bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of ketoconazole on the polymorphic 4‐hydroxylations of S‐ mephenytoin and debrisoquine.
Authors: Atiba JO , Blaschke TF , Wilkinson GR
Published: July 2012

Studies were undertaken in 12 normal, male subjects to determine whether a metabolic interaction occurs between ketoconazole and mephenytoin. A single dose (400 mg) of ketoconazole produced a reduction in the 0‐8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug and after 28 daily doses the median value was further reduced to 42.9% of its baseline value. Within 7 days following discontinuation of ketoconazole the enantiomeric ratio had returned to its pre‐study value. These findings are consistent with ketoconazole being a potent in vivo inhibitor of mephenytoin's 4‐ hydroxylation and confirm the ability of such an interaction to be predicted by in vitro studies with human liver microsomes. By contrast, ketoconazole had a much smaller effect on the 0‐8 h urinary metabolic ratio of debrisoquine, indicating that ketoconazole has a selective inhibitory effect on different forms of cytochrome P‐450.
Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro.
Authors: Back DJ , Stevenson P. , Tjia JF
Published: July 2012

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 microM (tolbutamide hydroxylase), 1.9 microM (ethinyloestradiol 2‐hydroxylase), 2.0 microM (cyclosporin N‐demethylase), 2.1 microM (cyclosporin hydroxylase) and 25 microM (ethoxycoumarin O‐deethylase). At 50 microM terbinafine concentration, inhibition was less than 5% for tolbutamide and ethoxycoumarin, approximately 12% for both cyclosporin pathways and 35% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P‐450 isozymes as ketoconazole.
Plasma protein binding of frusemide in liver disease: effect of hypoalbuminaemia and hyperbilirubinaemia.
Authors: Viani A. , Carrai M. , Pacifici GM
Published: July 2012

The binding of frusemide was studied in the plasma of 20 healthy subjects and 45 patients with liver disease. The unbound percentage (mean +/‐ s.d.) of frusemide was 1.64 +/‐ 0.21 healthy subjects) and 2.24 +/‐ 0.79 (patients) (P less than 0.01). By grouping the patients on the basis of plasma albuminaemia and bilirubinaemia four clusters namely: 'normal concentrations of albumin and bilirubin' (A), 'hyperbilirubinaemia and normal albumin concentration' (B), 'hypoalbuminaemia and normal bilirubin concentration' (C) and 'hypoalbuminaemia and hyperbilirubinaemia' (D) were defined. The unbound percentage of frusemide was 1.80 +/‐ 0.36 in (A); 2.44 +/‐ 1.05 in (B); 2.23 +/‐ 0.38 in (C); 2.76 +/‐ 0.77 in (D). The figure for healthy volunteers was not different from A, whereas it was significantly lower than those for B and D (P less than 0.01) and for C (P less than 0.05). A lowered binding of frusemide was associated with hypoalbuminaemia or hyperbilirubinaemia.
Investigations on plasma activity of low molecular weight heparin after intravenous and oral administrations.
Authors: Dryjski M. , Schneider DE , Mojaverian P. , Kuo BS , Bjornsson TD
Published: July 2012

This study investigated the absorption of low molecular weight heparin (LMWH) after oral administration in man. Six healthy subjects received 5,000 anti‐Xa units of LMWH (Kabi 2165) by both i.v. and oral administration. The oral formulations were prepared in pH 4.0 and pH 7.0 buffered solutions. Multiple blood samples were collected after each dose for measurements of anti‐Xa, anti‐IIa and APTT plasma heparin activities. Pharmacokinetic parameters based on the anti‐Xa activity measurements after the i.v. dose were as follows (mean +/‐ s.d.): t1/2, 1.82 +/‐ 0.23 h; V, 4.34 +/‐ 0.651; and CL, 28.0 +/‐ 6.2 ml min‐1. Half‐ life values based on the anti‐IIa and APTT activities were 1.63 +/‐ 0.43 and 1.09 +/‐ 0.51 h, respectively. Considerable prolongations in APTT were observed, with APTT at 30 min averaging 55.7 +/‐ 4.1 s (1.84 +/‐ 0.27 times baseline values). After oral administration, no measurable plasma heparin activities were observed with either LMWH preparation. The results of this investigation indicate that LMWH does not have detectable plasma activity after oral administration, and that after i.v. administration it has significant anti‐IIa and APTT activities in addition to its anti‐Xa activity.
Pharmacokinetics of intravenous buprenorphine in children.
Authors: Olkkola KT , Maunuksela EL , Korpela R.
Published: July 2012

Buprenorphine (3 micrograms kg‐1) was given intravenously as premedication to small children (age 4‐7 years) undergoing minor surgery. Because of the rapid decline of the plasma buprenorphine concentrations, the terminal elimination half‐life could not be estimated reliably. Given this constraint, values of clearance appeared to be higher than those in adults but values of Vss were similar.
Local anaesthetic cream for the alleviation of pain during venepuncture in Tanzanian schoolchildren.
Authors: Hellgren U. , Kihamia CM , Premji Z. , Danielson K.
Published: July 2012

