bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacokinetics of doxazosin in patients with hypertension and renal impairment.
Authors: Oliver RM , Upward JW , Dewhurst AG , Honeywell R , Renwick AG , Waller DG
Published: July 2012

1. The pharmacokinetics of doxazosin, following a single oral dose (1 mg) and chronic oral dosing (doubling doses up to a maximum of 16 mg day‐1), were studied in 18 patients with mild to moderate hypertension and stable renal function varying from normal to severely impaired. In addition, the effect of chronic administration of doxazosin on renal haemodynamics was evaluated. 2. Significant accumulation of doxazosin occurred with chronic dosing, but comparison of dose‐adjusted AUC after single and chronic dosing suggested that there was no change in clearance or bioavailability during chronic administration. 3. There was no significant relationship between plasma elimination half‐life or the AUC for doxazosin and the degree of renal impairment. 4. Symptomatic postural hypotension occurred in six patients following the initial dose of 1 mg doxazosin. Systolic and diastolic blood pressure measured 24 h after the previous dose were significantly reduced during chronic administration of doxazosin by a mean of 12/6 mm Hg supine and 10/7 mm Hg on standing. 5. During chronic administration of doxazosin, there was a significant reduction of 13% in glomerular filtration rate compared with pre‐treatment, but no change in effective renal plasma flow.
Effects of a selective thromboxane receptor antagonist (GR32191B) and of glyceryl trinitrate on bleeding time in man.
Authors: Ritter JM , Benjamin N , Doktor HS , Barrow SE , Mant TG , Schey S , Stewart‐Long P
Published: July 2012

1. GR32191B is a potent and selective thromboxane receptor antagonist. Glyceryl trinitrate (GTN) also inhibits platelet function in vitro. Both have been reported to prolong bleeding time. Since they may be used together in patients with coronary artery disease, we have investigated the possibility of an interaction between them. 2. Twenty‐ four healthy male volunteers were treated with GR32191B using a double‐ blind placebo‐controlled crossover design. Bleeding times were determined before and after GR32191B or placebo and during co‐ administration of GTN. Plasma GR32191B concentration was measured. Platelet aggregation in response to adenosine diphosphate and to a thromboxane mimetic, U46619, was measured ex vivo. Urinary excretion of thromboxane (TX)B2 and 2,3‐dinor‐TXB2 was determined in 24 h urine samples. 3. Twelve hours after GR32191B (80 mg; p.o.), the plasma concentration was 36.6 +/− 2.7 nM (mean +/− s.e. mean) and bleeding time was increased by 66%. Ninety minutes after a second dose (40 mg; p.o.) the plasma concentration was 431.9 +/− 23.6 nM but bleeding time was not further prolonged. 4. Responses of platelets to U46619 were selectively antagonised following GR32191B. Urinary excretion rates of TXB2 and 2,3‐dinor TXB2 were similar after treatment with GR32191B or placebo. 5. GTN (1 mg sub‐lingually) had no significant effect on bleeding time 90‐100 min following either placebo or GR32191B. 6. We conclude that GR32191B, in a dose that causes profound yet specific blockade of thromboxane receptors, causes only a modest prolongation of bleeding time that is unaffected by a therapeutic dose of GTN. This may prove advantageous when GR32191B is used in patients with ischaemic heart disease.
The effect of oral dosing of xamoterol on systolic time intervals in man and xamoterol plasma concentrations in heart failure patients.
Authors: James MA , Papouchado M , Channer KS , Jones JV , Marlow HF , Bastain W , Barker NP , Harry JD , Wardleworth AG
Published: July 2012

1. Six healthy male human volunteers of mean age 30.8 years (range 23‐ 37) were given single oral doses of xamoterol (20, 50, 100 or 250 mg) and placebo with a 1 week interval between each dose. Xamoterol produced a significant decrease in systolic time intervals (QS2I, LVETI and PEPI) and a significant increase in systolic blood pressure indicating a positive inotropic effect on the heart at rest. The changes in QS2I were dose‐related. Maximum decreases in QS2I were noted 1 to 2 h after dosing and were achieved with a dose of 100 mg. 2. In a second study, oral administration of xamoterol at 3 doses (100, 200 or 300 mg) and placebo were studied in 12 patients of mean age 60.4 years (range 52‐73) with mild to moderate heart failure. Each dose was given twice daily for 7 days in a random order. Each dose of xamoterol produced a significant decrease in systolic time intervals indicating a positive inotropic effect on the heart at rest in patients with heart failure. It was not possible to distinguish between the effects of the three doses of xamoterol. 3. In heart failure patients, peak plasma concentrations of xamoterol occurred 1 to 2 h after dosing at all dosage levels and there was a linear relationship between dose and plasma concentration. 4. In both studies xamoterol was well tolerated and only minor adverse experiences were reported. 5. We conclude that, at rest, xamoterol has a positive inotropic effect on the heart when given orally to healthy volunteers or patients with mild to moderate heart failure.
Comparison of once daily atenolol, nitrendipine and their combination in mild to moderate essential hypertension.
Authors: Maclean D , Mitchell ET , Lewis R , Irvine N , McLay JS , McEwen J , Coulson RR , Slater ND , Fitzsimons TJ , McDevitt DG
Published: July 2012

