bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic‐pharmacodynamic (PK‐PD) modelling in non‐steady‐state studies and arterio‐venous drug concentration differences.
Authors: Gumbleton M , Oie S , Verotta D
Published: July 2012

In conducting a non‐steady‐state pharmacokinetic (PK)‐pharmacodynamic (PD) study there is potential for the observed effect (E) vs time, and venous plasma drug concentration (C) vs time, profiles to display temporal displacement with respect to each other. This is most frequently observed when there exists a distributional nonequilibrium across the effect organ giving rise to hysteresis, i.e. observed C preceding E in the time domain, with the resulting potential for a counterclockwise loop to be generated in the observed E vs C plot (when data are connected in time‐order). Such temporal displacement does not afford direct prediction of the steady‐state E vs C PD relationship. When an arterio‐venous (A‐V) difference exists across the tissues of the blood sampling compartment (i.e. the arm), and this arises solely from an elimination process then drug concentration in the respective peripheral arterial plasma and venous plasma compartments will be in equilibrium at all times during a non‐steady‐state PK experiment. If there are no other sources of temporal displacement in the relationship between E and C then the observed E vs C plot will be a direct predictor of the steady‐state E vs C PD relationship. In contrast when the A‐V difference is of a distributional nature then proteresis, i.e. observed E preceding C in the time domain, will arise with the potential for the generation of a clockwise loop in the observed E vs C relationship. Simulated error‐incorporated E vs time, and C vs time, data was analysed by semi‐parametric implementation of an effect‐ compartment link‐model that affords accurate steady‐state E vs C PD predictions (without the requirement of sampling arterial blood) from data that incorporates the concurrent presence of: (i) distributional nonequilibrium across the effect organ, and (ii) distributional A‐V non‐ equilibrium. Accurate steady‐state E vs C PD predictions were achieved irrespective of the comparative magnitudes of the two nonequilibria, i.e. whether the rate of equilibration across the effect organ was faster than, or slower than, the rate of equilibration across the arm (resulting in a clockwise or counterclockwise loop in the observed E vs C plot, respectively), or indeed if one or other of the nonequilibria is essentially absent. When the rate of equilibration across the effect organ is slower than the rate of A‐V equilibration (i.e. counterclockwise loop generated in the observed E vs C plot) then the need to model for the underlying A‐V nonequilibrium is redundant, i.e. accurate steady‐state E vs C PD predictions can be achieved with implementation (strictly incorrectly) of a more simple link parameterised solely to model for distributional nonequilibrium across the effect organ.(ABSTRACT TRUNCATED AT 400 WORDS)
Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.
Authors: Byrom WD , Rotherham NE , Bratty JR
Published: July 2012

The relationships between blood glucose, plasma insulin and plasma BTS 67 582 concentrations were studied in a randomised, placebo‐controlled, four‐way crossover study involving 16 healthy male volunteers aged between 19 and 43 years. Single oral doses of 125, 250 and 500 mg BTS 67 582 were studied. Fasting blood samples were taken pre‐dose and half‐ hourly for 8 h post‐dose. Mean peak plasma concentrations of BTS 67 582 were 518, 1076 and 2435 ng ml‐1 for doses of 125, 250 and 500 mg, respectively. Mean maximum reductions in blood glucose were 1.13, 1.59 and 1.78 mmol l‐1, and mean maximum increases in plasma insulin were 26, 14 and 21 muu ml‐1 for the three doses, respectively. Changes in incremental area under the curve (AUC) of blood glucose were correlated with changes in plasma BTS 67 582 AUC. The maximum reduction in blood glucose was correlated with the peak plasma BTS 67 582 concentration. No correlations between plasma insulin and plasma BTS 67 582 concentrations were observed. Anticlockwise hysteresis was evident in concentration‐effect curves, but less evident following subtraction of placebo data, and was mainly due to an underlying downward trend in fasted blood glucose levels with time evident under placebo treatment. This suggests that hypoglycaemic effects were related to systemic BTS 67 582 concentrations, suggesting that active metabolites of the drug do not make a major contribution to acute hypoglycaemic effects. A log‐ linear model described the relationship between blood glucose and plasma BTS 67 582 concentrations for 14 of the 16 volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)
Ketoprofen and prednisolone do not modulate neutrophil CR1, CR3 and Fc gamma RIII expression in healthy volunteers.
Authors: Laroche F , Kahan A , Kahan A , Letrait M , Cohen C , Jamin P , Strauch G
Published: July 2012