The analgesic effect and the usefulness of EMLA cream 5% in connection with venous blood‐sampling was investigated in 42 Tanzanian schoolchildren. Approximately 2.5 g EMLA was applied to the right cubital fossa for a minimum of 120 min. The analgesic effect was pronounced‐93% of the venepunctures were pain‐free and no child experienced severe pain. No adverse reactions were observed and the children could continue normal school work during the application time.
A comparison of the effects of human alpha calcitonin gene‐related peptide and glyceryl trinitrate on regional blood velocity in man.
Authors: MacDonald NJ , Butters L. , O'Shaughnessy DJ , Riddell AJ , Rubin PC
Published: July 2012

1. Human alpha calcitonin gene‐related peptide (h alpha CGRP) is a potent vasodilator which in doses up to 1.5 micrograms min‐1 i.v. produces little or no fall in blood pressure in normal volunteers, but does cause a substantial tachycardia. 2. We have explored the underlying mechanism of this effect by comparing h alpha CGRP infused so as to maintain heart rate 25‐30% above baseline with glyceryl trinitrate (GTN) in a dose sufficient to maintain a throbbing headache. 3. Ten normal volunteers were studied. In addition to blood pressure and heart rate, blood velocity and pulsatility index (PI) were determined from Doppler signals recorded from the internal and external carotid, renal and femoral arteries. 4. Following h alpha CGRP blood pressure (mean +/‐ s.d., mm Hg) did not significantly change: 120 +/‐ 10/70 +/‐ 7 before compared with 121 +/‐ 12/67 +/‐ 7 during h alpha CGRP infusion. Heart rate (mean +/‐ s.d., beats min‐1) increased from 62 +/‐ 8 to 86 +/‐ 10 (P less than 0.0001). In contrast the blood pressure fell following GTN: 124 +/‐ 12/74 +/‐ 8 before compared with 111 +/‐ 13/62 +/‐ 6 following treatment (P less than 0.02). Heart rate did not change following GTN: 64 +/‐ 9 compared with 69 +/‐ 10. 5. GTN significantly increased PI (mean +/‐ s.d.) in the common carotid artery from 2.8 +/‐ 0.5 to 3.4 +/‐ 0.5 (P less than 0.003) while h alpha CGRP increased PI in the internal carotid from 1.3 +/‐ 0.2 to 2.1 +/‐ 0.4 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of a single oral dose of pergolide on intraocular pressure and pupil diameter.
Authors: al‐Sereiti MR , Quik RF , Turner P.
Published: July 2012

1. The ocular hypotensive effect of a single oral dose of 25 micrograms pergolide, a dopamine 2‐receptor agonist, was studied in 12 normal human volunteers, using a non‐invasive method. 2. An oral dose of timolol 20 mg was used as a positive control. 3. The effects of both drugs on pupil diameter were also studied, using a photographic method. 4. Considering the first 6 h post‐dosing measurements, using multiple linear regression analysis comparing drug with placebo and including the baseline values as continuous independent variables, both pergolide and timolol had a significant ocular hypotensive effect in both eyes (P less than 0.0001) with no significant effects on pupil diameter. 5. Further topical application studies in normal and glaucomatous eyes are needed to evaluate the usefulness of pergolide in the treatment of glaucoma.
Comparison of different dose regimes of aminohydroxypropylidene‐1,1‐ bisphosphonate (APD) in hypercalcaemia of malignancy.
Authors: Davis J.R. , Heath DA
Published: July 2012

1. The new intravenous bisphosphonate drug aminohydroxypropylidine bisphosphonate (APD) is effective in treating the hypercalcaemia of malignant disease, but the optimum dose regimen is not yet established. We have treated twenty‐seven patients with malignant hypercalcaemia (corrected calcium greater than 3.00 mmol l‐1) with intravenous APD, comparing three regimens of drug administration. 2. Patients were randomly allocated to receive a single dose of APD 30 mg on day 1 (group A, n = 9), two consecutive doses of 30 mg on days 1 and 2 (group B, n = 9) or a single 60 mg dose on day 1 (group C, n = 9). The patients were severely hypercalcaemic, and in nine (33%) the corrected serum calcium was higher than 4.00 mmol l‐1 and all were severely ill: three patients died within 48 h of receiving the initial dose and seven died within the first week. 3. Serum calcium levels fell by day 7 in all patients: in group A, from 3.91 +/‐ 0.40 (s.d.) mmol l‐1 to 2.91 +/‐ 0.49; in group B, from 3.59 +/‐ 0.33 to 2.63 +/‐ 0.23 mmol l‐1; and in group C, from 3.71 +/‐ 0.43 to 2.66 +/‐ 0.39 mmol l‐1. Complete response, defined by a nadir calcium (on days 5‐12) below 2.60 mmol l‐1 occurred in eleven of 24 surviving patients (4/9 in group A, 4/7 in group B, and 3/8 in group C). The remaining patients showed a partial response with serum calcium falling at least 0.25 mmol l‐1.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of the thromboxane A2 receptor antagonist sulotroban (BM 13.177) in renal failure.
Authors: Piper C. , Staiger C. , Jumeau‐Ziemendorff Y. , Uebis V. , Kaufmann B. , Stein K.
Published: July 2012

