bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of tenoxicam on renal function and the disposition of inulin and p‐aminohippurate in healthy volunteers and patients with chronic renal failure.
Authors: Freestone S , McAuslane JA , Prescott LF
Published: July 2012

1. The effects of tenoxicam on renal function were studied in 10 patients with chronic renal failure (creatinine clearance 46.7 +/‐ 11.9 ml min‐1 1.73 m‐2) and eight healthy volunteers. A parallel treatment control group of eight healthy volunteers received placebo. Tenoxicam was given orally in a dose of 40 mg daily for 2 days followed by 20 mg daily for a further 8 days. Renal function was assessed by measurement of the renal clearances of inulin and p‐aminohippurate (PAH) using the single injection technique before and during administration of tenoxicam. 2. In the healthy volunteers there were no changes in glomerular filtration rate, effective renal plasma flow, or the urinary excretion of N‐acetylglucosaminidase and beta 2‐microglobulin on the 3rd and 10th days of treatment with tenoxicam. The mean urinary excretion of prostaglandins E2 and 6‐keto F1 alpha decreased during treatment but there was great individual variation and the differences were not statistically significant. Tenoxicam had no effect on the half‐ life, clearance, volume of distribution or urinary recovery of inulin and PAH. 3. There was no significant change in the clearance of inulin and creatinine after treatment with tenoxicam for 10 days in the patients with chronic renal failure. However, in this group there was a significant increase in plasma creatinine on the 3rd and 6th days with a return to pretreatment levels by the 10th day. The administration of tenoxicam for 10 days was associated with a small but significant increase in the plasma half‐life and volume of distribution of inulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Age does not influence the serum protein binding of bupivacaine.
Authors: Veering BT , Burm AG , Gladines MP , Spierdijk J
Published: July 2012

The serum protein binding of bupivacaine was studied in 74 subjects, 39 males and 35 females, aged 20‐90 years, without evidence of acute or chronic inflammatory disease or malignancy. Subjects were drug free for at least 1 month. The free fractions of bupivacaine did not change with age in either males or females. This is in keeping with the lack of effect of age on AAG concentrations. Free fractions of bupivacaine were slightly higher in females as compared with males. The previously observed decline in clearance of bupivacaine with age probably reflects a concomitant decline in the metabolic activity of hepatic enzymes.
Compliance with drug therapy.
Authors: Pullar T
Published: July 2012

Although no single method is ideal for measuring compliance the methods now available allow accurate assessment of compliance in most settings. Studies using new and more accurate methods of measuring compliance have shown poor compliance to be an even greater problem than was previously thought. Using these methods, efforts in the future should be directed at relating compliance to treatment outcome, and investigating whether manoeuvres aimed at improving compliance actually improve patient outcome.
Selective effects of low doses of apomorphine on spatiotemporal contrast sensitivity in healthy volunteers: a double‐blind placebo‐ controlled study.
Authors: Blin O , Mestre D , Masson G , Serratrice G
Published: July 2012

1. Apomorphine (1 and 5 micrograms kg‐1) and placebo were given to nine normal volunteers, using a Latin‐square design and double‐blind procedures. The visual perception of static and moving patterns (static and motion contrast sensitivity) was evaluated before and 15 min after the dose administration. 2. Apomorphine (1 and 5 micrograms kg‐1), as compared with placebo, led to a significant overall reduction of the visual perception of movement. This effect was dose‐related, and apomorphine (5 micrograms kg‐1) induced a more pronounced decrease in the visual perception of movement than apomorphine (1 microgram kg‐1). With apomorphine (5 micrograms kg‐1), the reduction was more pronounced for low spatial frequencies, and was linearly inversely correlated to the spatial frequency for a temporal frequency of 3 Hz. Finally, no significant effect of apomorphine was observed for sensitivity to static patterns. 3. Several non exclusive hypotheses may be suggested: The effects of apomorphine may result from stimulation of retinal D1‐ and/or D2‐dopaminergic receptors. Apomorphine may increase the surround inhibition of ganglion cells' receptive‐fields. This modification of the centre‐surround balance may explain the decrease in contrast sensitivity for low spatial frequencies. The specific effects of apomorphine on the visual perception of movement support the hypothesis that apomorphine preferentially affects the magnocellular pathway which mediates sensitivity to moving patterns.
Theophylline therapy inhibits neutrophil and mononuclear cell chemotaxis from chronic asthmatic children.
Authors: Condino‐Neto A , Vilela MM , Cambiucci EC , Ribeiro JD , Guglielmi AA , Magna LA , De Nucci G
Published: July 2012

