices were able to detect CO and SV changes under physiological stress, but were less reproducible day to day during exercise. 3. At supine rest, the within subject coefficient of variation between time point for TEB was 4.6% for CO and 6.1% for SV, and 7.9% for CO and 7.4% for SV with Doppler. 4. The results from each device showed a linear correlation coefficient (r) of 0.69 for CO (P less than 0.0005) and 0.64 for SV (P less than 0.0005). The correlation coefficient improved to 0.76 (P less than 0.0005) when only changes in CO and SV were considered. There was no systematic difference in the changes detected by the two methods, but the individual variation was wide.
N‐acetylation phenotyping using dapsone in a Jordanian population.
Authors: Irshaid YM , al‐Hadidi HF , Abuirjeie MA , Rawashdeh NM
Published: July 2012

1. The N‐acetylation of dapsone (DDS) was studied in 160 unrelated healthy Jordanian volunteers. 2. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS), was 67.5% with a 95% confidence interval of 59 to 76%. Slow acetylators had an acetylation ratio of less than 0.42. 3. Applying the Hardy‐Weinberg Law, the frequency of the recessive allele controlling slow acetylation was found to be 0.82 +/‐ 0.02. 4. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. The number of homozygous (n = 16) and heterozygous (n = 36) rapid acetylators derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 5 and n = 47) according to the Hardy‐Weinberg Law. The suggested antimode used to discriminate the two groups was 0.82. 5. The mean plasma concentration of MADDS and the mean plasma acetylation ratio were about three times lower in slow than in rapid acetylators. However, there was no difference in mean plasma DDS concentration between slow and rapid acetylators. 6. There was a significant correlation (r = 0.853, P less than 0.001) between plasma MADDS concentration and the acetylation ratio. For DDS such a correlation was absent (r = 0.059, P = 0.23).
Differential foetal development of the O‐ and N‐demethylation of codeine and dextromethorphan in man.
Authors: Ladona MG , Lindstrom B , Thyr C , Dun‐Ren P , Rane A
Published: July 2012

1. Codeine and dextromethorphan were N‐demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O‐demethylation of these drugs at mid‐gestation. 2. The metabolic data were in accordance with the absence of P450IID6 and the presence of P450 IIIA as determined by Western blotting with anti‐human P450 IID6 (MAb 114/2) and anti‐rat P450 IIIA (PCN 2‐13‐1/C2) monoclonal antibodies, respectively. 3. The inhibitory effects of midazolam and dehydroepiandrosterone support the contention that the N‐demethylase is a human foetal form of the cytochrome P450 IIIA family. Consistent with this we found that blotting with the MAb PCN 2‐13‐1/C2, which recognizes an epitope specific for the P450 III family, correlated well with the N‐demethylase activities.
Direct and metabolism‐dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes.
Authors: Pirmohamed M , Coleman MD , Hussain F , Breckenridge AM , Park BK
Published: July 2012

1. The role of metabolites in sulphasalazine‐mediated toxicity has been investigated in vitro by the use of human red blood cells and mononuclear leucocytes as target cells, with methaemoglobin formation and cytotoxicity respectively, being the defined toxic end‐points. 2. Of the metabolites of sulphasalazine investigated, only sulphapyridine was bioactivated by human liver microsomes in the presence of NADPH to a metabolite which caused marked methaemoglobinaemia and a small, but statistically significant degree of mononuclear leucocyte cell death. 3. Methaemoglobinaemia was inhibited by ketoconazole but not by ascorbic acid (100 microM), glutathione (500 microM) and N‐ acetylcysteine (50 microM). In contrast, ascorbic acid and the thiols afforded complete protection for mononuclear leucocytes. 4. Sulphapyridine (100 microM) was converted in vitro to a metabolite (metabolite conversion 6.8 +/‐ 0.3%), the retention time of which on h.p.l.c. corresponded to synthetic sulphapyridine hydroxylamine. The half‐life of sulphapyridine hydroxylamine in phosphate buffer (pH 7.4) was found to be 8.1 min. 5. In the absence of microsomes and NADPH, sulphapyridine hydroxylamine caused a concentration‐dependent (10‐500 microM) increase in methaemoglobinaemia (2.9%‐24.4%) and cytotoxicity (5.4%‐51.4%), whereas sulphasalazine, sulphapyridine, 5‐hydroxy sulphapyridine and 5‐aminosalicylic acid had no effect.
The prediction of steady‐state plasma phenobarbitone concentrations (following low‐dose phenobarbitone) to refine its use as an indicator of compliance.
Authors: Pullar T , Kumar S , Chrystyn H , Rice P , Peaker S , Feely M
Published: July 2012