1. Ten healthy volunteers and 26 hospital in‐patients with endogenous creatinine clearances of 98 to 4 ml min‐1 received an oral dose of 800 mg sulotroban (BM 13.177). The plasma and urine concentrations of sulotroban were measured by gas‐chromatography over 72 h and the pharmacokinetic parameters were calculated. 2. The AUC rose from 28.5 mg l‐1 h in healthy volunteers to 631.4 mg l‐1 h in preterminal renal failure (medians). The CLR decreased from 317.0 ml min‐1 to 6.5 ml min‐ 1 at the lowest renal capacity. 3. According to the AUC values, reduction of the dose is not necessary at CLCr greater than 50 ml min‐ 1, a dose of 20‐40% of normal is appropriate at CLCr of 20‐50 ml min‐1 At CLCr less than or equal to 20 ml min‐1 the normal dose should be reduced to less than 20% of normal. 4. Vaginal spotting was noted in three female patients and a gastro‐intestinal haemorrhage that did not require transfusion in one male patient. These may be associated with the action of sulotroban.
Pharmacokinetics of (−)−folinic acid after oral and intravenous administration of the racemate.
Authors: Greiner PO , Zittoun J. , Marquet J. , Cheron JM
Published: July 2012

1. A pharmacokinetic study of the natural (−)−isomer of folinic acid ((−)−5 CHOTHF) and of total (−)−folates was performed in 12 healthy subjects after i.v. and oral administration of the racemic form of folinic acid. 2. After a 25 mg i.v. injection, (−)−5 CHOTHF kinetics were described by a biexponential function. The mean steady state volume of distribution (Vss) was 161; systemic and renal clearances averaged 335 and 53 ml min‐1, respectively. After the same oral dose, (−)−5 CHOTHF was rapidly absorbed. Plasma concentrations of unchanged drug were much lower than those achieved after i.v. administration but in nine subjects, the disposition kinetics were also biexponential. Absolute bioavailability was only 4% as a consequence of a significant intestinal first pass effect. 3. AUC and t1/2Z values for total (−)− folates were similar after both routes of administration, indicating that the drug was fully absorbed. However the AUC of the active metabolite after i.v. dosage was only half that after oral dosage. 4. The amounts of total (−)−folates excreted in urine after both routes of administration were not significantly different and averaged one third of the dose after 24 h, whereas excretion of (−)−5 CHOTHF was three times less after oral treatment than after parenteral treatment. 5. Oral administration is a more suitable route for folinic acid therapy because more of the active metabolite is produced than after parenteral injection.
Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.
Authors: Larrey D. , Babany G. , Tinel M. , Freneaux E. , Amouyal G. , Habersetzer F. , Letteron P. , Pessayre D.
Published: July 2012

1. The O‐demethylation of dextromethorphan to dextrorphan exhibits a genetically‐controlled polymorphism, co‐segregating with that of debrisoquine hydroxylation. Dextromethorphan has been proposed as a test compound to assess drug oxidation polymorphism. 2. We studied the effects of liver disease of varying severity on dextromethorphan oxidation capacity. Phenotyping was performed using the urinary dextromethorphan/dextrorphan metabolic ratio after oral administration of 40 mg dextromethorphan hydrobromide in 56 patients with cirrhosis and in 51 patients with moderately severe liver disease. 3. Dextromethorphan oxidation capacity was impaired in cirrhotic patients and, to lesser extent, in non cirrhotic patients, as compared with 103 control subjects. 4. The impairment in dextromethorphan oxidation induced by liver disease, was however, much less than that caused by the genetic deficiency. As a result, the prevalence of the poor metabolizer phenotype remained in the same range in patients with cirrhosis (1.8%) and with moderately severe disease (2.0%) as in controls (3.9%). 5. This observation shows that, although liver disease causes some impairment of dextromethorphan O‐demethylation, this impairment is not sufficient to modify the assignment of phenotypes.
Effects of a 5‐hydroxytryptamine3 receptor antagonist (ICS 205‐930) on colonic motor activity in healthy men.
Authors: Stacher G. , Gaupmann G. , Schneider C. , Stacher‐Janotta G. , Steiner‐Mittelbach G. , Abatzi TA , Steinringer H.
Published: July 2012

1. ICS 205‐930 (Sandoz) is a selective antagonist at 5‐ hydroxytryptamine3 receptors and exerts marked effects on gastrointestinal motility in animals. 2. This study investigated, under random double‐blind conditions, the effects of 10 and 20 mg ICS 205‐930 infused intravenously in comparison with placebo on colonic motor activity. 3. Twelve healthy men participated each in three studies in which they received, in random double‐blind fashion, each of the treatments. Colonic pressures were recorded pneumohydraulically with four catheter orifices 20‐40 cm from the anal verge. Treatments were administered after a basal 30 min. One hour later, subjects ingested a 4200 kJ meal and 90 min thereafter, 1 mg neostigmine was administered intramuscularly and recording continued for another 90 min. 4. After both doses of ICS 205‐930, the number of contractions as averaged over the entire recording time was slightly but significantly higher than after placebo. 5. After 10 mg but not after 20 mg ICS 205‐930, amplitude of contractions and area under the curve as averaged over the entire recording time were significantly higher than after placebo. 6. ICS 205‐930 induced few and mild side effects, but significantly more self‐rated drowsiness and tiredness than placebo.
The effect of oxytocin on basal and pethidine‐induced delayed gastric emptying.
Authors: Petring OU
Published: July 2012

1. Continuous infusion of oxytocin (0.33 u min‐1) accelerated gastric emptying of semisolid TC‐99m labelled Chelex‐100 resin/oatmeal in 10 healthy volunteers under basal conditions. 2. Administration of oxytocin did not change the pattern of gastric emptying delayed by pethidine. 3. The emptying pattern of semisolid has confirmed the existence of a lag phase.
Novel medicines marketed in the UK (1960‐87).
Authors: Lis Y. , Walker SR
Published: July 2012