1. Theophylline is commonly used to relieve symptoms of chronic asthma. Since neutrophil and mononuclear cell activation are associated with late phase asthmatic reactions, effects of theophylline on these cells may be of importance. 2. In the present investigation we compared neutrophil and mononuclear cell chemotaxis from chronic asthmatic children during and after theophylline therapy. 3. Thirty patients were recruited for the study. Each patient received theophylline orally for 10 days. The theophylline dose was 20 mg kg‐1 day‐1 given in four divided doses. On the tenth day, blood was collected into heparinized (100 u ml‐1) and siliconized tubes 2 h after the last theophylline dose for chemotactic assays, cAMP and theophylline plasma determinations. When clinical conditions allowed, theophylline was discontinued for 7 days and the chemotactic assays, cAMP and theophylline plasma concentrations repeated. Serum complement and IgE levels were also determined. 4. Theophylline therapy clearly inhibited both spontaneous and stimulated neutrophil and mononuclear cell chemotaxis. Twenty‐seven patients had therapeutic plasma concentrations of theophylline (5‐20 micrograms ml‐1). Discontinuation of theophylline therapy caused a significant decrease in plasma cAMP levels (44 and 31 pmol ml‐1 respectively during and after treatment, n = 30, P less than 0.001). 5. The inhibition of neutrophil and mononuclear cell migration by theophylline therapy in chronic asthmatic children may be beneficial for the control of the inflammatory response observed in these patients.
Preventive effects of octreotide (SMS 201‐995) on diabetic ketogenesis during insulin withdrawal.
Authors: Diem P , Robertson RP
Published: July 2012

1. Exogenous somatostatin inhibits glucagon secretion and prevents ketoacidosis in diabetic patients, but has the therapeutic disadvantage of requiring continuous intravenous infusion to exhibit these effects. 2. Consequently, we examined the effect of subcutaneous administration of the long‐acting somatostatin analogue octreotide (SMS 201‐995) on early ketogenesis in diabetic ketoacidosis. On two separate occasions insulin was withdrawn over a period of 9 h from seven type I diabetic patients. On the second occasion the patients were given 50 micrograms octreotide s.c. before the insulin withdrawal and every 3 h during insulin withdrawal. 3. Differences in integrated free fatty acid responses (4706 +/‐ 1227 mumol l‐1 h vs 3026 +/‐ 835 mumol l‐1 h, AUC, P = NS) were not significant, but the peak increments of acetoacetate (1413 +/‐ 354 mumol l‐1 vs 612 +/‐ 176 mumol l‐1, P less than 0.05), beta‐hydroxybutyrate (2180 +/‐ 475 mumol l‐1 vs 922 +/‐ 246 mumol l‐1, P less than 0.01) and the decrements in plasma bicarbonate (‐8 +/‐ 1 mumol l‐1 vs ‐4 +/‐ 1 mumol l‐1, P less than 0.05) and pH (‐0.07 +/‐ 0.01 vs ‐0.03 +/‐ 0.01, P less than 0.05) were significantly less with octreotide. 4. At the same time peak increments of glucagon were lower with octreotide treatment (329 +/‐ 206 pg ml‐1 vs 39 +/‐ 30 pg ml‐1, P less than 0.05). 5. We conclude that, despite accelerated lipolysis and provision of substrate for ketogenesis during insulin withdrawal, this somatostatin analogue significantly reduces ketogenesis resulting from insulin deprivation, probably secondary to decreasing glucagon secretion. This drug may be useful in short term prophylactic treatment of diabetic patients during periods of increased risk for ketoacidosis.
Lack of an interaction between propranolol and sumatriptan.
Authors: Scott AK , Walley T , Breckenridge AM , Lacey LF , Fowler PA
Published: July 2012

1. The effect of twice‐daily dosing with propranolol on the pharmacokinetics and pharmacodynamics of a single oral dose of sumatriptan was investigated in 10 healthy male subjects. 2. Each subject received 7 days dosing with propranolol (80 mg twice daily) plus a single dose of sumatriptan (300 mg orally) on day 7; on another separate occasion, placebo was administered for 7 days plus a single dose of sumatriptan on day 7. There was at least a 7 day washout interval between the two periods of dosing. Pulse and blood pressure were measured up to 10 h after dosing with sumatriptan and blood samples were taken up to 26 h post‐dose. 3. Propranolol had no significant effect on any of the derived pharmacokinetic parameters of sumatriptan. The appropriate average parameter values in the presence of propranolol were, respectively: Cmax (120 ng ml‐1 vs 126 ng ml‐1), tmax (4.5 h vs 3.0 h), AUC (580 ng ml‐1 h vs 566 ng ml‐1 h), t 1/2,z (1.9 h vs 1.8 h). 4. Propranolol had no significant effect on the pharmacodynamics of sumatriptan, as measured by pulse rate and blood pressure. 5. The results of this study would suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking propranolol prophylactic therapy.
Studies with abanoquil (UK‐52,046) a novel quinoline alpha 1‐ adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration‐effect relationships in normotensive subjects.
Authors: Schafers RF , Elliott HL , Meredith PA , Miller SH , Reid JL
Published: July 2012