1. A model for predicting the steady‐state plasma concentration of phenobarbitone following low‐dose phenobarbitone used as an indicator of compliance was derived using data for 10 healthy volunteers. 2. Each volunteer was given a single 30 mg oral dose of phenobarbitone and the pharmacokinetics were described. Subsequently, volunteers were given phenobarbitone 2 mg daily for 28 days and a further pharmacokinetic profile determined during and after this period. 3. An initial predicted estimate of steady‐state plasma drug concentration was made using each volunteer's demographic details. This estimate was revised by Bayesian analysis using single timed samples (24, 48, 72 or 96 h) following the single dose. 4. The model was tested on a further 10 healthy volunteers given a single 8 mg dose and who were subsequently given 2 mg daily for 28 days. 5. The revised estimate of peak steady‐ state plasma phenobarbitone concentration utilising the 96 h post‐ single dose concentration (356 ng ml‐1) was least biased (mean prediction error +/‐ 95% CI = 10.6 +/‐ 19.8 ng ml‐1) and most precise (root mean square error +/‐ 95% CI = 28.3 +/‐ 19.0 ng ml‐1). In all cases the peak or trough steady‐state drug concentration was within 13% of the predicted value. 6. The model reflected compliance accurately in a further eight volunteers with simulated partial (two‐thirds) compliance. 7. The use of a predictive model using Bayesian analysis to estimate expected steady‐state plasma phenobarbitone concentrations could increase further the usefulness of low‐dose phenobarbitone as an indicator of compliance.
A comparison of the central nervous system effects of caffeine and theophylline in elderly subjects.
Authors: Yu G , Maskray V , Jackson SH , Swift CG , Tiplady B
Published: July 2012

1. The effects of oral administration of 250 mg caffeine or theophylline and placebo on subjective ratings and psychological test performance were studied in a double‐blind crossover experiment in 20 healthy elderly subjects. 2. Performance on the continuous attention task showed a significant improvement compared with placebo with both active treatments. Performance with caffeine was significantly better than with theophylline. Mean error index scores (normalised AUCs) were: placebo‐0.130; caffeine‐0.083; theophylline‐0.093. No other objective measure shows significant treatment effects. 3. Subjective ratings showed that subjects felt significantly more alert on caffeine than on either theophylline or placebo. Subjects also rated themselves as more energetic and interested on caffeine than on placebo. 4. Plasma concentrations of caffeine were lower than those of theophylline (mean 5.76 and 8.72 mg l‐1 respectively at 2 h post‐drug. 5. These results suggest that caffeine is a more potent CNS stimulant than theophylline.
Effects of H1‐receptor blockade with terfenadine in nocturnal asthma.
Authors: Teale C , Morrison JF , Pearson SB
Published: July 2012

1. In a single‐blind placebo controlled study we have measured peak flow (PEFR) at 04.00 h and 16.00 h in eight asthmatics 6 h after placebo or terfenadine 120 mg, to determine if diurnal variation in histamine mediated effects contribute to nocturnal bronchoconstriction in asthma. 2. On placebo there was a significant diurnal variation in mean PEFR of 41 l min‐1 (P less than 0.05). Terfenadine improved 04.00 h baseline mean PEFR from 242 to 278 l min‐1 (P less than 0.05) but a 38 l min‐1 diurnal variation in mean PEFR persisted (P less than 0.05). 3. We conclude that H1‐receptor blockade with terfenadine may produce modest nocturnal bronchodilatation but does not influence the diurnal variation in PEFR in asthma suggesting that H1‐receptor mediated effects are not important in the pathogenesis of nocturnal asthma.
The effects of selective beta‐adrenoceptor antagonists and partial agonist activity on renal function during exercise in normal subjects and those with moderate renal impairment.
Authors: Taverner D , Mackay IG , Craig K , Watson ML
Published: July 2012