1. A total of six hundred and eighty three new chemical entities (NCEs), were marketed in the UK between 1960 and 1987. The number of NCEs introduced annually onto the UK market declined to an average of 20 per year in 1964 and subsequently to only 7 in 1985. 2. Average development times have increased fourfold since 1960 to a peak value of 13 years in 1984. The concomitant decline in effective patent life has resulted in a mean effective patent life of less than 10 years since the mid 1960s and no more than 6 years since the early 1980s, except for the cohort marketed in 1987. 3. The largest contribution to total development time was made by the clinical phase. For NCEs marketed in the mid 1960s it was 3.3 years increasing to a peak of almost 8 years in the early 1980s, and representing on average two‐thirds of research and development time. 4. Between 1960 and the early 1970s total development time for central nervous system (CNS) agents, cardiovascular products and anti‐infectives had doubled to 9, 8 and 7.3 years respectively. By the 1980s it was averaging 13 years for CNS agents and was 54% and 28% longer than for anti‐infectives and cardiovascular compounds respectively.
The benefits of prescription information leaflets (2).
Authors: Gibbs S. , Waters WE , George CF
Published: July 2012

Prescription information leaflets (PILs) for penicillins, diuretics and benzodiazepines were evaluated in a small Hampshire town. A second town, in which no leaflets were distributed, acted as a control. Knowledge about these medicines was greater amongst the 252 patients who received leaflets compared with 247 controls. Significantly more patients who received leaflets knew the potential side‐effects of their treatment and, with the exception of those taking penicillins, were more satisfied with the information they received. These findings add further support for the routine use of PILs in general practice.
Kinetics of digoxin and anti‐digoxin antibody fragments during treatment of digoxin toxicity.
Authors: Sinclair AJ , Hewick DS , Johnston PC , Stevenson IH , Lemon M.
Published: July 2012

Anti‐digoxin antibody fragments (ADAF, 80 mg) were infused intravenously to successfully treat severe digoxin toxicity in an 82 year old woman. During treatment, total and free digoxin were determined using an Abbot TDX analyser and an ultrafiltration technique. ADAF were measured by an enzyme‐linked immunosorbent assay. By 1 h after ADAF, total serum digoxin concentrations had risen 12‐fold from a pretreatment level of 15.4 nmol l‐1 but free digoxin fell from 10 to 0.1 nmol l‐1, indicating greater than 99.9% digoxin binding to ADAF. However, the low free levels had rebounded to 7.7 nmol l‐1 by 12 h, but despite this rise the patient's condition had improved. A serum ADAF/digoxin molar ratio of around five was associated with the low concentration of free digoxin at 1 h, while at later times with ratios roughly between 3 and 4, the free digoxin concentrations ranged between 2.0 and 7.7 nmol l‐1. ADAF were mainly confined to the plasma during the first hour, but subsequently distributed into an apparent volume of 193 ml kg‐1. The elimination half‐lives of ADAF and total digoxin were 96 and 55 h, respectively. More than 50% of the estimated digoxin load had been excreted in the urine by 5 days; for ADAF the equivalent figure was only about 3%. Renal and/or bacterial degradation may have contributed to the low detection of urinary ADAF.
Serum binding of nifedipine and verapamil in patients with ischaemic heart disease on monotherapy.
Authors: Rumiantsev DO , Piotrovskii VK , Metelitsa VI , Slastnikova ID , Martsevich Yu S. , Kokurina EV
Published: July 2012

Serum free fractions of nifedipine, verapamil and some of their metabolites were measured in patients with ischaemic heart disease receiving single oral dose and chronic monotherapy and were compared with those obtained in vitro. The percentages of unbound nifedipine and verapamil in vitro (concentration range 50‐200 and 150‐400 ng ml‐1, respectively) were 2.51 and 7.23%, respectively, and did not differ from those found on monotherapy with these drugs (2.05 and 8.08%, respectively), and after single dosing. It is suggested that, during treatment with nifedipine or verapamil, their serum metabolites do not affect binding of the parent drugs to serum proteins.
A controlled clinical trial on the cardiovascular effects of single doses of pseudoephedrine in hypertensive patients.
Authors: Chua SS , Benrimoj SI , Gordon RD , Williams G.
Published: July 2012

Twenty hypertensive patients received single oral doses of pseudoephedrine 60 mg or placebo in a double‐blind, randomised, crossover trial. Systolic, diastolic, mean arterial blood pressure, and heart rate were measured at 5 min intervals for 30 min prior to and 210 min after the administration of pseudoephedrine or placebo. Statistically significant differences between the two treatments were observed with changes in systolic blood pressure (P less than 0.03) and heart rate (P less than 0.01) but not in diastolic (P greater than 0.03) and mean arterial blood pressure (P greater than 0.1). Minor differences in the number of reported side effects between the two treatments were not statistically significant.
Tianeptine binding to human plasma proteins and plasma from patients with hepatic cirrhosis or renal failure.
Authors: Zini R , Morin D , Salvadori C , Tillement JP
Published: July 2012

