bluuebunny/crossref_metadata_2025 huggingface dataset:
The metabolism of mexiletine in relation to the debrisoquine/sparteine‐ type polymorphism of drug oxidation.
Authors: Broly F , Vandamme N , Libersa C , Lhermitte M
Published: July 2012

1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine‐type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug‐free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p‐ hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O‐demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4‐hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = −0.83; P = 0.006 and rs = −0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine‐type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
N‐acetylation and debrisoquine hydroxylation polymorphisms in patients with Gilbert's syndrome.
Authors: Siegmund W , Fengler JD , Franke G , Zschiesche M , Eike O , Eike E , Meisel P , Wulkow R
Published: July 2012

1. N‐acetylation and debrisoquine hydroxylation phenotypes were determined in 54 patients with Gilbert's syndrome and in 247 (sulphamethazine) and 76 (debrisoquine) non‐related healthy volunteers. 2. Forty (74.1%) of the patients and 135 (54.7%) of the healthy volunteers were slow acetylators (chi 2 = 6.87). In the patients, the cumulative urinary excretion of sulphamethazine up to 6 h (Ae(0,6)) was significantly lower. No differences in the frequency of debrisoquine poor metabolizers were observed: Gilbert's syndrome 5/54 (9.3%), healthy volunteers 5/76 (6.6%). The metabolic ratios were similar in both groups as well as the urinary recoveries of debrisoquine and its 4‐ hydroxy metabolite. 3. Gilbert's syndrome seems to be related in some way to N‐acetylation but not to the debrisoquine hydroxylation polymorphism.
Interactions between domperidone and ropinirole, a novel dopamine D2‐ receptor agonist.
Authors: de Mey C , Enterling D , Meineke I , Yeulet S
Published: July 2012

1. Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2‐receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone‐placebo, and those of a single dose of domperidone followed by ropinirole‐placebo. 2. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. 3. Pretreatment with 20 mg domperidone 1 h before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. 4. Ropinirole did not alter supine or standing catecholamine concentrations. 5. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 h earlier.
The influence of co‐administered organic acids on the kinetics and dynamics of frusemide.
Authors: Sommers DK , Meyer EC , Moncrieff J
Published: July 2012

1. This study examines the effects of pretreatment with probenecid with and without pyrazinamide on the elimination kinetics and diuretic action of frusemide. 2. Six normal male volunteers received 40 mg frusemide i.v. on three occasions; i.e. once on its own and twice after pretreatment with 2 g probenecid with and without 3 g pyrazinamide. Both these latter drugs were administered orally 3 h before frusemide administration thereby attempting optimal suppression of proximal tubular secretion. Urinary losses were replaced i.v. with isovolumetric amounts of normal saline while insensible losses were compensated for by taking tap water orally. 3. The mean cumulative urinary frusemide excretion was significantly and similarly decreased by pretreatment with probenecid (34.9%) and probenecid plus pyrazinamide (33.6%), but the mean total volume of diuresis and the mean cumulative urinary sodium excretion did not differ significantly between treatments over the 5 h period. 4. The diuretic efficiency of frusemide was significantly increased with probenecid pretreatment during the first 90 min period after frusemide administration. Furthermore, in the first 30 min after administration the percent sodium fractional excretion was higher after pretreatment with probenecid even though the mean frusemide excretion rate was more than three times with frusemide alone than with probenecid‐frusemide (374.4 micrograms min‐1 vs 119.1 micrograms min‐1). Pretreatment with probenecid results in a higher concentration on the peritubular or blood side of the tubules and these results lead us to question the unconditional acceptance of a luminal site of action for the loop diuretics. Alternatively, probenecid may act in some other way to increase the effects of frusemide.
Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations.
Authors: Sohn DR , Shin SG , Park CW , Kusaka M , Chiba K , Ishizaki T
Published: July 2012

We examined metoprolol oxidation capacity in 218 unrelated, healthy Korean subjects using the 8 h urinary metabolic ratio (MR) of metoprolol to alpha‐hydroxymetoprolol after an oral dose of 100 mg metoprolol tartrate. The results were compared with those from 295 Japanese and 107 mainland Chinese whose metoprolol oxidation capacities were assessed in a similar manner. The frequency of occurrence of poor metabolisers (PMs) was 0.5% (1/218) in the Korean, 0.7% (2/295) in the Japanese and 0% in the Chinese population. However, the respective mean (+/‐ s.d.) MRs (0.84 +/‐ 1.14 and 0.87 +/‐ 0.90) in the Korean and Japanese extensive metabolisers (EMs) were significantly (P less than 0.001) less than that in the Chinese EMs (2.81 +/‐ 2.35), and the mode of the distribution histogram and the probit plot of data for Chinese EMs were shifted to the right compared with those for Korean and Japanese EMs. The results indicate that Koreans, like Japanese and mainland Chinese, have a much lower frequency of the PM phenotype of debrisoquine/sparteine‐type oxidation compared with that reported for Caucasian populations. Chinese EMs appear to have a lower capacity to metabolise metoprolol to alpha‐hydroxymetoprolol compared with Korean or Japanese EMs.
Further insight into the stereoselective interaction between warfarin and cimetidine in man.
Authors: Niopas I , Toon S , Rowland M
Published: July 2012