1. The effects of sustained moderate exercise in the sitting position on renal haemodynamics and glomerular filtration were measured in six normotensive patients with moderately impaired renal function and seven age‐matched normal volunteers. 2. The changes in the effects of exercise on renal function induced by chronic cardioselective beta‐ adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. 3. Both beta‐ adrenoceptor blockers attenuated the heart rate increase with exercise, but only atenolol lowered blood pressure significantly. In resting volunteers on atenolol, associated with the fall in blood pressure there was a significant reduction in glomerular filtration rate. 4. Glomerular filtration fell significantly in all groups with exercise, and renal blood flow also fell in parallel. These changes were not influenced by drug treatment. 5. The exercise‐induced rise in PRA was suppressed by atenolol but not by epanolol. 6. The renal function and haemodynamic responses to moderate exercise does not appear to be mediated by the systemic renin‐angiotensin system or by beta 1‐ adrenoceptors.
The response to the first dose of an angiotensin converting enzyme inhibitor in uncomplicated hypertension‐a placebo controlled study utilising ambulatory blood pressure recording.
Authors: MacFadyen RJ , Bainbridge AD , Lees KR , Reid JL
Published: July 2012

1. The importance of total dose to the initial hypotensive response with an angiotensin converting enzyme inhibitor (quinapril) was assessed using a suggested ‘maintenance’ dose (20 mg) or matched placebo in a randomised double‐blind study in patients with uncomplicated hypertension. 2. Thirty‐two patients were recruited who were not on therapy or had not received diuretic therapy in their existing drug treatment in the preceding 4 weeks. Secondary causes of hypertension had previously been excluded and sustained clinic blood pressures of SBP greater than 160 mmHg and/or DBP greater than 90 mmHg were taken as indications for a trial of adjuvant or monotherapy with an ACE inhibitor. 3. After uneventful supervised therapy with quinapril in an open pilot study (n = 5) 27 patients entered a double‐blind, randomised, crossover study of quinapril or placebo using ambulatory monitoring to assess BP response. 4. All patients remained asymptomatic and both therapy and monitoring were well tolerated. A smooth onset of antihypertensive effect was noted with an overall 24 h placebo corrected fall in systolic BP of 9.9 mmHg (7.2‐12.6 95% CI) and diastolic BP of 6.4 mmHg (4.2‐8.8) with no significant effect on heart rate. Individual placebo corrected maximal responses during the first 8 h following quinapril showed a wide range for both systolic (+1.56 to 44.0 mmHg) and diastolic (+2.3 to −35.6 mmHg) pressure. Larger falls tended to be associated with higher baseline pretreatment pressures but in no case did absolute systolic pressure fall below 100 mmHg during the first 8 h following administration of placebo or quinapril.(ABSTRACT TRUNCATED AT 250 WORDS)
Penetration of minocycline into lung tissues.
Authors: Naline E , Sanceaume M , Toty L , Bakdach H , Pays M , Advenier C
Published: July 2012

The penetration of minocycline into different lung tissues and bronchial mucus was studied in 17 patients undergoing pulmonary surgery for cancer. The patients received oral minocycline 100 mg at night for 3 days preceding surgery. Minocycline concentrations were measured in plasma samples collected before the operation and in tissues and mucus taken from in and around the part of the lung that was surgically removed. Mean tissue or mucus concentration to plasma concentration ratios were 3.78 +/‐ 1.10 for lung parenchyma, 4.04 +/‐ 1.31 for bronchial walls, 3.37 +/‐ 1.00 for pulmonary arterial walls, 1.99 +/‐ 1.80 for intraluminal mucus collected from bronchi located in healthy tissue proximal to the tumour, 5.16 +/‐ 3.26 for intraluminal mucus collected in a bronchus distal to the tumour, and 3.06 +/‐ 1.99 for catheter‐collected mucus from the trachea and principal bronchi. These results indicate that minocycline is found in high concentration in all types of lung tissue and mucus in man.
Spontaneous reporting: how many cases are required to trigger a warning? [see comments]
Authors: Tubert P , Begaud B , Haramburu F , Pere JC
Published: July 2012