1. The binding of tianeptine to human plasma, isolated plasma proteins, red blood cells and to plasma from patients with cirrhosis or renal failure was studied in vitro by equilibrium dialysis. 2. Tianeptine is highly bound to plasma (95%) at therapeutic concentrations (0.3‐1 microM). No saturation of the binding sites was seen. 3. Human serum albumin (HSA) was shown to be mainly responsible for this binding (94%) with a saturable process characterized by one binding site with a moderate affinity (Ka = 4.2 x 10(4) M‐1) and a non‐saturable process with a low total affinity (nKa = 1.2 x 10(4) M‐1). 4. Like many basic and amphoteric drugs, tianeptine showed a saturable binding to alpha 1‐ acid glycoprotein (AAG) with one site and a moderate affinity (Ka = 3.7 x 10(4) M‐1). Its binding to lipoproteins and red blood cells (RBC) was weak and non‐saturable. Over the range of therapeutic drug concentrations (0.3‐1 microM), the unbound fraction in blood remains constant (4.5%). 5. Interactions were studied using non‐esterified fatty acids (NEFA) at pathological concentrations; they altered tianeptine binding to plasma and to isolated HSA. Tianeptine seems to bind to a HSA site different from sites I (warfarin) and II (diazepam), but close to site II. It also shares the only basic‐site on AAG. However, at therapeutic drug concentrations (0.3‐1 microM), not all of these interactions occur. 6. The binding of tianeptine varied according to HSA, AAG and NEFA concentrations both in patients and healthy subjects. In patients with chronic renal failure having high NEFA concentrations the unbound fraction of tianeptine (fu) increased from 0.045 to 0.153 compared with normal (P less than 0.001). In cirrhotic patients, with relatively low HSA concentrations, the fu of tianeptine increased from 0.045 to 0.088 compared with normal (P less than 0.01). 7. Multiple regression analysis of all of the data indicated that the fu of tianeptine was related significantly to HSA, NEFA and AAG concentrations, with a particularly strong correlation with NEFA concentrations. Therefore, variation of HSA and NEFA concentrations in patients on maintenance therapy may cause an increase of tianeptine fu.
Plasma concentration profiles and antihypertensive effect of conventional and extended‐release felodipine tablets.
Authors: Blychert E , Wingstrand K , Edgar B , Lidman K
Published: July 2012

1. The rate and extent of felodipine absorption from an oral solution, conventional and extended‐release tablets were investigated in two groups of healthy volunteers (n = 18 + 15). 2. The antihypertensive effect of felodipine conventional tablets twice daily (n = 71) and extended‐release tablets once daily (n = 76) were compared in a parallel‐group study in hypertensive patients. 3. As from a solution, felodipine was completely absorbed from the two solid dosage forms. The rate of absorption increased in the order extended‐release tablets, conventional tablets, solution. 4. The extended‐release tablet gave more sustained plasma concentrations than the conventional tablet. 5. The extended‐release tablet given once daily gave similar blood pressure control to the conventional tablet given twice daily.
Effect of increasing oral doses of loperamide on gallbladder motility in man.
Authors: Hopman WP , Rosenbusch G , Jansen JB , Lamers CB
Published: July 2012

1. Loperamide, a peripherally acting opiate receptor agonist with antidiarrhoeal action, inhibits ileal and colonic motor function. To determine the effect of loperamide on gallbladder motility, we have pretreated five healthy volunteers with 2 mg oral loperamide 24 h, 20, 12 and 2.5 h before; six healthy volunteers with 16 mg oral loperamide 2.5 h before; and eight healthy volunteers with 16 mg oral loperamide 12 and 2.5 h before intravenous infusion of a ‘physiological dose’ of 12.5 pmol kg‐1 cholecystokinin (CCK) for 1 h to stimulate gallbladder contraction. All subjects served as their own controls. Gallbladder volume was measured by ultrasonography and plasma CCK by radioimmunoassay until 90 min after start of the CCK infusion. 2. Infusion of CCK resulted in plasma CCK concentrations similar to those after intraduodenal fat. Integrated gallbladder contraction after 4 X 2 mg loperamide (4600 +/‐ 891% min) was similar to that without pretreatment (5270 +/‐ 1037% min; NS). Integrated gallbladder contraction after 1 X 16 mg loperamide diminished from 5458 +/‐ 412% min without to 2632 +/‐ 816% min with loperamide (P less than 0.05), and was completely abolished to ‐596 +/‐ 762% min (P less than 0.0005 vs without loperamide) after 2 X 16 mg loperamide. 3. It is concluded that loperamide inhibits gallbladder contraction in response to a physiological dose of cholecystokinin in a dose‐dependent manner.
The effect of 2 weeks treatment with cetirizine on bronchial reactivity to methacholine in asthma.
Authors: Finnerty JP , Holgate ST , Rihoux JP
Published: July 2012

1. We investigated the effect of 2 weeks therapy with oral cetirizine (10 mg twice daily) on methacholine bronchial reactivity in 14 asthmatics. All had bronchial hyperreactivity to methacholine on entry to the study, with a geometric mean cumulative PC20 of 0.83 mg ml‐1 (range 0.1‐3.61 mg ml‐1) and eight were atopic on skin prick testing. 2. The study was placebo‐controlled and in randomised order, with a minimum 1 month washout period between cetirizine and placebo study periods. Four methacholine challenges were performed in all, at the beginning and at the end of each study period. 3. No significant change in methacholine reactivity was found following 2 weeks therapy with cetrizine. The repeatability coefficient for the PC20 methacholine over 2 weeks was found to be 2.90 doubling dilutions for the placebo period and 1.73 doubling dilutions for the cetirizine period. The study had a 80% power at the 5% significance level (two‐tailed) to detect a 1.16‐ doubling concentration change in methacholine reactivity. 4. We conclude that 2 weeks therapy with cetirizine has no significant effect on non‐specific bronchial hyperreactivity.
Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population.
Authors: Horai Y , Taga J , Ishizaki T , Ishikawa K
Published: July 2012