1. The aim of the study was to compare the efficacy and the tolerability of treatment with atenolol (50‐100 mg once daily), nitrendipine (20‐40 mg once daily) and their combination (atenolol 50 mg + nitrendipine 20 mg) once daily in patients with mild to moderate essential hypertension. 2. The study was a randomised, double‐blind, placebo controlled parallel groups design: blood pressures were measured at ‘trough’ effect (i.e. 24 h after dosing) to assess the adequacy of once‐daily treatment. 3. Mean blood pressures (mm Hg) recorded on four occasions over 12 weeks of treatment were significantly lower both with atenolol (155/97 sitting: 155/104 standing) and with the combination of atenolol plus nitrendipine (153/96 sitting: 152/104 standing) than with placebo (169/108 sitting: 169/114 standing). Nitrendipine alone had no significant effect on blood pressure 24 h after dosing (165/104 sitting: 165/110 standing). 4. Withdrawals due to adverse effects were more common during treatment with nitrendipine: 7/32 of the patients experienced adverse effects attributable to intense systemic vasodilatation (e.g., flushing, erythema, headache). 2/37 patients taking atenolol were withdrawn: one because he developed a psoriatic rash and the other because of impaired peripheral circulation. Of the 35 patients taking combination treatment, two were withdrawn: one developed headaches and dyspnoea, and the other asthma. 5. The results suggest that once daily dosing with nitrendipine does not control blood pressure throughout the 24 h period in the majority of patients, and is associated with a considerable burden of adverse effects. Combination treatment was better tolerated but appeared to offer no advantages over atenolol alone in terms either of blood pressure control or adverse effects.
Effect of intermittent administration of omeprazole on serum pepsinogens in duodenal ulcer patients and healthy volunteers.
Authors: Biemond I , Crobach LF , Jansen JB , Lamers CB
Published: July 2012

1. Omeprazole, a substituted benzimidazole inhibitor of the gastric H+/K(+)‐APT‐ase, was administered orally at a dose of 20 mg in the morning of 3 consecutive days, followed by a period of 4 days without medication, and this intermittent dosage regimen was continued for 4 weeks. 2. During intermittent administration of omeprazole to 10 patients with duodenal ulcer disease and 10 healthy volunteers concentrations of serum pepsinogen A and serum pepsinogen C were monitored by sensitive and specific radioimmunoassays to study whether the effect of this treatment on serum pepsinogens is different between patients and normal subjects and to evaluate whether serum pepsinogen levels can be used to assess compliance with therapy. 3. Administration of omeprazole for 3 days induced significant increases in pepsinogen A and pepsinogen C serum concentrations, which rapidly fell after stopping the omeprazole intake. The pattern of serum pepsinogens after stopping the drug was different for duodenal ulcer patients and normal subjects. Both pepsinogens were intra‐individually related in both patients and healthy subjects when compared during the first and last 3‐ day course with omeprazole, but in duodenal ulcer patients both pepsinogens tended to be higher in the last treatment course, while the opposite was found in the normal subjects. 4. The present study confirms that serum pepsinogen concentrations are higher in duodenal ulcer patients than in normal subjects, but also shows for the first time that serum pepsinogens in the patients respond differently upon stimulation with omeprazole.(ABSTRACT TRUNCATED AT 250 WORDS)
The toxicity of amodiaquine and its principal metabolites towards mononuclear leucocytes and granulocyte/monocyte colony forming units.
Authors: Winstanley PA , Coleman JW , Maggs JL , Breckenridge AM , Park BK
Published: July 2012

The cytotoxicity of amodiaquine (AQ), amodiaquine quinoneimine (AQQI) and desethylamodiaquine (AQm) has been assessed in comparison with that of chloroquine (CQ) using mononuclear leucocytes (MNL) and granulocyte/monocyte colony forming units (GM‐CFU) from haematologically normal subjects. Toxicity toward MNL was assessed after 2 h and 16 h incubations with each compound. After 2 h, AQ, AQm and AQQI but not CQ (within the concentration range 1‐100 mumols l‐1) produced a significant decrease in cell viability. After 16 h, all four compounds significantly increased cell death. After both 2 h and 16 h incubations CQ was the least toxic and AQQI the most toxic of the four compounds towards MNL. Toxicity to GM‐CFU was assessed by the inhibition of colony formation in vitro. After 10‐14 days incubation, there was significant concentration‐dependent inhibition of colony formation by AQ, AQm, AQQI and CQ (within the range 0.1‐10.0 mumols l‐ 1). There were no significant differences between the ability of the four compounds to inhibit colony formation but toxicity towards GM‐CFU was observed at drug concentrations at least 10‐fold lower than those that were toxic to MNL. These data show that the four compounds are equally toxic in vitro toward GM‐CFU, although some differences in their toxicity toward MNL were seen. The possible mechanisms of AQ's toxicity are discussed.
Carvedilol increases the systemic bioavailability of oral digoxin.
Authors: De Mey C , Brendel E , Enterling D
Published: July 2012