The urinary profile of R‐ and S‐warfarin, following administration of a single (25 mg) oral dose of racemic warfarin, alone or on day 4 of a 9‐ day chronic administration of cimetidine (800 mg once daily), was investigated in eight healthy male volunteers. Based on estimated apparent formation clearance values, cimetidine inhibited significantly only the formation of R‐6‐hydroxywarfarin and R‐7‐hydroxywarfarin.
Effect of RG 12525, an oral leukotriene D4 antagonist, on the airway response to inhaled leukotriene D4 in subjects with mild asthma.
Authors: Wahedna I , Wisniewski AS , Tattersfield AE
Published: July 2012

We have studied the effect of RG 12525, an oral leukotriene D4 (LTD4) antagonist, on LTD4‐induced bronchoconstriction in eight male subjects with mild asthma (baseline FEV1 greater than 80% predicted) in a double‐ blind, placebo‐controlled fashion. RG 12525 800 mg displaced the dose‐ response curve for LTD4 to the right. The mean (95% confidence intervals) difference in log PC20FEV1 following RG 12525 and placebo was 2.88 (1.61, 4.17) doubling doses of LTD4 (P less than 0.01), a 7.5 fold difference. We conclude that RG 12525 when administered orally is an effective LTD4 antagonist in subjects with mild asthma.
The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.
Authors: Khan A , Langley SJ , Mullins FG , Dixon JS , Toon S
Published: July 2012

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/‐ s.d. values of AUC were 105 +/‐ 40 micrograms l‐1 for placebo treatment, 111 +/‐ 45 micrograms l‐1 h for ranitidine and 211 +/‐ 64 micrograms l‐1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/‐ 14, 39 +/‐ 27 and 76 +/‐ 40 micrograms l‐1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.
Central effects of the calcium antagonist, nifedipine.
Authors: McDevitt DG , Currie D , Nicholson AN , Wright NA , Zetlein MB
Published: July 2012

1. Central effects of the calcium antagonist, nifedipine retard (10, 20 and 40 mg) and nifedipine capsules (10 mg) were studied in 14 healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included. Medication was administered double‐blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5‐2.5 h and 3.5‐4.5 h after ingestion, and recordings of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short‐term memory, together with critical flicker fusion and two flash fusion. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. Subjects assessed their mood and well‐being on a series of 12 visual analogue scales. 3. Nifedipine did not alter performance levels on any of the skills tested, while oxazepam (15 mg) increased the number of errors (P less than 0.01) and reduced accuracy at continuous attention (P less than 0.01). 4. Nifedipine (10 mg) reduced total power of the EEG in the frequency range (0.5‐30 Hz), and nifedipine (20 mg) increased total alpha power (7.5‐13 Hz) (P less than 0.05). Oxazepam reduced alpha and increased beta 1 power (13.5‐21 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of age on the pharmacokinetics, antihypertensive efficacy and general tolerability of dilevalol.
Authors: Macphee GJ , Howie CA , Meredith PA , Elliott HL
Published: July 2012

1. This study investigated the influence of age on the pharmacokinetics, pharmacodynamics, general tolerability and concentration‐effect relationships in 18 patients with essential hypertension (age range 23‐73 years) during treatment with dilevalol, a non selective beta‐adrenoceptor antagonist with vasodilator properties. 2. There were no significant age‐related changes in pharmacokinetics for either acute or chronic treatment with dilevalol, although there were significant changes in elimination half‐life from 7.8 to 11.7 h (P less than 0.05) and in AUC from 261 to 352 ng ml‐1 h (P less than 0.005) following translation from acute to chronic dosing. 3. In absolute terms, dilevalol treatment (as compared with placebo) produced numerically larger falls in average blood pressure in the six oldest as compared with the six youngest patients: for example, supine blood pressure fell by, respectively, 29/15 and 10/7 mm Hg during chronic treatment. 4. Using an integrated kinetic‐dynamic model, blood pressure responsiveness was characterised by relating the fall in blood pressure (mmHg) to the plasma drug concentrations in each individual patient. No independent age‐related effect was demonstrated. There was a significant relationship between response and the height of initial blood pressure which tended to be higher in the elderly patients. 5. Patient tolerability was generally satisfactory and there was no differential age‐related effect. 6. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no significant age‐related differences in pharmacokinetics or pharmacodynamics.
Studies with abanoquil (UK‐52,046) a novel quinoline alpha 1‐ adrenoceptor antagonist: I. Effects on blood pressure, heart rate and pressor responsiveness in normotensive subjects.
Authors: Schafers RF , Elliott HL , Howie CA , Reid JL
Published: July 2012