1. This study further examines the quinoline‐derivative abanoquil with particular respect to the duration of its alpha 1‐adrenoceptor antagonist activity and its concentration‐effect relationship following a single intravenous bolus dose of 0.5 micrograms kg‐1 in young, normotensive males. 2. alpha 1‐adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5‐fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose‐response curve for diastolic blood pressure. 3. Despite evidence of substantial alpha 1‐adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4. The degree of alpha 1‐adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD‐ ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P less than 0.05) and r = 0.78 for diastolic blood pressure (P less than 0.005). 5. In conclusion, abanoquil produced significant alpha 1‐adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.
Plasma metronidazole concentrations after single and repeated vaginal pessary administration.
Authors: Salas‐Herrera IG , Lawson M , Johnston A , Turner P , Gott DM , Dennis MJ
Published: July 2012

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration‐time curve (AUC(0,12 h) was 8.4 +/‐ 3.9 micrograms ml‐1 h (mean +/‐ s.d.) on day 1 and 20.6 +/‐ 7.1 micrograms ml‐1 h (mean +/‐ s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/‐ 0.6 micrograms ml‐1 (mean +/‐ s.d.) and on day 5 it was 2.0 +/‐ 0.7 micrograms ml‐1 (mean +/‐ s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.
The effects of frusemide and triamterene on the hypokalaemic and electrocardiographic responses to inhaled terbutaline.
Authors: Newnham DM , McDevitt DG , Lipworth BJ
Published: July 2012

Fifteen normal volunteers were given 5000 micrograms inhaled terbutaline following three separate 4 day oral treatment periods with placebo, frusemide 40 mg, and frusemide 40 mg plus triamterene 50 mg. Serum potassium (K), and electrocardiographic (ECG) responses were measured after 30 min rest and 30 min after inhalation of terbutaline. Frusemide produced significant hypokalaemia compared with placebo (means and 95% CI): 3.58 mmol l‐1 (3.5‐3.66) vs 3.88 mmol l‐1 (3.8‐ 3.96) (P less than 0.001), and this effect was significantly attenuated by the addition of triamterene: 3.80 mmol l‐1 (3.72‐3.88) (P less than 0.05). Terbutaline alone also caused significant hypokalaemia: from 3.88 mmol l‐1 (3.8‐3.96) to 3.35 mmol l‐1 (3.24‐3.46) (P less than 0.001), and a lower absolute level of K was seen when combined with frusemide: 3.13 mmol l‐1 (3.02‐3.24) (P less than 0.05). The addition of triamterene conferred no significant protection against the combined hypokalaemia: 3.29 mmol l‐1 (3.18‐3.4). Changes in T wave amplitude during the study periods showed a similar pattern of response to the hypokalaemic effects. These results show that the hypokalaemic response to terbutaline was additive to that of frusemide, and that triamterene attenuated the hypokalaemic response to frusemide, but not terbutaline.
The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.
Authors: Choudry NB , Gray SJ , Posner J , Fuller RW
Published: July 2012

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double‐blind crossover design, each subject inhaled either saline, 1 mg ml‐1 443C81 or 4 mg ml‐ 1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml‐1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin‐induced cough or reflex bronchoconstriction in healthy volunteers.
Salbutamol inhibits metabisulphite‐induced bronchoconstriction.
Authors: Iredale MJ , Dixon CM , Ind PW
Published: July 2012

The effect of salbutamol on bronchoconstriction induced by inhaled sodium metabisulphite has been studied in 12 atopic subjects. Salbutamol (200 micrograms, 3.5 x 10(‐7) M) and matched placebo were administered by identical metered dose inhaler 15 min before a dose‐ response to sodium metabisulphite (1.25‐100 mg ml‐1) was performed. Geometric mean provocative dose of metabisulphite causing a 35% fall in sGaw after placebo pretreatment was 12.8 [5.75‐28.1, 95% Cl] mumol, and after salbutamol was 75.9 [46.5‐126] mumol. Mean maximum fall in sGaw after placebo pre‐treatment was 47.4 [41‐53.9]%. At the same metabisulphite concentration mean maximum fall in sGaw after salbutamol was 2.9 [‐8.2‐14.1]%.
Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo‐oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)‐ ibuprofen.
Authors: Evans AM , Nation RL , Sansom LN , Bochner F. , Somogyi AA
Published: July 2012

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four‐way Latin‐square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)‐ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/‐ s.d. of 93.4 +/‐ 1.2% after the 200 mg dose to 98.8 +/‐ 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time‐course of unbound S(+)‐ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)‐ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)‐ ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/‐ 1.0 micrograms l‐1.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral bioavailability of omeprazole before and after chronic therapy in patients with duodenal ulcer.
Authors: Ching MS , Mihaly GW , Angus PW , Morgan DJ , Devenish‐Meares S. , Yeomans ND , Smallwood RA
Published: July 2012