The effects of a single oral dose of 25 mg carvedilol on the plasma and urinary kinetics of digoxin after an oral and intravenous 0.5 mg dose, were investigated in two separate double‐blind, placebo‐controlled, period‐balanced cross‐over studies in healthy male subjects. Carvedilol increased the mean maximum plasma concentration and the area under the plasma concentration time‐curve of digoxin when administered orally. The effects were virtually confined to the first 4 h after dosing, and the apparent terminal disposition rate constant was not changed. Carvedilol did not alter the plasma and urinary kinetics of intravenously administered digoxin.
Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers.
Authors: Schoors DF , Vercruysse I , Musch G , Massart DL , Dupont AG
Published: July 2012

1. The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg was investigated in twelve healthy volunteers. 2. Co‐administration of nicardipine significantly increased the AUC and the mean Cmax of propranolol. 3. Blood pressure and heart rate tended to decrease more when propranolol and nicardipine were administered together than when propranolol was given alone, but differences are of doubtful significance. 4. The results indicate that nicardipine alters the pharmacokinetics of propranolol by impaired hepatic ‘first‐pass’ clearance, but pharmacodynamics were little affected.
Influence of acetylator status on the haemodynamic effects and pharmacokinetics of cadralazine in healthy subjects.
Authors: Brunel P , Lecaillon JB , Guyene TT , Imhof P , Menard J
Published: July 2012

1. Cadralazine is a new antihypertensive agent which causes peripheral vasodilation, probably mediated by a hydrazinopyridazine metabolite. 2. The possible influence of acetylator status on the pharmacokinetics and haemodynamics of the drug was studied in six fast and six slow acetylators over a period of 24 h after administration of a single 10 mg oral dose. 3. There were no differences between the two groups in AUC and Cmax values of cadralazine and apparent metabolite, the latter defined as the sum of the free and conjugated hydrazinopyridazine. Peak plasma concentrations of these compounds were reached after 1 h. Thereafter, the concentration of the metabolite declined more slowly than that of cadralazine. 4. No effects on blood pressure were noted. Changes in heart rate and plasma renin were delayed by 3‐5 h with respect to the time‐course of drug and metabolite in plasma; maximum responses occurred at 4‐6 h after drug administration. The extent of the increase in plasma renin activity was slightly greater in slow than in fast acetylators, but the difference was not significant statistically.
Relationship between positive inotropic responses and plasma concentrations of xamoterol in middle‐aged and elderly patients.
Authors: Marlow HF , Hine FL , Snow HM , Pouleur H , Rousseau MF
Published: July 2012

1. We examined the relationship between the contractile state of the left ventricle and the plasma concentration of xamoterol in patients with ischaemic heart failure. 2. Identical studies were conducted in 14 middle‐aged (all male; mean age 51.3 years, range 42‐61) and 10 elderly patients (six male, four female; mean age 67.7 years, range 64‐72). 3. Patients received seven cumulative doses (0.0005‐0.2 mg kg‐1) of xamoterol. After each dose the rate of change of pressure in the left ventricle at a developed pressure of 40 mm Hg and normalised for this pressure, (dP/dt)/DP40, and plasma concentrations of xamoterol were measured. 4. There were dose‐related increases in (dP/dt)/DP40. Curves relating changes in (dP/dt)/DP40, expressed as a percent of the maximum observed response, to changes in xamoterol plasma concentrations were constructed for the middle‐aged and elderly patients. From these curves the mean effective concentration (EC) value to produce a particular response could be calculated. In the sample sizes studied, the difference between the EC values over a range of responses for the middle‐aged and elderly patients did not reach statistical significance, indicating that cardiac responsiveness to xamoterol was similar in the two groups of patients. 5. Plasma concentrations of xamoterol over the range of 39 to 150 ng ml‐1 produced positive inotropic responses which varied between 70% and 90% of the maximum observed effect of xamoterol.
The effects of flosequinan on submaximal exercise in patients with chronic cardiac failure.
Authors: Elborn JS , Riley M , Stanford CF , Nicholls DP
Published: July 2012

1. Twenty patients with moderate to severe chronic cardiac failure were entered into a double‐blind parallel group study comparing flosequinan 100 mg daily with matching placebo. 2. After at least three prior exercise tests, cardiopulmonary parameters were assessed at rest and during submaximal exercise before and after 2 and 8 weeks of active drug or placebo. 3. Resting minute ventilation and respiratory rate were reduced by flosequinan compared with placebo, but oxygen uptake was unchanged. 4. Comparison of minute ventilation, carbon dioxide production and venous lactate levels at the end of the exercise stage approximating to 50% of peak oxygen uptake demonstrated significant reductions in the flosequinan group compared with placebo at week 2 and week 8 (P less than 0.05). 5. Flosequinan increased the oxygen uptake at anaerobic threshold from 13.2 +/− 2.8 ml min‐1 kg‐1 to 15.9 +/− 3.4 ml min‐1 kg‐1 at week 2 and 15.8 +/− 3.7 ml min‐1 kg‐1 at week 8. These increases were significant when compared with placebo (P less than 0.05). 6. We conclude that flosequinan improves submaximal exercise performance in patients with chronic cardiac failure, probably by enhancing skeletal muscle blood flow.
The abnormal in vitro response to aspirin of platelets from aspirin‐ sensitive asthmatics is inhibited after inhalation of nedocromil sodium but not of sodium cromoglycate.
Authors: Marquette CH , Joseph M , Tonnel AB , Vorng H , Lassalle P , Tsicopoulos A , Capron A
Published: July 2012