1. Abanoquil (UK 52,046) is a novel, quinoline‐derivative, alpha 1‐ adrenoceptor antagonist which, on the basis of animal studies, possesses antiarrhythmic activity at doses which have little or no effect on blood pressure. 2. In two placebo‐controlled, double‐blind, crossover studies the alpha 1‐adrenoceptor antagonist activity (phenylephrine pressor responses) and the effects on blood pressure and heart rate (in the presence and absence of concomitant beta‐ adrenoceptor blockade) have been investigated in healthy, normotensive subjects following the intravenous administration (i.v.) of abanoquil. 3. In the first study, abanoquil at a dose of 0.4 micrograms kg‐1 i.v. (as a bolus or by increments) produced significant alpha 1‐adrenoceptor antagonism (with rightward shifts of more than two‐fold in the phenylephrine pressor dose‐response curves) but no significant effects on supine or erect blood pressure and heart rate. 4. In the second study, a dose of 0.5 micrograms kg‐1 i.v. had no significant effect on supine or erect blood pressure but pre‐treatment with atenolol promoted a small fall in erect blood pressure without causing significant orthostatic hypotension. 5. In conclusion, significant alpha 1‐ adrenoceptor antagonism without marked reflex tachycardia or profound postural hypotension suggest that abanoquil has a different haemodynamic profile from that of ‘classical’ peripheral alpha 1‐ adrenoceptor antagonists.
Mechanism of diuretic action of spiradoline (U‐62066E)‐a kappa opioid receptor agonist in the human.
Authors: Rimoy GH , Bhaskar NK , Wright DM , Rubin PC
Published: July 2012

1. The mechanism of the diuretic effect of the kappa opioid receptor agonist spiradoline was investigated in 10 healthy male subjects in a placebo‐controlled, double‐blind cross‐over study. 2. Urine volume and osmolality, plasma vasopressin and Doppler renal blood velocity indices were recorded for 1.25 h before and 6 h following injection. 3. Spiradoline caused a significant increase in urine output which was antagonized by high but not low dose naloxone. The urine increase was accompanied by a significant decrease in osmolality which was also antagonised by high but not low dose naloxone. 4. Spiradoline had no effect on plasma vasopressin concentration or on renal blood velocity indices. 5. We conclude that kappa agonists induce diuresis in humans by a mechanism not involving suppression of vasopressin or changes in renal blood velocity indices.
Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics of quinine.
Authors: Wanwimolruk S , Chalcroft S
Published: July 2012

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics of quinine after a single dose (600 mg) of quinine sulphate was studied in eight extensive metabolizers (EM) and five poor metabolizers (PM). The mean elimination half‐life of quinine in the PMs (10.2 +/‐ 1.6 (s.d.)h) was similar to that in the EMs (10.9 +/‐ 1.7 h). The oral clearance of quinine in the PM subjects was 0.092 +/‐ 0.021 l h‐1 kg‐1 and was not significantly different (P greater than 0.05) from that observed in the EM subjects (0.073 +/‐ 0.019 l h‐1 kg‐1). This suggests that even though quinine is extensively metabolized by oxidative biotransformation, this is carried out largely by P450 isoenzymes different from P450IID6 which oxidizes debrisoquine.
Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.
Authors: Back DJ , Tjia JF
Published: July 2012

Four antimycotic drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine have been studied for their effect on the metabolism of cyclosporin by human liver microsomes (n = 3) in vitro. Ketoconazole caused marked inhibition of cyclosporin hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/‐ 0.01 and 0.022 +/‐ 0.004 microM, respectively. Based on IC50 values, itraconazole was ten times less potent (IC50 value of 2.2 +/‐ 0.2 microM) and both fluconazole and terbinafine had values above 100 microM. Ki values for itraconazole and fluconazole were 0.7 +/‐ 0.2 and 40 +/‐ 5.6 microM, respectively. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Based on these data, ketoconazole is confirmed as being a potent inhibitor of cyclosporin metabolism and this has clinical relevance. Although inhibition by fluconazole was much less than that by itraconazole at equimolar concentrations, it should be noted that in patients plasma concentrations of fluconazole are much greater than those of itraconazole. Clinical interactions of cyclosporin with both fluconazole and itraconazole have been reported. In contrast to the azoles, terbinafine does not have the same potential for interaction.
Inhibition of the metabolism of paracetamol by isoniazid.
Authors: Epstein MM , Nelson SD , Slattery JT , Kalhorn TF , Wall RA , Wright JM
Published: July 2012

1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non‐oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre‐isoniazid values.
A comparison of the pharmacokinetic properties of streptokinase and anistreplase in acute myocardial infarction.
Authors: Gemmill JD , Hogg KJ , Burns JM , Rae AP , Dunn FG , Fears R. , Ferres H. , Standring R. , Greenwood H. , Pierce D. , et al
Published: July 2012