1. This study investigated the mechanism of the increase in oral bioavailability of omeprazole during repeated oral dosing. Eight patients with duodenal ulcer received an i.v. dose of omeprazole before and after a 4‐week course of oral omeprazole, 20 mg daily, given as enteric‐coated granules. 2. AUCoral and oral bioavailability (F) increased during omeprazole treatment by 50% (P less than 0.01) and 35% (P less than 0.05), respectively. 3. There was no change in the systemic clearance of omeprazole after i.v. dosage following the course of treatment. 4. We conclude that the increased omeprazole AUC observed on repeated administration of enteric‐coated granules is due to increased systemic availability rather than decreased systemic elimination. The increased availability appears to be due to increased gastrointestinal absorption rather than decreased first‐pass hepatic extraction.
Lack of effect of oral contraceptive use on the pharmacokinetics of quinine.
Authors: Wanwimolruk S. , Kaewvichit S. , Tanthayaphinant O. , Suwannarach C. , Oranratnachai A.
Published: July 2012

The pharmacokinetics of quinine after a single 600 mg oral dose of quinine sulphate were studied in seven female subjects who used oral contraceptives and in seven age‐matched female controls who did not. There were no significant differences (P greater than 0.05) in the maximum plasma concentration (Cmax) and the time of peak concentration (tmax) between the subjects who used oral contraceptives (Cmax = 5.3 +/‐ 1.0 (s.d.) mg l‐1; tmax = 1.4 +/‐ 0.7 h) and the control subjects (Cmax = 5.6 +/‐ 0.9 mg l‐1; tmax = 2.1 +/‐ 0.9 h). The mean elimination half‐ life of quinine in the oral contraceptives user group (12.5 +/‐ 1.9 h) was similar (P greater than 0.05) to that in the control group (11.8 +/‐ 2.7 h). The oral clearance of quinine in the oral contraceptive user group was 0.133 +/‐ 0.055 l h‐1 kg‐1 (range 0.073‐0.233) and was not significantly different (P greater than 0.05) from that observed in the control group (0.125 +/‐ 0.025 l h‐1 kg‐1, range 0.075‐0.148).
Pharmacokinetics of metoclopramide in patients with liver cirrhosis.
Authors: Magueur E. , Hagege H. , Attali P. , Singlas E. , Etienne JP , Taburet AM
Published: July 2012

The pharmacokinetics of metoclopramide were investigated after intravenous and oral administration in eight patients with severe alcoholic cirrhosis and in eight healthy volunteers. As a consequence of a 50% lower clearance (0.16 +/‐ 0.07 vs 0.34 +/‐ 0.09 l h‐1 kg‐1, plasma drug concentrations and the half‐life of metoclopramide were greater in patients following both routes of drug administration. Volume of distribution (3.1 +/‐ 0.8 vs 3.4 +/‐ 1.2 l kg‐1) and absolute bioavailability (79 +/‐ 19 vs 84 +/‐ 15%) were similar in the two groups. The adverse effects of metoclopramide observed in patients with marked hepatic impairment are likely to result from increased accumulation of the drug as a result of impaired clearance. Consequently a reduction in dose of 50% is recommended in patients with severe liver cirrhosis.
Geographical differences in adverse drug reaction reporting rates in the Northern Region.
Authors: Bateman DN , Lee A. , Rawlins MD , Smith JM
Published: July 2012

The reporting rates of adverse drug reactions in the Northern Region have been examined with respect to source (hospital or general practice) and district of origin for the 3 years 1986‐88. Mean annual reporting rates, corrected for population, or clinical activity, varied approximately 4‐fold in general practice (0.066 to 0.257 reports per 1000 resident population) and more than 12‐fold in hospitals (0.14 to 1.77 reports per 1000 deaths and discharges). There was no correlation between hospital and general practice reporting rates in the same health district. Overall more reports were received from general practice (1606) than hospitals (1000), although proportionally more reports of serious adverse reactions originated from hospitals. The reasons for these differences are unclear.
Hospital prescribing and usage of hypnotics and anxiolytics.
Authors: Edwards C. , Bushnell JL , Ashton CH , Rawlins MD
Published: July 2012

In‐patient prescribing and usage of hypnotic and anxiolytic drugs were surveyed in a teaching hospital for 4 to 6 weeks. Twenty‐one percent of admissions were prescribed these drugs which were predominantly benzodiazepines. Few patients (1.6%) were discharged with such prescriptions and subsequent usage in the community was similar to that before admission to hospital (6.1% and 6.4% respectively). In‐patient consumption increased with patient age and both prescriptions and consumption were greater in women than men.
A dose‐response study examining the effects of ritanserin on human slow wave sleep.
Authors: Idzikowski C. , Mills FJ , James RJ
Published: July 2012

This study investigated the effects of placebo, 1 mg, 3 mg, 10 mg and 30 mg ritanserin and 10 mg diazepam on human sleep. Twelve normal volunteers participated in this randomized, double‐blind, placebo‐ controlled cross‐over sleep study. A clear dose‐response relationship was found for ritanserin with higher doses evoking increased duration of slow wave sleep.
Influence of menstrual cycle phase on serum concentrations of alpha 1‐ acid glycoprotein.
Authors: Parish RC , Spivey C.
Published: July 2012