1. Blood platelets from patients with aspirin‐sensitive asthma (ASA) generated cytotoxic mediators in the presence of aspirin. This abnormal in vitro response to aspirin was abolished within 1 h after nedocromil sodium inhalation but not after sodium cromoglycate inhalation. 2. Platelets recovered this reactivity to aspirin by 12 hours after nedocromil sodium treatment of ASA‐patients. 3. The in vitro reactivity to aspirin of ASA platelets isolated before inhalation was inhibited in the presence of serum isolated 15 and 60 min after nedocromil sodium inhalation.
Transdermal delivery of theophylline to premature infants using a hydrogel disc system.
Authors: Cartwright RG , Cartlidge PH , Rutter N , Melia CD , Davis SS
Published: July 2012

1. Preterm infants show incompletely developed skin with reduced barrier function. The possibility of transdermal delivery of theophylline from hydrogel discs swollen with choline theophyllinate has been investigated. 2. Drug loaded hydrogel discs 2 cm2 in area were applied to the abdomen and occluded. Serum theophylline concentrations were measured in twenty‐one infants of less than 31 weeks gestation. 3. Therapeutic concentrations were achieved in 18 individuals, and maintained for up to 15 days after repeated application of discs. A correlation between maximum serum drug concentration and transepidermal water loss, gestation and birthweight was demonstrated.
The effect of food and bile acid administration on the relative bioavailability of cyclosporin.
Authors: Lindholm A , Henricsson S , Dahlqvist R
Published: July 2012

1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant increase in the area under the blood concentration vs time curve (AUC) of cyclosporin when the drug was taken together with breakfast and bile acid tablets (9078 ng ml‐1 h) as compared with breakfast alone (7453 ng ml‐1 h, P less than 0.05) or fasting conditions (7283 ng ml‐1 h, P less than 0.01). 3. A blood drug concentration vs time curve displaying two peaks was present in 9/11 subjects when cyclosporin was taken with breakfast or with breakfast and bile acid tablets, but only one peak was present when cyclosporin was taken during fasting, suggesting an enterohepatic circulation of cyclosporin or a second absorption phase after the meal. 4. In a separate study, 12 h trough blood cyclosporin concentrations were measured before and after 1 week of bile acid treatment in 19 clinically stable, out‐patient transplant recipients who were treated with oral cyclosporin solution (mean dose 2.0 mg kg‐1 twice daily). The administration of cyclosporin was not standardized with regard to food intake. There was no significant difference in the blood concentrations of cyclosporin before and after bile acid treatment (114 +/− 38 ng ml‐1 vs 121 +/− 38 ng ml‐1).(ABSTRACT TRUNCATED AT 250 WORDS)
Metabolism of ciamexon by human liver microsomes: an investigation into the formation of stable, chemically reactive and cytotoxic metabolites.
Authors: Tingle MD , Park BK
Published: July 2012

1. The in vitro generation of stable, protein‐reactive and cytotoxic metabolites from ciamexon by human liver microsomes has been assessed. Stable metabolites were characterized by h.p.l.c./mass spectrometry, protein reactive metabolites by radiometric analysis and cytotoxic metabolites by assessment of cell viability after exposure to metabolites formed in situ. 2. Human livers were obtained from renal transplant donors. All 16 livers investigated metabolized ciamexon in a NADPH‐dependent reaction, the major metabolite being the 6‐hydroxy‐ methyl derivative. The hydroxylase activity of the livers varied from 34‐577 pmol mg‐1 min‐1, with a mean activity of 306 +/− 156 pmol mg‐1 min‐1. The further oxidation product, 6‐carboxy ciamexon, was also detected in some incubations. A third, unidentified, polar metabolite was present in all incubations (3.34‐11.11% of incubated radioactivity). 3. Only very low levels (less than 1%) of radioactivity became irreversibly bound to microsomal protein, which suggests that ciamexon undergoes little or no oxidative bioactivation in vitro. 4. Human liver microsomes did not metabolize ciamexon to a cytotoxic species, whereas microsomes prepared from mouse livers did generate a cytotoxic species. The degree of toxicity was enhanced if animals were pre‐treated with either phenobarbitone or beta‐naphthoflavone.
Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.
Authors: Andersson T , Andren K , Cederberg C , Lagerstrom PO , Lundborg P , Skanberg I
Published: July 2012

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]‐omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first‐pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.
The pharmacokinetics of midazolam in patients with congestive heart failure.
Authors: Patel IH , Soni PP , Fukuda EK , Smith DF , Leier CV , Boudoulas H
Published: July 2012

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age‐ and weight‐matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC‐MS. In the CHF patients, the elimination half‐life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min‐1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml‐1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.
Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man.
Authors: Sesardic D , Boobis AR , Murray BP , Murray S , Segura J , de la Torre R , Davies DS
Published: July 2012