The study was aimed at defining the relationships among the oxidative capacities for three prototype drugs, metoprolol, debrisoquine and sparteine, used for assessing genetically determined polymorphism of drug oxidation in a Japanese population. Among 292 unrelated healthy Japanese subjects who had been defined as extensive (EMs, n = 291) or poor (PM, n = 1) metabolisers of metoprolol oxidation, 55 subjects (EMs = 54 and PM = 1) were selected. One PM of metoprolol oxidation was also identified as a PM not only of debrisoquine but also of sparteine, and no misclassification by the three phenotypic methods was observed. All three correlations among the metabolic ratios of the three test probes assessed by Spearman's rank test were highly significant (P less than 0.001). These findings indicate that in Japanese subjects the oxidation capacities of metoprolol, debrisoquine, and sparteine are closely related. It appears that in Japanese the polymorphic oxidation of the three drugs is co‐regulated, either by the same enzyme or gene‐ controlling system.
The effects of phenytoin and carbamazepine on serum concentrations of mono‐unsaturated metabolites of valproic acid.
Authors: Kondo T , Otani K , Hirano T , Kaneko S , Fukushima Y
Published: July 2012

Serum concentrations of valproic acid (VPA) and its mono‐unsaturated metabolites, 2‐propyl‐2‐pentenoic acid (2‐en), 2‐propyl‐3‐pentenoic acid (3‐en) and 2‐propyl‐4‐pentenoic acid (4‐en), were measured in 36 epileptic patients. The subjects were divided into three subgroups, i.e., receiving VPA alone (n = 20: VPA group), VPA with phenytoin (n = 9: VPA + DPH group), and VPA with carbamazepine (n = 7: VPA + CBZ group). In the VPA group, the correlations between the serum concentration of VPA and those of the metabolites were significantly positive (r = 0.693, P less than 0.01 for 2‐en; r = 0.584, P less than 0.01 for 3‐en; and r = 0.868, P less than 0.001 for 4‐en). The concentration/dose ratio of VPA was significantly lower, and the 4‐ en/VPA ratio was significantly higher in the VPA + CBZ group than in the VPA group (P less than 0.05). However, DPH had less effect on the concentration/dose ratio of VPA and the 4‐en/VPA ratio than CBZ. This may be due partly to the relatively smaller therapeutic dose of DPH. These results suggest a correlation between the serum concentration of VPA and that of 4‐en, and an increased metabolic conversion of VPA to 4‐ en by coadministration of CBZ. High serum concentrations of VPA and concomitant use of CBZ resulted in an elevation of the serum concentration of 4‐en, which has been reported to be the most toxic metabolite of VPA.
Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam.
Authors: Dusci LJ , Good SM , Hall RW , Ilett KF
Published: July 2012

The excretion of diazepam, N‐desmethyldiazepam, temazepam and oxazepam in breast milk was studied during withdrawal of a 22‐year‐old patient from combined high dose diazepam and oxazepam therapy. Concentrations of these benzodiazepines in plasma from both the woman and her nursing infant (1 year old) were also documented. Diazepam, N‐ desmethyldiazepam, temazepam and oxazepam were found in the maternal plasma and milk with mean milk: plasma ratios of 0.2, 0.13, 0.14 and 0.10 respectively. It was calculated on a mg kg‐1 basis that the infant received some 4.7% of the maternal dose. Diazepam could not be detected in the infant's plasma, but low levels of N‐desmethyldiazepam (20 and 21 micrograms l‐1), temazepam (7 micrograms l‐1) and oxazepam (7.5 and 9.6 micrograms l‐1) were present. The infant showed no overt physical or mental symptoms of benzodiazepine intoxication.
The effect of indomethacin on the kinetics of histamine, 48/80 and antigen wealing.
Authors: Humphreys F , Shuster S
Published: July 2012

1. The kinetics of weal formation and disappearance following intradermal injection of histamine, compound 48/80 and antigen were measured in indomethacin and inert geltreated human forearm skin. 2. Rates of formation went in descending order for histamine, 48/80 and antigen; rate constants of disappearance for equal sized weals were the same for histamine and 48/80 but were much less for antigen. The corresponding half‐lives were 77, 73 and 160 min for histamine, 48/80 and antigen weal disappearance respectively. 3. Cyclo‐oxygenase inhibition by topical indomethacin had no effect either on the immediate weal and flare responses or on the rates of formation and disappearance of the weals. 4. These findings together with previous studies using H1‐receptor antagonists indicate that 48/80 acts by histamine release but that antigen releases both histamine and an additional material or materials which are not related to cyclo‐ oxygenase activity. 5. Exacerbation of chronic idiopathic urticaria by cyclo‐oxygenase inhibitors is therefore likely to be part of the urticarial disease process.
99mTc‐neoglycoalbumin (NGA)‐binding to human hepatic binding protein (HBP) in vitro.
Authors: Virgolini I , Angelberger P , Muller C , O'Grady J , Sinzinger H
Published: July 2012