1. The pharmacokinetics of streptokinase (SK) and anistreplase in conventional dosage regimens of 1.5 x 10(6) i.u. of SK infused over 60 min and 30 units of anistreplase over 5 min were studied in 24 consecutive patients presenting with acute myocardial infarction, using a functional bioassay to assess concentrations. 2. The two agents were found to have similar volumes of distribution (5.68 and 5.90 l), but SK was cleared significantly more rapidly than anistreplase, resulting in a shorter terminal phase half‐life (0.61 vs 1.16 h) and a shorter mean residence time (0.76 vs 1.55 h).
A study of the acute pharmacodynamic interaction of ramipril and felodipine in normotensive subjects.
Authors: Bainbridge AD , MacFadyen RJ , Lees KR , Reid JL
Published: July 2012

1. The possibility of an acute pharmacokinetic or pharmacodynamic interaction between the ACE inhibitor ramipril and the calcium antagonist felodipine was examined in 12 normotensive male volunteers. 2. Ramipril (5 mg) and felodipine ER (10 mg) were administered orally in a double‐blind, randomised, placebo‐controlled, Latin square design to fasting subjects. 3. There was no evidence of a pharmacokinetic interaction between agents. The concentration‐time profiles remained unaltered by coadministration of both agents. 4. Plasma ACE inhibition by ramiprilat was unaffected by concurrent felodipine. The trend towards increased fractional sodium excretion after felodipine was not influenced by ramipril. Plasma renin activity, aldosterone and catecholamines remained unaltered. 5. Combination therapy produced a statistically significant fall in blood pressure supine and erect which was not evident with monotherapy. The reflex tachycardia associated with felodipine monotherapy was significantly attenuated by the coadministration of ramipril. 6. This study presents further evidence for the effective combination of ACE inhibitors and calcium antagonists to lower blood pressure. The reflex tachycardia associated with calcium antagonist therapy can be significantly reduced by coadministration with sustained antihypertensive effect.
The effects of time and dose on the relative beta 1‐ and beta 2‐ adrenoceptor antagonism of betaxolol and atenolol.
Authors: Lipworth BJ , Irvine NA , McDevitt DG
Published: July 2012

1. Six normal subjects were given single oral doses of betaxolol 10 mg (B10), 40 mg (B40), 80 mg (B80); atenolol 50 mg (A50), 200 mg (A200); or placebo (PL). Measurements of beta 1‐adrenoceptor blockade (reduction of exercise heart rate) and of beta 2‐adrenoceptor blockade (attenuation of isoprenaline responses) were made at baseline, and at 2, 4, 6, 8 and 24 h after drug ingestion. 2. Mean values for Cmax and tmax were as follows: B10 (33 ng ml‐1, 3.7 h), B40 (84 ng ml‐1, 4.0 h), B80 (179 ng ml‐1, 3.7 h); A50 (261 ng ml‐1, 2.7 h), A200 (1369 ng ml‐1, 2.0 h). 3. Reduction of exercise heart rate (EHR) occurred in dose‐ dependent fashion up to a ceiling at B40 (as % reduction c.f. placebo, at peak and 24 h): B10 16.2 to 10.2%, B40 27.1 to 16.2%, B80 27.0 to 18.7%; A50 20.9 to 9.1%, A200 28.8 to 15.8%. There were also dose‐ related increases in beta 2‐adrenoceptor antagonism (IT100 dose ratios, at peak and 24 h): B10 2.1 to 1.2, B40 4.7 to 2.6, B80 6.0 to 4.7; A50 2.0 to 1.2, A200 4.7 to 1.8. There were similar trends for attenuation of heart rate and DBP responses to isoprenaline. 4. Ratios of beta 1:beta 2‐adrenoceptor antagonism were calculated (as % reduction EHR divided by IT100 dose ratio); to provide an index of beta 1‐ adrenoceptor selectivity at peak and 24 h: B10 7.7 to 8.5, B40 5.8 to 6.2, B80 4.5 to 4.0; A50 10.5 to 7.6, A200 6.1 to 8.8.(ABSTRACT TRUNCATED AT 250 WORDS)
Rapid reversal of alpha 2‐adrenoceptor agonist effects by atipamezole in human volunteers.
Authors: Karhuvaara S. , Kallio A. , Salonen M. , Tuominen J. , Scheinin M.
Published: July 2012