1. Furafylline (1,8‐dimethyl‐3‐(2′‐furfuryl)methylxanthine) is a methylxanthine derivative that was introduced as a long‐acting replacement for theophylline in the treatment of asthma. Administration of furafylline was associated with an elevation in plasma levels of caffeine, due to inhibition of caffeine oxidation, a reaction catalysed by one or more hydrocarbon‐inducible isoenzymes of P450. We have now investigated the selectivity of inhibition of human monooxygenase activities by furafylline. 2. Furafylline was a potent, non‐competitive inhibitor of high affinity phenacetin O‐deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 microM. 3. Furafylline had either very little or no effect on human monooxygenase activities catalysed by other isoenzymes of P450, including P450IID1, P450IIC, P450IIA. Of particular interest, furafylline did not inhibit P450IA1, assessed from aryl hydrocarbon hydroxylase activity of placental samples from women who smoked cigarettes. 4. It is concluded that furafylline is a highly selective inhibitor of P450IA2 in man. 5. Furafylline was a potent inhibitor of the N3‐demethylation of caffeine and of a component of the N1‐ and N7‐demethylation. This confirms earlier suggestions that caffeine is a selective substrate of a hydrocarbon‐inducible isoenzyme of P450 in man, and identifies this as P450IA2. Thus, caffeine N3‐ demethylation should provide a good measure of the activity of P450IA in vivo in man. 6. Although furafylline selectively inhibited P450IA2, relative to P450IA1, in the rat, this was at 1000‐times the concentration required to inhibit the human isoenzyme, suggesting a major difference in the active site geometry between the human and the rat orthologues of P50IA2.
Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.
Authors: Schellens JH , van der Wart JH , Breimer DD
Published: July 2012

1. In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4‐hydroxy metabolites (OH‐). 2. On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4‐hydroxy metabolites of all compounds were measured by h.p.l.c. 3. Urinary recovery of OH‐phenytoin was 31.0 +/− 11.7%, of OH‐ methylphenytoin 3.4 +/− 2.7% and of OH‐phenobarbitone 1.4 +/− 1.2%. No correlation was found between the recovery of OH‐mephenytoin and OH‐ phenytoin. A subject who produced virtually no OH‐phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4. The correlation coefficient for OH‐ mephenytoin and OH‐methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH‐ methylphenytoin, suggesting a cosegregation of the 4‐hydroxylation pathways. No correlation was found between the urinary recovery of OH‐ phenobarbitone and that of the other 4‐hydroxy metabolites.
Pharmacokinetic and pharmacodynamic studies of glibenclamide in non‐ insulin dependent diabetes mellitus.
Authors: Coppack SW , Lant AF , McIntosh CS , Rodgers AV
Published: July 2012

1. The pharmacokinetic and pharmacodynamic properties of oral glibenclamide have been studied in 31 hospitalised in‐patients and 79 ambulant out‐patients with diabetes mellitus. 2. Breakfast was found to have no significant influence on the kinetic behaviour of glibenclamide or on the effect of this drug on blood glucose utilisation. 3. The time course of glibenclamide kinetics after 20 mg dosing was adequately described by a two‐compartment open model, yielding mean half‐lives of 3.3 +/− 1.5 h (t1/2, lambda 1) and 9.7 +/− 1.2 (t1/2, z) for the initial and terminal elimination phases respectively. 4. No significant accumulation or change in kinetic profile occurred in patients who had normal renal and hepatic function, were treated continuously with glibenclamide, and then rechallenged after 8‐12 weeks. 5. Despite inter‐ individual variations in drug absorption, peak plasma concentrations (Cmax) and the area under the plasma concentration‐time curve (AUC(0‐ 24] were dose‐dependent over the dose range 5‐20 mg. No significant dose‐response behaviour was observed in respect of glucose utilisation, suggesting that there is little clinical benefit in using doses of glibenclamide above 5 mg day‐1. 6. Comparison of plasma glibenclamide concentrations at different time‐bands following doses of 5 and 10 mg showed a wider range in ambulant out‐patients than in age‐, sex‐matched in‐patients treated with the same dosages of drug. Mean plasma drug concentrations attained at all time bands up to 8 h after dosing were higher in out‐patients than in in‐patients, suggesting a tendency to ‘over‐compliance’ by patients in anticipation of attendance at clinic.
Inter‐ and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and paracetamol absorption.
Authors: Petring OU , Flachs H
Published: July 2012

1. Inter‐ and intrasubject variability in the gastric emptying of semisolids and liquids was measured by scintigraphic emptying of radionuclide‐labelled semisolid and from paracetamol absorption in ten healthy volunteers of both sexes. 2. The intrasubject variability was not statistically significant for any of scintigraphic or paracetamol absorption parameters. 3. The intersubject variation was significant for all scintigraphic and paracetamol absorption parameters. 4. In women, the gastric emptying rate of semisolid decreased linearly during the menstrual cycle. 5. The lag period and paracetamol absorption parameters were unrelated to the day of the menstrual cycle day. 6. There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters.
The pharmacokinetics of recombinant human erythropoietin after intravenous and subcutaneous administration to healthy subjects.
Authors: Salmonson T , Danielson BG , Wikstrom B
Published: July 2012