1 Neoglycoalbumin (NGA) was synthesised by covalent coupling of 2‐imino‐ 2‐methoxyethyl‐1‐thio‐beta‐D‐galactopyranoside (IME‐thiogalactose) to the primary amino groups of human serum albumin (HSA). NGA was purified by ultrafiltration and size exclusion h.p.l.c. (SEC). 99mTc‐labelling was performed with and without SEC purification. 2 Estimation of 99mTc‐ NGA‐binding to human hepatic binding protein (HBP) revealed a complex behaviour indicating saturable high‐ and low‐affinity sites. The high‐ affinity binding capacity was 1.1 +/‐ 0.4 pmol mg‐1 human liver plasma membrane protein, the low‐affinity binding capacity was 6.2 +/‐ 1.8 pmol mg‐1 liver plasma membrane protein. The apparent equilibrium dissociation constants were 2.4 +/‐ 1.2 and 18.4 +/‐ 4.8 nM, respectively. 3 Specific binding of 99mTc‐NGA to human HBP in the presence of 100 microM unlabelled NGA, Ca++ and Mg++ at pH 7.5 and 37 degrees C reached 85 +/‐ 5% at equilibrium. The amount of ligand specifically bound increased with the amount of human liver membrane protein added. The concentration of unlabelled agonist necessary to displace 50% of ligand bound amounted to 100 nM.
Evidence for the polymorphic oxidation of debrisoquine in the Thai population.
Authors: Wanwimolruk S , Patamasucon P , Lee EJ
Published: July 2012

Debrisoquine polymorphism has been studied extensively in Caucasian populations. The prevalence of the poor metaboliser phenotype is 3‐10% in European and American Caucasian populations but appears to be very low in Asian populations. This study was carried out to determine the metabolic oxidation status in 173 Thai subjects. Phenotyping was performed using the metabolic ratio (MR) calculated as the 0‐8 h urinary output of debrisoquine/0‐8 h urinary output of 4‐ hydroxydebrisoquine after oral administration of 10 mg debrisoquine hemisulphate. Two subjects (1.2%) were phenotyped as poor metabolisers; they had MR values of 13.17 and 92.04. The incidence of the poor metaboliser phenotype of debrisoquine oxidation of 1.2% seems to be lower in the Thai population compared with that in various Caucasian populations.
Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man.
Authors: Brosen K , Davidsen F , Gram LF
Published: July 2012

The kinetics at a single oral dose (400 mg) of quinidine were studied in four extensive metabolizers (EM) and four poor metabolizers (PM) of sparteine. The clearance of quinidine by 3‐hydroxylation was significantly lower in PM than in EM, but the difference was small (25‐ 30%). This finding suggests that 3‐hydroxylation, in part, is catalyzed by the same isoenzyme of cytochrome P450, P450db1 which oxidizes sparteine. Otherwise, no significant phenotypic differences in total or metabolic clearance were found and it is concluded that the metabolism of quinidine is largely carried out by P450 isoenzymes different from P450db1. A biexponential decline in the log plasma quinidine concentration vs time curves was observed in all subjects, and the mean elimination half‐life was 11‐12 h. This is about twice as long as generally reported in the literature.
The effects of a single dose of dilevalol on [3H]‐noradrenaline plasma kinetics and plasma lipoprotein cholesterol concentrations.
Authors: Howes LG , Rowe PR , Krum H , Louis WJ
Published: July 2012

1. A single oral dose of dilevalol (200 mg or 400 mg) or placebo was administered to 15 normal male volunteers in a double‐blind, random order crossover study. 2. Dilevalol had no significant effect on supine blood pressures or heart rates, but caused a significant fall in systolic blood pressure 1 and 30 min following standing, and attenuated the rise in diastolic blood pressure and heart rate that accompanies standing. 3. Dilevalol caused a dose dependent increase in plasma noradrenaline levels from arterialized blood which was due to an increase in noradrenaline spillover with no change in clearance. 4. Dilevalol increased plasma levels of the noradrenaline metabolite 3,4‐ dihydroxyphenylethylene glycol (DHPG) (which is formed in sympathetic nerves following neuronal uptake of noradrenaline), indicating that the increase in noradrenaline spillover was not due to the blockade of neuronal uptake. 5. Acute dilevalol administration had no effect on total plasma cholesterol, HDL‐cholesterol or LDL‐cholesterol levels.
The effects of ibuprofen and indomethacin on renal function in the presence and absence of frusemide in healthy volunteers on a restricted sodium diet.
Authors: Passmore AP , Copeland S , Johnston GD
Published: July 2012

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide‐induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.
Acute haemodynamic effects of cromakalim in patients with angina pectoris.
Authors: Thomas P , Dixon MS , Winterton SJ , Sheridan DJ
Published: July 2012

1. We studied the acute haemodynamic effects of cromakalim, a vasodilator which activates smooth muscle potassium channels, in 11 patients with ischaemic heart disease undergoing routine cardiac catheterisation. A similar group of six patients given placebo were studied under identical conditions. 2. There were no significant differences in baseline haemodynamic parameters between the two groups. 3. Following intravenous cromakalim (15 micrograms kg‐1) cardiac output increased by 30% (P less than 0.05 vs placebo) while systolic arterial pressure decreased by 8% (P less than 0.05), systemic vascular resistance decreased by 29% (P less than 0.01) and pulmonary vascular resistance decreased by 24% (P less than 0.01) at plasma concentrations of the (+)‐ and (‐)‐enantiomers of cromakalim of 6.2 +/‐ 0.5 ng ml‐1 and 10.0 +/‐ 1.0 ng ml‐1 respectively. 4. There were no significant differences in diastolic arterial pressure, left ventricular dP/dt and stroke volume between the two groups. Heart rate increased by 11% following cromakalim but this did not achieve significance. 5. These findings confirm that cromakalim acts primarily as an arteriolar vasodilator producing an improvement in cardiac performance. Cromakalim may be of benefit in the treatment of patients with ischaemic heart disease.
Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris.
Authors: Hosie J , Scott AK , Petrie JC , Cockshott ID
Published: July 2012