1. The ability of atipamezole, a specific and selective alpha 2‐ adrenoceptor antagonist, to reverse the pharmacological effects induced by the alpha 2‐adrenoceptor agonist dexmedetomidine was studied in six healthy male volunteers. Each volunteer received in four sessions in a randomized and single‐blind manner three different doses (6.7 micrograms kg‐1, 27 micrograms kg‐1 and 67 micrograms kg‐1) of atipamezole or saline placebo as 5 min i.v. infusions preceded by a fixed i.v. dose of dexmedetomidine (0.67 micrograms kg‐1). 2. Dexmedetomidine caused profound sedation, with the subjects actually falling asleep. This was effectively reversed by the two highest doses of antipamezole. 3. Dexmedetomidine reduced salivary flow on average by 70%. A rapid and full reversal of this effect was seen after the highest dose of antipamezole. 4. Hypotension induced by dexmedetomidine was also effectively antagonized by atipamezole. Bradycardia was very modest after dexmedetomidine in this study, and thus no reversal of alpha 2‐adrenoceptor agonist‐induced bradycardia could be demonstrated. 5. Plasma noradrenaline concentrations were reduced by 80% by dexmedetomidine. This was effectively antagonized by atipamezole, and the highest dose caused a 50% overshoot in plasma noradrenaline concentrations over the basal levels. 6. It is concluded that the effects of dexmedetomidine are effectively reversible by atipamezole. A dose ratio of 10:1 for atipamezole:dexmedetomidine was clearly insufficient for this purpose, but ratios in the range of 40:1 to 100:1 were found to be effective in the current experimental situation.
Lack of pharmacokinetic interaction between nifedipine, sparteine and phenytoin in man.
Authors: Schellens JH , Soons PA , van der Wart JH , Hoevers JW , Breimer DD
Published: July 2012

Nifedipine, sparteine and phenytoin were administered orally to eight healthy subjects separately and as a 'cocktail' on four different occasions to investigate any kinetic interactions. All subjects were extensive metabolizers of sparteine. After drug intake plasma and urine samples were collected up to 32 h and the concentrations of parent drugs and main metabolites were measured. Clearances and formation clearances were not significantly different after single substrate and 'cocktail' administration. Low or non significant correlation coefficients were found between the oxidation of the individual substrates or formation of their metabolites. With this strategy of simultaneous administration of substrates ('cocktail') it appears possible to characterize (and correlate) activities of different cytochrome P‐450 isoenzymes, without the disturbing influence of intraindividual variation of drug oxidation with time.
The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children.
Authors: Olkkola KT , Maunuksela EL
Published: July 2012

Ketorolac tromethamine (0.5 mg kg‐1) was given intravenously to 10 children (age 4‐8 years) after minor surgery. Values of steady‐state volume of distribution and plasma clearance were approximately two times higher than those in adults but values of elimination half‐life were similar.
Magnesium deficiency may be an important determinant of ventricular ectopy in digitalised patients with chronic atrial fibrillation.
Authors: Lewis R. , Durnin C. , McLay J. , McEwen J. , McDevitt DG
Published: July 2012

Digitalised patients with chronic atrial fibrillation (AF) have a high prevalence of ventricular premature beats (VPB); magnesium deficiency may be a contributory factor. We have used a magnesium loading‐test to examine the relationship between ventricular ectopy and magnesium status in 14 digitalised patients with chronic AF. Among seven patients with infrequent VPB (less than 250 24 h‐1; mean 107 24 h‐1) mean magnesium retention was 10.1% and four subjects retained no significant quantities of magnesium, indicating magnesium repletion. Among the remaining seven patients, mean magnesium retention was significantly higher (33.1%, P less than 0.02) and all patients retained 20% or more of the load given. There was an overall relationship between Mg retention and numbers of VPB (rs = 0.54; P less than 0.05). Magnesium deficiency may be determinant of ventricular ectopy in digitalised patients with chronic AF.
A non‐bronchoconstrictor, bacteriostatic preservative for nebuliser solutions.
Authors: Summers QA , Nesbit MR , Levin R. , Holgate ST
Published: July 2012

We have studied the bacteriostatic and airways effects of the preservatives chlorocresol and chlorbutol, to assess if they may be safely used in nebuliser solutions. The bacteriostatic study was carried out according to standard techniques, and the preservatives were able to inhibit the growth of a range of bacteria and yeasts for a period of 28 days. The airways effects were studied in eight asthmatic subjects, who were challenged with either the preservatives or saline (as placebo). Pulmonary function was followed as FEV1 for 60 min after inhalation, and there was no change in FEV1 following inhalation. We conclude that these preservatives may be used safely in nebuliser solutions.
The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac.
Authors: Neuvonen PJ
Published: July 2012

1. The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac was investigated in two randomized cross‐over studies, both consisting of two phases. 2. Single doses of magnesium hydroxide (850 mg) or of water (150 ml) only were given to six healthy volunteers immediately after the ingestion of ibuprofen (400 mg, Study 1), ketoprofen (50 mg, Study 2) or diclofenac (50 mg, Study 2). Plasma drug concentrations were measured up to 24 h. 3. Magnesium hydroxide increased the area under the plasma ibuprofen concentration‐time curve between 0 and 1 h by 65% (P less than 0.05) and the peak concentration of ibuprofen in plasma by 31% (P less than 0.01). The time to peak was shortened by about 0.5 h. The extent of bioavailability of ibuprofen was not increased by magnesium hydroxide. 4. Neither the rate nor the extent of absorption of ketoprofen or diclofenac was changed significantly by magnesium hydroxide. 5. When rapid onset of the analgesic effect of ibuprofen is required, concomitant ingestion of an antacid, which contains magnesium hydroxide without aluminium, is recommended.
A comparison of the hypoalgesic effect of paracetamol in slow‐release and plain tablets on laser‐induced pain.
Authors: Nielsen JC , Bjerring P. , Arendt‐Nielsen L.
Published: July 2012