Serum concentrations of alpha 1‐acid glycoprotein (AAG) were studied in nine healthy women at four times in their menstrual cycles. AAG concentrations were significantly higher on day 4 than on days 12, 20, and 28 (with the first day of menstrual flow considered to be day 1). The mean AAG concentration (mg dl‐1) on day 4 was 78.55 +/‐ 5.03 (mean +/‐ s.e. mean), 70.19 +/‐ 4.80 on day 12, 70.63 +/‐ 6.67 on day 20, and 70.40 +/‐ 5.97 on day 28. Although these results should be considered preliminary because of the small sample size, we conclude that physiologic changes over the course of the menstrual cycle may affect serum AAG concentrations. Since AAG is a major binding protein for several important drugs, the potential exists for altered drug binding and drug effects, and further study of individual drugs is justified.
Effect of sulindac on the cough reflex of healthy subjects.
Authors: Foster G. , Yeo WW , Ramsay LE
Published: July 2012

The effects of a single dose of sulindac 200 mg and placebo on the capsaicin‐induced cough reflex were studied in a two‐phase double‐blind crossover study in 18 healthy subjects. Sulindac increased the threshold for capsaicin cough response significantly, but did not alter D5, peak response, or the total cough response when compared with placebo values.
Iron supplements: a common cause of drug interactions.
Authors: Campbell NR , Hasinoff BB
Published: July 2012

Iron‐drug interactions of clinical significance may occur in many patients and involve a large number of therapies. Concurrent ingestion of iron causes marked decreases in the bioavailability of a number of drugs. The affected drugs, tetracycline, tetracycline derivatives (doxycycline, methacycline and oxytetracycline), penicillamine, methyldopa, levodopa, carbidopa and ciprofloxacin have diverse chemical structures and clinical effects. The major mechanism of these drug interactions is the formation of iron‐drug complexes (chelation or binding of iron by the involved drug). A large number of other important and commonly used drugs such as thyroxine, captopril and folic acid have been demonstrated to form stable complexes with iron. There is little known about the effects of concurrent therapy with iron supplements for most of the drugs.
Clinical and chemical interactions between iron preparations and ciprofloxacin.
Authors: Kara M. , Hasinoff BB , McKay DW , Campbell NR
Published: July 2012

1. The effect of ferrous sulphate (300 mg), ferrous gluconate (600 mg), and a combination tablet of iron (10 mg), magnesium (100 mg), zinc (15 mg), calcium (162 mg), copper (2 mg), and manganese (5 mg) (Centrum Forte) co‐administration on ciprofloxacin bioavailability was tested in eight healthy subjects. 2. Peak serum ciprofloxacin concentrations and area under the curve (AUC) were significantly reduced when ciprofloxacin was administered with 300 mg ferrous sulphate (3.0 vs 2.0 mg l‐1, P less than 0.05 and 12.3 vs 6.7 mg l‐1 h, P less than 0.01, respectively). Reductions in peak ciprofloxacin concentrations and AUC also occurred when ciprofloxacin was ingested with 600 mg ferrous gluconate (1.3 mg l‐1, P less than 0.01 and 4.1 mg l‐1 h, P less than 0.01, respectively) and a Centrum Forte tablet (1.4 mg l‐1, P less than 0.01 and 5.4 mg l‐1 h, P less than 0.01, respectively). 3. When ferrous ion was mixed with ciprofloxacin, rapid spectral changes occurred (t1/2 = 1.9 min). Additional studies were consistent with oxidation of the ferrous form of iron to its ferric form, which is followed by rapid formation of a Fe(3+)‐ciprofloxacin complex. Ciprofloxacin seems to bind to ferric ion in a ratio of 3:1 by interacting with the 4‐keto and 3‐carboxyl groups on ciprofloxacin. 4. The formation of a ferric ion‐ ciprofloxacin complex is probably the cause of the reduction in ciprofloxacin bioavailability in the presence of iron.
Measurement of glomerular function during cisplatin therapy.
Authors: Waller DG , Juer L. , Fleming JS
Published: July 2012

1. Creatinine‐based methods for measuring glomerular filtration rate (GFR) were compared with the plasma clearance of 99mTc DTPA as an accurate index of GFR in patients prior to and during cisplatin therapy. 2. Measured creatinine clearances using either unsupervised 24 h or supervised 4 h collections correlated less well with the reference GFR than did predicted creatinine clearances derived from serum creatinine using formulae or a nomogram. 3. Predicted creatinine clearance appears to be at least as sensitive as measured creatinine clearance for screening GFR in patients receiving cisplatin. However, owing to the inherent inaccuracy in any creatinine‐based method, if the prediction is within 20% of the value at which dose reduction of cisplatin is considered, an isotopically determined GFR should be carried out to optimise dosage adjustments.
Population pharmacokinetics of quinidine.
Authors: Fattinger K. , Vozeh S. , Ha HR , Borner M. , Follath F.
Published: July 2012