1. The pharmacokinetics of recombinant erythropoietin, r‐Epo, were evaluated after intravenous and subcutaneous administration of 50 u kg‐ 1 to six healthy male volunteers. 2. The calculated mean values (+/− s.d.) for volume of distribution at steady state and clearance after an i.v. dose were 76 (+/− 33) ml kg‐1 and 12 (+/− 3) ml h‐1 kg‐1, respectively. 3. Serum concentrations of r‐Epo peaked at 13 (+/− 6) h after the s.c. dose and the bioavailability over 72 h was 36 (+/− 23)%. The mean residence time and half‐life of erythropoietin were 6.2 (+/− 1.0) and 4.5 (+/− 0.9) h respectively after i.v. and 46 (+/− 18) and 25 (+/− 12) h after s.c. administration. 4. The results demonstrate the possibility of changing the profile of the concentration‐time curve by changing the mode of administration of r‐Epo, with implications for the time‐course of clinical response.
Comparative effects of dilevalol and atenolol on lung function and airway response to methacholine in hypertensive subjects.
Authors: Boulet LP , Lacourciere Y , Milot J , Lampron N
Published: July 2012

1. In this double‐blind randomized study, after a 4‐weeks placebo period, 18 patients with mild to moderate primary hypertension were assigned to treatment with either dilevalol (n = 9) daily or atenolol (n = 9) over a period of 3 months. 2. Expiratory flows, lung volumes and airway responsiveness (AR) to methacholine were assessed at the end of the placebo period and after an active treatment of 12 weeks. Blood pressure (BP), heart rate (HR) and ECG were monitored during the methacholine challenges. Twice daily peak expiratory flow rates and respiratory symptoms were recorded on a diary card. 3. No significant effects on ECG, HR and BP were observed after methacholine inhalation. In all but one subjects there was no significant change in expiratory flows, lung volumes or AR throughout the study. Mean FEV1, FVC, PEFR, FRC and PC20 methacholine were unchanged after 3 months of treatment, and not statistically different between patients on dilevalol or atenolol. 4. One subject, without previous history of asthma, developed transient airflow obstruction 8 weeks after beginning dilevalol. 5. Dilevalol and atenolol have no significant effects on pulmonary function and AR in most subjects with no baseline airflow limitation. 6. Airflow obstruction may develop in normal subjects on dilevalol. Methacholine challenges are safe in subjects with uncomplicated hypertension.
Haemodynamic dose‐response effects of UK‐52,046 in ischaemic disease with or without impaired left ventricular function.
Authors: Silke B , Zezulka AV , Verma SP , Tham TC , Taylor SH
Published: July 2012

1. The haemodynamic effects of a new cardioselective postsynaptic alpha 1‐adrenoceptor antagonist UK‐52,046, were evaluated in 25 patients with stable coronary disease, with or without impaired left ventricular function. At rest the haemodynamic effects to two dose‐response regimens were determined. In an initial eight patients 0.125, 0.125 and 0.25 micrograms kg‐1 were administered peripherally at 15 min intervals; the haemodynamic measurements were determined between 10 to 15 min after each dose. In a further 17 patients, the dose regimen was doubled yielding a cumulative dose‐regimen of 0.25, 0.5 and 1.0 micrograms kg‐1. The exercise effects were determined by comparison of measurements during 4 min of supine sub‐maximal bicycle exercise at a fixed workload before and after drug treatment. 2. At rest, the lower dose regimen of UK‐52,046 significantly reduced systemic mean arterial blood pressure (‐5 mm Hg; P less than 0.05) and increased cardiac index (+0.2 l min‐1 m‐2, P less than 0.01). The higher dose regimen of UK‐ 52,046 reduced systemic mean arterial blood pressure (‐7 mm Hg; P less than 0.01), pulmonary artery occluded pressure (PAOP) (‐2 mm Hg, P less than 0.01) and vascular resistance index (‐314 dyn s cm‐5 m2; P less than 0.05) with an increase in heart rate (+7%, P less than 0.05) and cardiac index (+0.2 l min‐1 m‐2, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.
Authors: Robbins DK , Wedlund PJ , Kuhn R , Baumann RJ , Levy RH , Chang SL
Published: July 2012

The effect of valproic acid (VPA) on the disposition of carbamazepine‐ 10,11‐epoxide (epoxide) was studied in five epileptic patients on chronic carbamazepine (CBZ) therapy. The individual pharmacokinetic parameters influencing epoxide disposition were determined in the presence and absence of VPA. VPA significantly decreased the clearance of unbound epoxide (an in vivo index of epoxide hydrolase activity), but did not appear to affect epoxide formation. VPA also increased the free concentrations of both CBZ and epoxide.
Lack of effect of the specific cholecystokinin receptor antagonist loxiglumide on cholecystokinin clearance from plasma in man.
Authors: Jebbink MC , Jansen JB , Masclee AA , Lamers CB
Published: July 2012