A statistical method is proposed to aid decisions on the recognition of new adverse drug reactions on the basis of spontaneous reports. The maximal number of associations between drug exposure and event is calculated from an independence test between drug and event, taking into account the expected incidence of that particular event in the general population. An example is given which illustrates the method.
Effect of simvastatin and fenofibrate on the fatty acid composition of hypercholesterolaemic patients.
Authors: Agheli N , Jacotot B
Published: July 2012

1. The effects of simvastatin (one of a new class of 3‐hydroxy‐3‐methyl‐ glutaryl coenzyme A reductase inhibitors) and fenofibrate on the fatty acid composition of cholesterol esters, phospholipids and triglycerides of different lipoproteins of 15 patients with primary hypercholesterolaemia were compared in a double‐blind study. 2. Fenofibrate (300 mg day‐1) increased the relative content of saturated fatty acids of cholesterol esters, phospholipids and triglycerides in VLDL, IDL and HDL. It also increased the relative content of monounsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. In contrast, it decreased the proportion of polyunsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. The polyunsaturated/saturated (P/S) ratio was reduced in cholesterol esters and phospholipids in VLDL and in phospholipids in IDL by fenofibrate. The drug significantly increased the 18:1w9/18:2w6 ratio in cholesterol esters and phospholipids in VLDL, LDL and HDL, but produced a non‐significant increase in the ratio in IDL. 3. Simvastatin (20 mg day‐1) produced a significant decrease in saturated fatty acid and an increase in polyunsaturated fatty acid in triglycerides in VLDL. Simvastatin, in contrast to fenofibrate caused a slight decrease in saturated and monounsaturated fatty acids in the three other lipoprotein fractions, and an increase in polyunsaturated fatty acids. The P/S and 18:1w9/18:2w6 ratios were not modified by simvastatin.
A dose‐ranging study of UK‐68,798, a novel class III anti‐arrhythmic agent, in normal volunteers.
Authors: Gemmill JD , Howie CA , Meredith PA , Kelman AW , Rasmussen HS , Hillis WS , Elliott HL
Published: July 2012

1. UK‐68,798, a novel class III anti‐arrhythmic agent was administered intravenously to twelve healthy volunteers in a placebo controlled, double‐blind, dose‐escalating study. 2. Doses of 5 and 10 micrograms kg‐ 1 of UK‐68,798 selectively and significantly prolonged the QT interval, with mean maximum changes of 35 and 107 ms respectively, without affecting other ECG intervals. 3. There were dose‐related increases in AUC but clearance (23 l h‐1), terminal elimination half‐life (8 h) and volume of distribution (245 l) were found to be independent of dose with low levels of intra‐ and inter‐patient variability. 4. UK‐68,798 has electrophysiological effects indicative of selective class III anti‐ arrhythmic activity and merits further assessment in clinical studies.
Nicardipine sustained release in hypertension.
Authors: Webster J , Petrie JC , Jeffers TA , Roy‐Chaudhury P , Crichton W , Witte K , Jamieson M , MacDonald FC , Beard M , Dow RJ , et al
Published: July 2012