1. Population pharmacokinetic parameters of quinidine were determined based on 260 serum drug concentration measurements in 60 patients treated for arrhythmias with quinidine sulphate or quinidine bisulphate (Kinidin duriles) orally. 2. Quinidine kinetics were best described by a two compartment model with zero order absorption from the gastrointestinal tract. The pharmacokinetics are influenced by severe heart or liver failure and renal function impairment. No effect was found for mild or moderate heart failure, for age, for body weight or for coadministration of nifedipine. 3. Population pharmacokinetic parameters of quinidine (assuming 100% bioavailability of oral quinidine sulphate) were: nonrenal clearance for patients without severe heart and liver failure 12.6 l h‐1, reduction in patients with severe heart or liver failure to 6.8 l h‐1, renal clearance (l h‐1) related to creatinine clearance (ml min‐1), proportionality constant 0.0566, volume of distribution of the central compartment 161 l, maximum serum drug concentration 1.4 h after administration of quinidine sulphate and 6.0 h after administration of quinidine bisulphate. 4. The results were validated by predicting the serum drug concentration in a separate group of 30 patients. The model reliably predicted both the population average and the variability of the serum concentration of quinidine. 5. Using Monte Carlo computer simulations, an a priori dosing regimen was derived that should maximize the proportion of patients having quinidine serum concentrations within the recommended range (2‐5 mg l‐1): initial dose of 600 mg quinidine sulphate in all patients, 3 h later first maintenance dose of quinidine bisulphate.(ABSTRACT TRUNCATED AT 250 WORDS)
A competitive kinin receptor antagonist, [DArg0, Hyp3, DPhe7]‐ bradykinin, does not affect the response to nasal provocation with bradykinin.
Authors: Pongracic JA , Naclerio RM , Reynolds CJ , Proud D.
Published: July 2012

1. In two double‐blind, placebo controlled studies, we tested the effects of intranasal administration of 500 micrograms of a competitive kinin receptor antagonist, [DArg0, Hyp3, DPhe7]‐bradykinin (NPC 567), on the response to nasal provocation with 20 micrograms of bradykinin. Nasal lavage was performed before and after provocation, and subjects recorded symptom scores. Lavages were assayed for albumin and TAME‐ esterase activity (indicators of vascular permeability). 2. In our initial study, 12 subjects received NPC 567 or placebo 5 min before bradykinin. After placebo, bradykinin challenge resulted in values (mean +/‐ s.e. mean) for albumin, TAME‐esterase activity and total symptom scores of 275 +/‐ 51 micrograms ml‐1, 32.1 +/‐ 7.2 counts min‐1 x 10(‐3), and 1.8 +/‐ 0.5, respectively. After NPC 567, bradykinin challenge resulted in values of 317 +/‐ 99 micrograms ml‐1, 31.4 +/‐ 6.9 counts min‐1 x 10(‐3), and 2.6 +/‐ 0.4 for these parameters. No significant difference was observed between placebo and drug treatment for any parameter. 3. To evaluate if the lack of drug effect was due to its enzymatic degradation prior to bradykinin administration, a second study was performed in which NPC 567 was coadministered with bradykinin (n = 8). After placebo‐bradykinin challenge, values of 168 +/‐ 42 micrograms ml‐1, 11.3 +/‐ 4.0 counts min‐1 x 10(‐3), and 2.8 +/‐ 0.6 were recorded for albumin, TAME‐esterase activity, and symptom scores, respectively, while following NPC 567‐bradykinin challenge, these values were 174 +/‐ 51 micrograms ml‐1, 12.3 +/‐ 4.1 counts min‐1 x 10(‐ 3), and 3.1 +/‐ 0.7.(ABSTRACT TRUNCATED AT 250 WORDS)
Objective outcome criteria in trials of anti‐parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady‐ and hypo‐kinesia.
Authors: Bowes SG , Clark PK , Charlett A. , O'Neill CJ , Leeman AL , Weller C. , Nicholson PW , Deshmukh AA , Dobbs SM , Dobbs RJ
Published: July 2012

1. We compare the sensitivity and specificity of chosen outcome criteria in a placebo‐controlled, randomised cross‐over study of the efficacy of maintenance therapy with the levodopa/carbidopa combination (Sinemet Plus) alone. Patients were characterised by having idiopathic Parkinsonism with no overt fluctuations in control in relation to individual doses of medication. 2. The effect of omission of a morning dose of maintenance therapy on simple timed tests of mobility and manual dexterity, and on distance/time parameters of gait was studied in fourteen patients (aged 64 to 88 years). Measurements made 2, 4 and 6 h after morning active and placebo treatments were standardised by taking the pre‐treatment measurement on that day as baseline. 3. In a linear model, which allowed for the structure of the study, neither the total time taken by each patient to get up from a chair, walk an individually set distance, turn, return to and sit in the chair, nor the rate of progress at fastening the same set of buttons, was sensitive to the treatment effect. 4. Three of the gait parameters, free walking speed, mean stride length and mean double support time, were sensitive to the treatment effect. Correction for the speed of each walk, caused some reduction in the sensitivity of stride length to treatment effect, but that of double support time remained. Speed, and double support time or stride length, appeared to be complementary in defining the treatment effect. 5. The linear modelling revealed the complexity of the treatment effect. Although active treatment, by comparison with placebo, increased free walking speed (P = 0.019), the more levodopa found in the plasma following treatment, (P = 0.0005) and the greater the increment in the concentration of its peripheral metabolite, 3‐O‐methyldopa (P = 0.006), the less the beneficial effect. This model may reflect reduced uptake into the brain and/or an adverse effect of parent drug or a metabolite. 6. The specificity of free walking speed for the treatment effect was good, as was that of mean stride length, after it had been corrected for speed of each walk, and of mean double support time, after correction for speed and incorporation of the change in lying blood pressure accompanying treatment into the model. 7. The measurements of gait parameters were ranked according to reliability.(ABSTRACT TRUNCATED AT 400 WORDS)
A comparison of the chronic effects of oral xamoterol and enalapril on blood pressure and renal function in mild to moderate heart failure.
Authors: Jamieson MJ , Webster J. , Fowler G. , Rawles J. , Smith FW , Petrie JC
Published: July 2012