1. In a double‐blind, three way, cross‐over study 15 volunteers received plain paracetamol tablets 1000 mg every 6th hour, paracetamol slow‐release tablets 2000 mg every 12th hour, and placebo. Steady state conditions were established over a 5 day period preceding each test session. 2. Plain paracetamol was given twice in the 12h test session, initially and after 6 h, and the slow‐release formulation was given once at the start of the session. 3. Hypoalgesia, measured by experimentally laser‐induced pain (pain threshold), and plasma concentrations of paracetamol were measured hourly for 12 h. 4. Both formulations of paracetamol were significantly superior (P = 0.0003) to placebo, but not difference in analgesic efficacy was found between the two regimens.
Influence of acid secretory status on absorption of omeprazole from enteric coated granules.
Authors: Andersson T. , Bergstrand R. , Cederberg C.
Published: July 2012

1. In order to study the absorption of omeprazole under normal acidic conditions in the stomach as well as when the granules are exposed to minimal gastric acid, eight healthy males were given 20 mg omeprazole as enteric coated (EC) granules either alone or 2 h after a ranitidine dose of 300 mg, respectively. 2. Blood samples were collected at intervals for 12 h following both omeprazole administrations. The pH was recorded during the first 4 h in half the subjects in each experiment to document the difference in pH during the absorption phase of omeprazole. 3. The area under the plasma concentration‐time curve, AUC, of omeprazole was virtually the same irrespective of whether or not the granules were exposed to gastric acid. However, the maximum plasma concentration (Cmax) was higher and the time to reach Cmax was shorter when omeprazole was administered after a ranitidine dose. 4. It is concluded that gastric acidity has negligible influence on the AUC of omeprazole, which is directly correlated to the antisecretory effect, when administered as EC granules.
Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension.
Authors: Mikus G. , Mast V. , Fischer C. , Machleidt C. , Kuhlmann U. , Eichelbaum M.
Published: July 2012

1. The pharmacokinetics, bioavailability, metabolism and antihypertensive effects of nitrendipine have been studied in 12 patients with impaired renal function and moderate to severe hypertension. The drug was administered simultaneously by the i.v. [13C4] and oral (commercial tablet 20 mg) routes. 2. No differences in the pharmacokinetic parameters were observed between the two routes of administration. The systemic clearance after i.v. administration in patients with renal impairment (18.2 +/‐ 6.1 ml min‐1 kg‐1) was similar to that observed in healthy volunteers. Despite complete absorption of drug from the tablet the bioavailability of the parent compound was 21.2 +/‐ 12.5%. Cumulative urinary excretion of nitrendipine metabolites was correlated with the creatinine clearance (r = 0.946). 3. Significant reductions in mean arterial blood pressure (mean: 23.6%) at the end of the nitrendipine infusion and after oral administration of 20 mg (mean: 17.5%) were observed. The blood pressure lowering effect of nitrendipine could be correlated within individuals with serum nitrendipine concentrations using a log linear model. 4. Following 4 weeks of therapy an average dose of 77 mg nitrendipine day‐ 1 was required to achieve a systolic blood pressure below 160 mm Hg or a diastolic blood pressure below 90 mm Hg. The reduction in blood pressure during multiple dosing was related to the nitrendipine steady‐ state concentration. There was a significant relationship between the nitrendipine bioavailability and the dose required for sufficient blood pressure control. 5. No accumulation of nitrendipine caused by impaired renal function was observed during multiple dosing. Thus, no reduction of the nitrendipine dose in patients with renal impairment is necessary.
Effects of granisetron and lorazepam, alone and in combination, on psychometric performance.
Authors: Leigh TJ , Link CG , Fell GL
Published: July 2012

The effects of granisetron (160 micrograms kg‐1 body weight) and lorazepam (2.5 mg) on psychometric performance were investigated in a randomized, single‐blind, crossover, placebo controlled study of twelve healthy male volunteers. There was strong evidence that lorazepam impaired psychometric performance. In contrast there was very little evidence to suggest that granisetron had any impact on performance or that there was any interaction between the two compounds. The findings from this study suggest that granisetron does not impair psychometric performance and that it can be co‐administered with lorazepam without producing unwanted synergistic effects.
Human responses to inhaled capsaicin are not inhibited by granisetron.
Authors: Choudry NB , McEwan J.R. , Lavender EA , Williams AJ , Fuller RW
Published: July 2012

Cough is a common respiratory symptom, the mechanism of which is poorly understood. In this study the role of 5‐HT3 receptors was investigated. Capsaicin‐induced cough and increase in airways resistance were measured in six male volunteers before and after infusion with granisetron 160 micrograms kg‐1 or placebo. Neither cough nor the increase in respiratory resistance was altered by the active treatment. These results suggest that 5‐HT3 receptors are not involved in these two respiratory responses to inhaled capsaicin in humans.
Limitation to the use of the urinary S‐/R‐mephenytoin ratio in pharmacogenetic studies.
Authors: Zhang Y. , Blouin RA , McNamara PJ , Steinmetz J. , Wedlund PJ
Published: July 2012