1. A novel formulation of nicardipine (25% standard, 75% sustained release‐SR) was evaluated in mild hypertension in a double‐blind, randomized, placebo‐controlled comparison with standard nicardipine (STD), using clinic measurements (Hawksley) augmented by home recorded blood pressures (Copal UA 251). 2. At 2 h after dosing (peak effect) both STD nicardipine (30 mg three times daily) and SR nicardipine (60 mg twice daily) for 28 days produced a highly significant reduction in sitting and standing blood pressure. The mean sitting blood pressure was reduced by 20/16 mm Hg (STD) and by 25/18 mm Hg (SR) compared with placebo. 3. Predose (8‐11 h after last dose of STD, 12‐15 h after last dose of SR) the reductions in sitting blood pressure relative to placebo were 11/6 mm Hg (STD) and 14/7 mm Hg (SR). 4. Home recordings confirmed the hypotensive effect of both formulations. Both exhibited a distinct ‘peak dose’ effect between 1‐3 h after dosing. The effect of the SR formulation was sustained throughout the 12 h dosing interval. 5. Of the 60 patients entering the study, one died of unexplained staphylococcal septicaema, two were withdrawn for non drug‐related reasons and 14 (32%) were withdrawn because of adverse effects on active therapy (headaches, facial flushing, leg oedema, chest pain, dizziness). 6. In the 43 patients who completed the study adverse symptoms were reported more frequently while they were on the two active formulations of nicardipine compared with placebo. Most of these reactions were again of vasodilator origin.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of nifedipine on the disposition of strontium gluconate used as a kinetic marker for calcium in healthy volunteers.
Authors: Moraes ME , Aronson JK , Grahame‐Smith DG
Published: July 2012

1. We have studied the disposition of stable strontium after the intravenous administration of strontium gluconate to eight healthy male volunteers both in control conditions and while they were taking the calcium antagonist nifedipine 10 mg three times daily. 2. Nifedipine, presumably by its action in blocking voltage‐operated calcium channels, altered the in vivo disposition of strontium, causing large reductions in the half‐life and the apparent volume of distribution of strontium. Total and renal clearances of strontium were unaltered by nifedipine. 3. These results support our previous suggestion that the delineation of strontium disposition can be used as a means of studying calcium disposition in vivo in man, and of studying the effects of drugs and diseases on that disposition.
The bioavailability of sustained release nicotinic acid formulations.
Authors: Neuvonen PJ , Roivas L , Laine K , Sundholm O
Published: July 2012

1. The bioavailability of three nicotinic acid formulations was investigated in a randomized cross‐over study. 2. Single doses of nicotinic acid (500 mg) were given to seven healthy volunteers. The concentrations of nicotinic acid and its main metabolite nicotinuric acid were measured in serum up to 8 h and in urine up to 24 h. 3. The relative bioavailability of unchanged nicotinic acid from two slow release formulations compared with a rapid‐release form was only 1% and 25%, respectively. Relative values of AUC (0.8 h) for nicotinuric acid were 15% and 58%, and relative urinary recoveries were 18% and 59%, respectively. Facial flushing was less when slow release formulations were used. 4. The bioavailability of unchanged nicotinic acid is low and the ratio of nicotinuric acid to nicotinic acid in serum and urine is high when slow release formulations are used.
Evidence for pre‐hepatic metabolism of oral cyclosporine in children.
Authors: Hoppu K , Koskimies O , Holmberg C , Hirvisalo EL
Published: July 2012

1. The pharmacokinetics of cyclosporine were investigated before renal transplantation in 20 children aged 1.1 to 16.8 years. Cyclosporine was given as a single oral dose (10 mg kg‐1) or as a 4 h i.v. infusion (3 mg kg‐1). 2. The blood drug concentration was measured by both specific and nonspecific monoclonal radioimmunoassays. 3. The mean oral availability of cyclosporine was 20.6% (range 10.8‐34.1%). 4. The mean ratio of AUCs measured by nonspecific and specific r.i.a. was 1.96 (range 1.4‐2.7) after oral administration and 1.43 (range 1.1‐2.0) after i.v. administration. The mean difference between the ratios was 38.5% (P = 0.0001). The ratio of AUCnonspecific to AUCspecific was inversely related to blood drug clearance (r = 0.57; P = 0.009). 5. The findings are suggestive of presystemic, pre‐hepatic metabolism of cyclosporine which could contribute to the low, and highly variable bioavailability of this drug.