1. We compared the effects, after 3 weeks oral therapy, of xamoterol 200 mg twice daily and enalapril 2.5, 5 or 10 mg twice daily on home and clinic blood pressure, glomerular filtration rate (GFR) and renal plasma flow, stroke and minute distances, linear resistance and on plasma renin activity in 19 patients with mild to moderate heart failure in a single‐blind randomised crossover study. 2. Enalapril reduced mean home blood pressure by 17/7 mm Hg compared with xamoterol (P less than 0.0001) and by 19/7 mm Hg compared with placebo. Compared with placebo xamoterol had no effect. Enalapril reduced predose blood pressure, compared with xamoterol, on average by 15/5 mm Hg (P = 0.02 systolic, 0.09 diastolic) and by 20/7 mm Hg compared with placebo. At 4 h post‐dose the mean differences were: xamoterol‐enalapril 13/10 mm Hg (P = 0.01 systolic, 0.0007 diastolic) and placebo‐enalapril 23/9 mm Hg. 3. Stroke and minute distances were marginally less 4 h following xamoterol than following enalapril: mean (s.e. mean) values were 9.4 (0.7) vs 10.4 (0.8) cm (P = 0.23) and 699 (51.7) vs 767 (62.1) cm (P = 0.04) respectively. Linear resistance was reduced by enalapril, from the placebo value of 13.2 (1.2) to 11.0 (0.9) mm Hg m‐1 and marginally increased by xamoterol, to 14.2 (1.2) mm Hg m‐1, the difference between active treatments being statistically significant (P = 0.03). 4. Renal plasma flow, GFR and filtration fraction were not influenced by enalapril or xamoterol therapy. There were no significant correlations between glomerular filtration rate and either blood pressure or stroke distance.(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.
Authors: Murdoch DL , Thomson GD , Thompson GG , Murray GD , Brodie MJ , McInnes GT
Published: July 2012

1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double‐blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre‐treatment with propranolol. When verapamil and propranolol were co‐administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8‐38%) but the measured increase after the combination was 40% (95% C.I. 26‐54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.
Simvastatin in severe hypercholesterolaemia: a placebo controlled trial.
Authors: McDowell IF , Smye M. , Trinick T. , Shortt JA , Archibald MP , Trimble ER , Nicholls DP
Published: July 2012

The effect of simvastatin in 27 patients with severe primary hypercholesterolaemia was assessed by a double‐blind placebo controlled parallel group trial. Total serum cholesterol, LDL‐cholesterol and apoprotein B (ApoB) were significantly reduced by simvastatin 40 mg daily. Reductions in triglyceride and VLDL‐cholesterol and an increase in HDL‐cholesterol levels were only significant when calculated as a percentage of baseline, because of wide inter‐individual variability. No changes in apoprotein A1, lipoprotein (a), fibrinogen, viscosity or blood pressure were observed. Leucocyte HMG‐CoA reductase activity was unchanged after 4 weeks of active treatment but increased by 87% after 3 months (n = 21, P less than 0.05). No severe adverse effects or changes in CK or AST levels were noted. We conclude that simvastatin is effective in the treatment of severe and resistant hypercholesterolaemia, and well tolerated in the short term.
Cyclosporin metabolism by the gastrointestinal mucosa.
Authors: Tjia JF , Webber IR , Back DJ
Published: July 2012