1. Epanolol is a novel anti‐anginal agent which is a beta 1‐ adrenoceptor partial agonist exhibiting selective beta 1‐adrenoceptor antagonist and selective beta 1‐adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/‐ s.d.) after the single dose (25.7 +/‐ 17.0 ng ml‐1) were not significantly different (P = 0.35) from those at steady state (32.4 +/‐ 20.9 ng ml‐1). There was wide inter‐individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half‐ life of 17 h and 5 fold inter‐individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/‐ 29.8 ng ml‐1 h) from that at steady state (78.4 +/‐ 55.0 ng ml‐1 h). There was also wide inter‐individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.
Development of tolerance to nifedipine in patients with stable angina pectoris.
Authors: Martsevich SY , Metelitsa VI , Rumiantsev DO , Piotrovskii VK , Slastnikova ID , Egorov LV , Vygodin VA
Published: July 2012

1. The possibility of development of tolerance to the anti‐ischaemic and anti‐anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20‐30 mg) substantial anti‐ischaemic and anti‐anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti‐ischaemic effect during a day (mean daily dose 82.7 +/‐ 6.0 mg, range 60‐120 mg) a substantial attenuation of this effect was registered. The duration of the anti‐ischaemic effect was 5.4 +/‐ 0.3 h after acute administration, decreasing significantly to 3.6 +/‐ 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti‐ ischaemic, anti‐anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.
An acute study of the electrophysiological and haemodynamic effects of intravenous UK‐52,046, a novel alpha 1‐adrenoceptor antagonist.
Authors: Barin ES , Wong CK , Elstob JE , Davies DW , Nathan AW
Published: July 2012

The acute electrophysiological and haemodynamic effects of UK‐52,046, a novel alpha 1‐adrenoceptor antagonist (0.5 microgram kg‐1) were studied in 10 patients. Resting and paced conduction intervals, refractory periods, Wenckebach cycle length and sinus node recovery time were measured and compared with baseline values. Haemodynamic measurements including cardiac output were measured before and after drug administration. Changes in QRS interval (83 to 105 ms) and QRS duration during sinus rhythm (83 to 105 ms) or during constant atrial pacing (85 to 109 ms), were not significant (P greater than 0.05). Myocardial refractoriness and sinus node recovery time were not altered by the drug. Slight increases in mean heart rate (72.5 to 78.8 beats min‐1), mean right atrial pressure (4.5 to 5.5 mm Hg) and mean cardiac output (5.4 l min‐1 to 5.7 l min‐1), were not significant (P greater than 0.05). Systolic and diastolic arterial pressure, cardiac work indices, and vascular resistance remained unchanged. These results demonstrate the safety of this drug given intravenously in a non‐ischaemic setting, and warrant its further investigation as an antiarrhythmic agent in myocardial ischaemia.
Rapid screening for polymorphisms in dextromethorphan and mephenytoin metabolism.
Authors: Guttendorf RJ , Britto M , Blouin RA , Foster TS , John W , Pittman KA , Wedlund PJ
Published: July 2012

1. The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3‐way crossover design. 2. Neither the urinary S‐/R‐ mephenytoin ratio nor the dextromethorphan metabolic ratio were altered significantly by coadministration of the probe drugs. 3. Five‐hundred and nineteen subjects were screened for expression of mephenytoin 4‐ hydroxylase and dextromethorphan O‐demethylase activity following the coadministration of mephenytoin and dextromethorphan. The activity was determined in each case by methods not requiring any quantitative measurements. 4. Nineteen (3.7%) of the subjects were identified as poor metabolizers (PMs) of mephenytoin and 35 subjects (6.7%) as PMs of dextromethorphan. 5. All PMs of dextromethorphan were confirmed by more rigorous evaluation of the metabolic ratio.
The pharmacokinetics of oral indoramin during pregnancy.
Authors: Schabort I , Odendaal HJ , Pierce DM
Published: July 2012

1. The pharmacokinetics of indoramin (Baratol; Wyeth) and its active metabolite 6‐hydroxyindoramin administered to 13 women as a single 37.5 mg dose of indoramin were compared under pregnant and post‐partum conditions. 2. No significant differences were observed between values determined under pregnant and post‐partum conditions, for any pharmacokinetic parameter. Cmax and AUC values in individual subjects differed, in most cases, by no more than two‐fold, i.e. the same order of magnitude as intra‐subject variation seen in volunteers dosed repeatedly with indoramin. 3. Median values of Cmax, AUC(0.24) and t 1/2,z were of a similar order to values seen previously in normal volunteers after a single 37.5 mg dose. 4. It is concluded that in treating hypertension associated with pregnancy, this study does not provide evidence to depart from the usual clinical practice of titrating indoramin dosage with control of blood pressure as the end‐ point, keeping in mind the restriction of the dose‐limiting side‐effect of sedation.