The reproducibility of the S‐/R‐mephenytoin ratio was examined in urines stored at ‐20 degrees C over 2 years. Large changes in this ratio were observed in some urine samples stored for only a few months under these conditions. The changes observed in the S‐/R‐mephenytoin ratio are attributed to the decomposition of an acid labile metabolite of S‐mephenytoin which is eliminated in the urine. The instability of this metabolite makes it desirable to process urine shortly after its collection in order to avoid inaccurate phenotype assignments based upon the urinary S‐/R‐mephenytoin ratio. If rapid processing of urines is impractical, additional methods are described for preventing improper phenotype assignment of subjects.
Cardiovascular effects of a chlorpheniramine/paracetamol combination in hypertensive patients who were sensitive to the pressor effect of pseudoephedrine.
Authors: Chua SS , Benrimoj SI , Gordon RD , Williams G.
Published: July 2012

Twelve hypertensive patients who were classified as pseudoephedrine‐ sensitive in a preliminary trial were selected for further investigation with single doses of pseudoephedrine 60 mg, a combination of chlorpheniramine 4 mg with paracetamol 650 mg and placebo. A double‐ blind, randomised, crossover study design was followed. Treatment with pseudoephedrine produced significant effects on all the four variables measured (systolic, diastolic and mean arterial blood pressure, and heart rate). Effects of the chlorpheniramine/paracetamol combination were found to be not significantly different from placebo. It was concluded that the combination may be useful as a medication for 'colds' in hypertensive patients, since it does not induce cardiovascular effects such as those observed with pseudoephedrine.
Interaction of indomethacin and sulindac with labetalol.
Authors: Abate MA , Neely JL , Layne RD , D'Alessandri R.
Published: July 2012

The effects of sulindac and indomethacin on the blood pressure response to labetalol were determined in well‐controlled predominantly obese hypertensive patients (n = 26). A stabilized dose of labetalol alone was administered on weeks 1 and 3, and either indomethacin or sulindac was administered with labetalol on week 2, with cross‐over to the other drug on week 4. Indomethacin and sulindac increased the sitting and standing systolic blood pressure (BP) to a statistically significant extent compared with placebo. The effects of indomethacin on systolic BP, diastolic BP, and weight were not significantly different from those with sulindac. Indomethacin but not sulindac produced minor increases in diastolic BP and weight compared with placebo.
Influence of ACE inhibitors on free radicals and reperfusion injury: pharmacological curiosity or therapeutic hope?
Authors: McMurray J. , Chopra M.
Published: July 2012

1. The currently available evidence shows that thiol containing ACE inhibitors are free radical (FR) scavengers in vitro; in particular the OH. radical is effectively scavenged by these compounds. There is also good evidence that, in vivo, ACE inhibitors can preserve myocardial contractile function following a period of reversible ischaemia (by directly protecting myocytes and/or preserving coronary flow through protection of endothelial cells). These in vivo benefits are probably also due to FR scavening, mainly due to the presence of a thiol group but, also as a consequence of augmented prostanoid production. 2. Use of more relevant animal models and testing of a range of doses of ACE inhibitors might be undertaken before clinical investigation is considered. Because of its nature, however, the existence and importance of reperfusion injury in man will only be proven or disproven by pharmacological intervention. One option is to compare a thiol containing agent with absent or minimal haemodynamic effects with placebo as an adjunct to thrombolysis. This is the simplest approach. An alternative approach is to conduct a comparative study of a ‐SH containing ACE inhibitor and a non ‐SH containing ACE inhibitor given prior to thrombolysis. There are many problems with either approach. The lack of reliable measures of FR activity in man and difficulty in measuring accurately left ventricular function post‐myocardial infarction means that mortality is likely to be the only reliable end‐ point in such a study.(ABSTRACT TRUNCATED AT 250 WORDS)
Ethnic differences in the pharmacokinetics of oral nifedipine.
Authors: Ahsan CH , Renwick AG , Macklin B. , Challenor VF , Waller DG , George CF
Published: July 2012

1. The pharmacokinetics of a single oral dose of 20 mg nifedipine, given as capsules, has been compared in five South Asian volunteers with data for 27 Caucasian volunteers. 2. The area under the plasma concentration‐time curve (AUC) of nifedipine was three fold higher in South Asians (989 +/‐ 166 ng ml‐1 h) than in Caucasians (323 +/‐ 116 ng ml‐1 h). 3. The ratio of the AUC of nifedipine to that of the nitropyridine analogue, which is formed largely as a first pass metabolite, was significantly higher in South Asians (4.6 +/‐ 1.9) than in Caucasians (2.3 +/‐ 1.1) indicating a lower first pass metabolism in South Asians. 4. The terminal half‐lives of nifedipine and the nitropyridine metabolite were significantly greater in South Asians than in Caucasians. 5. Consumption of a spicy curry diet for 3 days by Caucasians did not significantly affect the pharmacokinetics of a single oral dose of nifedipine. 6. The treatment of patients of South Asian origin with nifedipine should be initiated with lower doses than would be given to Caucasians.
The influence of protein containing meals on the pharmacokinetics of levodopa in healthy volunteers.
Authors: Robertson DR , Higginson I. , Macklin BS , Renwick AG , Waller DG , George CF
Published: July 2012