Saline or loxiglumide (2.5 mg kg‐1 in 10 min, followed by 5 mg kg‐1 h‐1 for 200 min) was administered intravenously in random order to six healthy subjects. After 60 min cholecystokinin (CCK‐33) was infused (0.5 i.d.u. kg‐1 h‐1 for 1 h then 1.0 i.d.u. kg‐1 h‐1 for 1 h). Loxiglumide did not change basal levels of CCK and did not augment plasma CCK‐immunoreactivity during CCK‐33 infusion. After cessation of the CCK‐infusion, plasma CCK concentrations decreased rapidly to basal values within 12 min, and the elimination half‐life during loxiglumide infusion (4.8 +/− 0.8 min) was not significantly different from that during saline infusion (4.2 +/− 1.0 min). These results suggest that loxiglumide does not interfere with the distribution and metabolism of CCK.
The effect of local converting enzyme inhibition on the dilator response to substance P in the human forearm.
Authors: Benjamin N , Webb DJ
Published: July 2012

It has been proposed that angiotensin converting enzyme (ACE) may play a part in the metabolism of substance P. Reduced metabolism following treatment with ACE inhibitors may cause accumulation of substance P to produce the adverse effect of cough. It has been shown in this study that, in contrast to angiotensin I and bradykinin, inhibition of local vascular ACE does not interfere with the vascular effects of substance P on forearm resistance vessels when this peptide is infused into the brachial artery of normal volunteers. These results suggest that endothelial ACE plays little part in the metabolism of intravascular substance P.
Use of sodium aurothiomalate during lactation.
Authors: Bennett PN , Humphries SJ , Osborne JP , Clarke AK , Taylor A
Published: July 2012

The report concerns a mother who breast fed her infant whilst receiving sodium aurothiomalate for the treatment of rheumatoid arthritis. The milk:serum concentration ratio was not constant, reflecting the non‐ concurrence of the concentration‐time profiles of gold in milk and maternal serum after i.m. injection. Gold was detected in the infant's serum. Calculations indicate that the weight‐adjusted dose to the infant exceeded that received by the mother.
Quinine induces reversible high‐tone hearing loss.
Authors: Roche RJ , Silamut K , Pukrittayakamee S , Looareesuwan S , Molunto P , Boonamrung S , White NJ
Published: July 2012

Serial audiometry was performed in ten patients receiving quinine treatment for acute falciparum malaria. Quinine reduced high tone auditory acuity in all patients, resulting in flattening of the audiograms. The effect was rapid in onset, usually unnoticed (although tinnitus was reported in seven patients), and resolved completely after treatment was completed.
Screening for aminoglycoside auditory toxicity in the old.
Authors: Cheung R , Clark P , Nicholson PW , Deshmukh AA , O'Neill CJ , Dobbs SM , Dobbs RJ
Published: July 2012

1. We have investigated 22 patients receiving gentamicin, mean (s.d.) age 78 (6) years for auditory toxicity, using a standard audiometric technique in a sound‐treated room (Study 1). 2. Use of a portable audiometer might allow a larger and more representative proportion of patients treated with aminoglycosides to be screened for ototoxicity. A method for detecting high frequency loss suitable for use in the ward was evaluated in 12 volunteers aged 27 (4) years (Study 2). 3. The error inherent in taking hearing at the start of treatment as a reference point was measured in 16 patients, aged 81 (8) years, prescribed non‐ototoxic antibacterials (Study 3). 4. A significant (P = 0.05) reduction in hearing threshold was detected in Study 1, although psychometric tests revealed unchanged or improved ability to co‐ operate. This occurred only at 4000 Hz, the highest frequency used. The magnitude of this loss, mean 2.5 dB, was similar to that of the improvement in threshold detected (P = 0.0004) early in the course of treatment in Study 3. Thus, underestimation of ototoxicity is likely. 5. If a change of threshold of 10 dB or more is taken arbitrarily to represent a real change in hearing, then there was a significant excess of patients in Study 1 with losses at 4000 Hz only (P = 0.032). The six with such losses at this frequency were older than the rest. However, there was a significant (P less than 0.02) positive correlation between log mean predose serum gentamicin concentration and age. Thus, it remains to be determined whether presbyacusis sensitizes those hair cells which it does not destroy to toxic damage. 6. The cumulative dose of gentamicin (for a course of the duration given) was calculated according to published prescribing aids. There was no systematic reduction in the ratio of the dose recommended by a given aid to the dose prescribed in the six with hearing losses as defined above. 7. In Study 2, thresholds obtained at 6000 Hz in the open ward were, on average, 0.9 dB higher than in the sound treated room, but the effect of venue did not reach statistical significance. In the morning thresholds were marginally, but significantly (P = 0.04), lower than in the afternoon. Precision, as measured by the standard deviation of replicate determination, was independent of test conditions. Using multiple (ten) threshold determinations appeared to improve resolution.(ABSTRACT TRUNCATED AT 400 WORDS)
Effect of intravenous atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate in young and fit elderly volunteers.
Authors: Rashid MU , Bateman DN
Published: July 2012