The intestinal mucosal metabolism of the immunosuppressant cyclosporin (CsA) has been studied in vitro using the Ussing chamber technique. Histologically normal colon was obtained from six patients undergoing resections. The mucosal sheets were mounted between two perspex chambers. Three hours after addition of [3H]‐CsA (0.2 microCi; 10 microM) to the mucosal chamber, more than 90% of the radioactivity was present in that chamber. Metabolite analysis, by high performance liquid chromatography, indicated that 77.6 +/‐ 9.2% (mean +/‐ s.d.) of the drug present was CsA, 9.9 +/‐ 4.4% and 8.7 +/‐ 4.7% were the oxidative metabolites M17 and M21 respectively (metabolites identified by co‐chromatography with authentic standards). Total metabolite production in tissues from the six individuals was variable (10.1‐30.6% at 3 h) and increased over the time period of the study. A different pattern of metabolism was obtained from a single sample of gastric mucosa. More than 20% of CsA was metabolised although neither M17 nor M21 were detected. The results of this study suggest that the gut wall is involved in the first pass metabolism of CsA in vivo and that this could be a contributory factor to the poor systemic availability of CsA seen in some patients.
The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates.
Authors: Sakai H. , Kobayashi S. , Hamada K. , Iida S. , Akita H. , Tanaka E. , Uchida E. , Yasuhara H.
Published: July 2012

Six healthy male subjects were given single oral doses of antipyrine (7 mg kg‐1), trimethadione (4 mg kg‐1) and debrisoquine (10 mg) before and during diltiazem treatment (30 mg three times daily orally for 8 days). Antipyrine clearance decreased from 33.7 +/‐ 9.1 to 22.5 +/‐ 4.9 ml min‐ 1 (P less than 0.05, mean +/‐ s.e. mean) after diltiazem treatment without any significant change in apparent volume of distribution (0.59 +/‐ 0.06 to 0.60 +/‐ 0.04 1 kg‐1), resulting in an increase in antipyrine elimination half‐life from 13.4 +/‐ 4.8 to 19.7 +/‐ 3.2 h (P less than 0.05). The formation clearance of antipyrine to 4‐ hydroxyantipyrine was decreased significantly from 10.8 +/‐ 2.7 to 6.6 +/‐ 2.7 ml min‐1 (P less than 0.05), while that to 3‐ hydroxymethylantipyrine and norantipyrine was not altered by diltiazem. The metabolic ratio of debrisoquine (urinary excretion of debrisoquine/4‐hydroxydebrisoquine) was increased significantly from 0.70 +/‐ 0.05 to 1.95 +/‐ 0.20 (P less than 0.05), while that of trimethadione (serum concentration of dimethadione/trimethadione) was not changed significantly (0.48 +/‐ 0.08 vs 0.41 +/‐ 0.06) after diltiazem treatment. Diltiazem selectively inhibits cytochrome P‐450 isoenzymes.
Cough and enalapril: assessment by spontaneous reporting and visual analogue scale under double‐blind conditions.
Authors: Yeo WW , Maclean D. , Richardson PJ , Ramsay LE
Published: July 2012

The incidence and prevalence of cough related to enalapril was assessed by spontaneous reporting and a visual analogue scale during a 6 month random double‐blind parallel‐group study comparing enalapril with nifedipine. Cough was reported spontaneously by 6.2% of enalapril‐ treated patients, and by none on nifedipine (NS). No patient had to discontinue enalapril because of cough. After 24 weeks treatment increases in visual analogue scale scores for cough frequency greater than or equal to 8 mm were more common for enalapril than nifedipine (difference 21.5%, 95% CI 7.3‐35.7%). Increased cough frequency by visual analogue scale was present throughout the study in women, but less consistently in men. High scores for cough were not related to the dose of enalapril. Cough with enalapril was not an important problem during the 6 months of treatment. However increased cough frequency could be detected by visual analogue scale, with a frequency consistent with that observed in open clinic‐based studies of longer duration. These findings suggest that ACE inhibitor‐induced cough may increase in severity over time, and that even a period of 6 months treatment is too short to evaluate this side‐effect adequately.
Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.
Authors: Chen ZR , Somogyi AA , Reynolds G. , Bochner F.
Published: July 2012

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine‐6‐glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine‐6‐glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/‐ 0.31 h (mean +/‐ s.d.) and for codeine‐6‐glucuronide it was 1.28 +/‐ 0.49 h. The plasma AUC of codeine‐ 6‐glucuronide was 15.8 +/‐ 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/‐ 1.1 times higher than that in plasma. The elimination half‐life of codeine was 3.2 +/‐ 0.3 h and that of codeine‐6‐glucuronide was 3.2 +/‐ 0.9 h. 3. The renal clearance of codeine was 183 +/‐ 59 ml min‐1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine‐6‐glucuronide was 55 +/‐ 21 ml min‐1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine‐6‐glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine‐6‐glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/‐ 11.4% of the dose was recovered in urine, of which 59.8 +/‐ 10.3% was codeine‐6‐glucuronide, 7.1 +/‐ 1.1% was total morphine, 6.9 +/‐ 2.1% was total norcodeine and 11.8 +/‐ 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/‐ 31 ml min‐1 in the seven extensive metabolisers and 8 ml min‐1 in the poor metaboliser; to norcodeine the values were 103 +/‐ 33 ml min‐1 and 90 ml min‐1; to codeine‐6‐ glucuronide the values were 914 +/‐ 129 ml min‐1 and 971 ml min‐1; and intrinsic clearance was 1568 +/‐ 103 ml min‐1 and 1450 ml min‐1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)