1. The pharmacokinetics of levodopa and paracetamol after single oral doses have been investigated in eight healthy young volunteers in the fasted state and following isocaloric meals containing either 10.5 g or 30.5 g of protein. 2. The initial peak and maximum plasma drug concentrations and the times at which these occurred were not affected by food. 3. The mean area under the plasma concentration‐time curve (AUC) for paracetamol following an overnight fast did not differ significantly from that observed following the low and high protein meals. 4. By contrast, the AUC for levodopa following the low protein meal (193.9 +/‐ 15.7 micrograms ml‐1 min) was significantly lower compared with administration in the fasted state (216.5 +/‐ 26.1 micrograms ml‐1 min). However, there were no significant differences in the kinetics of levodopa between the fasting state and following the high protein meal. 5. There was no evidence that consumption of a meal containing 30.5 g of protein impaired either the rate or extent of absorption of levodopa. Therefore the reported beneficial effects of a low protein diet in the treatment of patients with Parkinson's disease probably result from reduced competition for levodopa transport across the blood‐brain barrier.
Disposition of gamma‐glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.
Authors: Boateng YA , Barber HE , MacDonald TM , Petrie JC , Lee MR
Published: July 2012

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg‐1 and 100 micrograms kg‐1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/‐ 1.50 ml min‐1 kg‐1 and 4.92 ml min‐1 kg‐1 at the higher and lower doses, respectively. Corresponding half‐lives were 29.2 +/‐ 3.7 min and 32.5 +/‐ 5.6 min, and volumes of distribution were 0.183 +/‐ 0.052 l kg‐ 1 and 0.235 +/‐ 0.07/ l kg‐1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro‐drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.
Intravenous strontium gluconate as a kinetic marker for calcium in healthy volunteers.
Authors: Moraes ME , Aronson JK , Grahame‐Smith DG
Published: July 2012

1. We have studied the pharmacokinetics of stable strontium in 10 healthy male volunteers. We gave each volunteer 5 mmol strontium gluconate by intravenous infusion over 1 h and measured strontium concentrations in plasma and urine samples for 20 days. The plasma strontium concentration vs time data for each volunteer were fitted by a triexponential function using NONLIN. Compartmental model‐dependent and model‐independent pharmacokinetic variables were then calculated. 2. The mean half‐life we report (5.4 days) is longer than that previously reported (about 2 days), since we continued sampling for 20 days. However, the rates of clearance (CL 9.4 ml min‐1. CLR 5.4 ml min‐ 1, and CLNR 4.0 ml min‐1) are similar to those previously reported, and the apparent volume of distribution at steady state (64 l) is similar to the values previously reported for the size of the exchangeable pool of both strontium and calcium. 3. The similarities in the pharmacokinetic behavior of strontium and calcium suggest that the in vivo disposition of strontium may be used as a marker of calcium disposition and for studying the effects of drugs such as the calcium antagonists.
Human jejunal secretion induced by prostaglandin E1: a dose‐response study.
Authors: Sobhani I. , Vidon N. , Huchet B. , Rambaud JC
Published: July 2012

1. Intraluminally infused prostaglandins induce jejunal secretion of water and electrolytes in man, and a receptor‐mediated process in the intestinal epithelial cells has been suggested to explain this secretion. In an attempt to obtain data under basal conditions for pharmacological studies, we tested the dose‐response effect of PGE1 on jejunal hydroelectrolytic movements in 10 healthy volunteers. 2. Accordingly, a solution with or without PGE1 was infused via a four‐ lumen tube with a proximal occluding balloon and jejunal water and electrolyte transport were determined. The segment tested was 40 cm long. Seven randomized doses of PGE1 ranging from 0.01 to 1.3 micrograms kg‐1 min‐1 (2.83 to 364 pmol kg‐1 min‐1) were infused in an isotonic control saline solution. The secretion induced by PGE1 was evaluated in each subject as the difference between fluxes in response to the control saline solution and to PGE1. 3. Whatever the dose, PGE1 induced secretion of water, Na+, K+ and Cl‐ which was dose‐dependent and saturable, with a mean Km of congruent to 6‐8 pmol kg‐1 min‐1, suggesting that at the pharmacological doses used, enterocytes have a saturable membrane site similar to a single class of receptor for PGE1. 4. These findings may be of great importance if prostaglandins are administered as drugs or used as jejunal secretory agents in vivo when the antisecretory effect of another drug is studied.