1. The effects of atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate were examined in young and elderly subjects. 2. Seven healthy young male subjects of age 23 +/− 1.3 years (mean +/− s.e. mean) and seven fit elderly subjects of age 70 +/− 1.6 years received placebo (P), 300 micrograms atropine (A300) or 600 micrograms atropine (A600) in randomized order at weekly intervals. After 10 min they ingested a 500 ml orange drink containing 1 g paracetamol. Gastric emptying was measured by ultrasound, blood samples were taken to measure plasma paracetamol concentration by h.p.l.c., salivary flow was measured by dental cotton wool cylinder technique and pulse rate was recorded. 3. In young subjects, the gastric 5 min volumes were 260.1 +/− 17.9 ml (s.e. mean) with P, 310.6 +/− 10.5 ml with A300 and 317.9 +/− 8.9 ml with A600. In elderly subjects, the gastric 5 min volumes were 166.7 +/− 10.1 ml with P, 252.6 +/− 13.7 ml with A300 and 266.0 +/− 14.8 ml with A600. Thus the early adaptive phase of gastric emptying was more rapid in the elderly than the young with all treatments (P less than 0.05). The gastric emptying half‐lives were 18.8 +/− 2.5 min with P, 30.0 +/− 2.7 min with A300 and 34.5 +/− 3.3 min with A600 in young subjects (P less than 0.01). In elderly subjects, the gastric emptying half‐lives were 16.1 +/− 2.5 min with P, 23.7 +/− 2.4 min with A300 and 30.0 +/− 2.9 min with A600 (P less than 0.01). Thus atropine intravenously in therapeutic dose (300 and 600 micrograms) delayed gastric emptying in both young and elderly subjects. The inhibitory effect of atropine on the early adaptive phase of gastric emptying appeared to be greater in the elderly. The maximum plasma concentration (Cmax) of paracetamol was greater in the elderly than young with all treatments (P less than 0.05). There was a close relationship between the early adaptive phase of gastric emptying and paracetamol absorption (P less than 0.05). Atropine reduced salivary flow and increased resting heart rate in both young and old subjects. The effect of atropine on salivary flow was greater in the elderly. 4. The dose‐response relationship varied in the three systems (stomach, salivary glands and heart rate) studied. Age had an effect on the magnitude of the response, but not on the slope of the dose‐response curve for the two doses of atropine studied.(ABSTRACT TRUNCATED AT 400 WORDS)
Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf‐capsule.
Authors: Harder S , Fuhr U , Beermann D , Staib AH
Published: July 2012

1. The absorption of ciprofloxacin from different regions of the human gastrointestinal tract was investigated in four healthy males using a remote‐controlled drug delivery device (hf‐capsule). 2. Significant differences in AUC were observed in the control study (oral administration of ciprofloxacin solution without the hf‐capsule = 100%) and after release of ciprofloxacin in the jejunum (geometric mean: 37%), the ileum (mean: 23%), the ascending colon (mean: 7%) and the descending colon (mean: 5%), whereas tmax showed no difference for any of the absorption sites. Ciprofloxacin release in the stomach resulted in the greatest AUC (mean: 140%). Thus, it is concluded that the main absorption site of ciprofloxacin is the upper gastrointestinal tract, up to the jejunum. 3. Differences in presystemic metabolism of known drug metabolites along the gut could be excluded, as the pattern of urinary recovery of desethylene‐, sulpho‐, and oxo‐ciprofloxacin and the parent compound was similar for all drug release sites.
Effects of the 5‐HT3 receptor antagonist ICS 205‐930 on fat‐delayed gastric emptying and antral motor activity.
Authors: Stacher G , Bergmann H , Schneider C , Steiner‐Mittelbach G , Gaupmann G , Steinringer H , Abatzi TA , Stacher‐Janotta G
Published: July 2012

1. The selective 5‐HT3 receptor antagonist, ICS 205‐930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205‐930 on fat‐delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205‐930 or placebo were infused i.v. in a random double‐blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205‐930 than after placebo. Emptying after 20 mg of ICS 205‐930 was significantly slower than after 10 mg of ICS 205‐ 930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205‐930 than after placebo, whereas the effects of 10 mg ICS 205‐ 930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205‐930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.
Acipimox in combination with low dose cholestyramine for the treatment of type II hyperlipidaemia.
Authors: Series JJ , Gaw A , Kilday C , Bedford DK , Lorimer AR , Packard CJ , Shepherd J
Published: July 2012

1. This study was designed to examine the effects of acipimox 250 mg three times daily and cholestyramine 4 g three times daily on plasma lipids and lipoproteins in 28 hypercholesterolaemic individuals in a prospective double‐blind placebo controlled parallel group fashion. 2. Combined treatment with the two agents produced a mean reduction of 27% in plasma total cholesterol and a 32% fall in LDL cholesterol. Plasma triglyceride was reduced by 13% due to a 38% decrement in VLDL cholesterol. 3. In comparison treatment with cholestyramine alone resulted in a 12% fall in plasma cholesterol and a 15% fall in LDL cholesterol. In this group triglycerides and VLDL showed no significant change. 4. Studies of HDL subfraction mass showed that the addition of acipimox to resin therapy produced a mean increment of 45% in HDL2. 5. These results demonstrate the effectiveness of such a well tolerated low dosage combination therapy.