We assessed the effect of ketoprofen and prednisolone on the complement receptors (CR1 and CR3) and Fc gamma RIII expression on polymorphonuclears in an ex vivo study, using a randomized, single‐ blind, placebo‐controlled, parallel design. Twenty‐four healthy, male, Caucasian volunteers received either oral ketoprofen 100 mg twice daily, or prednisolone 5 mg twice daily, or placebo twice daily for 7.5 days. CR1, CR3 and Fc gamma RIII on unstimulated and FMLP‐, C5a‐, LTB4‐, and GM‐CSF‐stimulated neutrophils were assessed using specific monoclonal antibodies and flow cytometry. No statistically significant drug effect was found for CR1, CR3, and Fc gamma RIII expression on polymorphonuclears. An in vitro study also yielded negative results. These findings do not support the hypothesis that the effect of non‐ steroidal antiinflammatory drugs on neutrophils is due to CR1, CR3, or Fc gamma RIII modulation.
Debrisoquine and mephenytoin oxidation in Sinhalese: a population study.
Authors: Weerasuriya K , Jayakody RL , Smith CA , Wolf CR , Tucker GT , Lennard MS
Published: July 2012

The frequency distributions of the 0‐8 h urinary metabolic ratios of debrisoquine and mephenytoin were measured in 111 healthy, unrelated Sinhalese resident in Sri Lanka. Blood samples were taken from 77 of these subjects for CYP2D6 genotyping. Bimodality in the distribution of the log10 debrisoquine/4‐hydroxydebrisoquine ratio was not evident from visual inspection and by kernel density analysis. The results of genotyping indicated that 82% of the population were either homozygous for the wild‐type CYP2D6 gene or heterozygous for the wild type allele and the whole gene deletion. Eighteen per cent of the Sinhalese population were heterozygous for the CYP2D6B mutation and the wild‐type allele. All of these genotypes give rise to the extensive metaboliser phenotype in white Caucasians. No CYP2D6A mutations were identified and no individuals who were homozygous for the mutant alleles were detected, which is in accord with an absence of phenotypic poor metabolisers of debrisoquine. The mutant CYP2D6 allele frequency in Sinhalese (9%) is only half that observed in white Caucasians. The S/R‐ mephenytoin ratio ranged from 0.09 to 2.27 (median 0.38). By visual inspection and kernel density analysis the distribution of the S/R‐ mephenytoin ratio was bimodal and, using a value of 0.9 for the antimode, 16 (14%) subjects were poor metabolisers. In conclusion, the prevalence of the poor metaboliser phenotype in Sinhalese appears much lower for debrisoquine and higher for mephenytoin than in white Caucasians. These findings are similar to those observed in Indians living in Bombay and in Oriental populations.
Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.
Authors: Bertilsson L , Carrillo JA , Dahl ML , Llerena A , Alm C , Bondesson U , Lindstrom L , Rodriguez de la Rubia I , Ramos S , Benitez J
Published: July 2012

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S‐mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3‐ demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1‐ and N7‐demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N‐ acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.
A comparison of the systemic bioactivity of inhaled budesonide and fluticasone propionate in normal subjects [see comments]
Authors: Grove A , Allam C , McFarlane LC , McPhate G , Jackson CM , Lipworth BJ
Published: July 2012

1. The aim of this study was to compare the systemic bioactivity of low and high doses of inhaled budesonide and fluticasone propionate given by respective dry powder inhaler devices. 2. A randomised, single blind cross‐over design was used in nine healthy subjects who were given 800 micrograms day‐1 of budesonide Turbohaler (B800) for 1 week, followed by 1 week of 1600 micrograms day‐1 (B1600), or fluticasone Diskhaler 750 micrograms day‐1 (F750) for 1 week followed by 1 week of 1500 micrograms day‐1 (F1500). There was a 1 week washout between treatments with fluticasone or budesonide. A twice daily dosing regime was used and mouth‐rinsing was employed to reduce gut bioavailability as well as to obviate local adverse effects. 3. Parameters of hypothalmic‐ pituitary adrenal (HPA) axis activity and bone metabolism were measured at baseline (B0/F0), at the end of each week of treatment and after the 1 week washout (F0 or B0). 4. Both fluticasone and budesonide significantly (P < 0.05) attenuated the post tetracosactrin serum cortisol at low and high doses whilst early morning cortisol was unchanged. No dose‐response effect was observed with either drug, and there was no significant difference between treatment with fluticasone or budesonide. 5. Neither budesonide nor fluticasone produced significant suppression of plasma osteocalcin, although the higher doses of both drugs significantly reduced fasting urinary calcium levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.
Authors: Bloomer JC , Baldwin SJ , Smith GJ , Ayrton AD , Clarke SE , Chenery RJ
Published: July 2012

1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7‐hydroxy and 9'‐desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron the 7‐hydroxy metabolite predominated. Rates of granisetron 7‐hydroxylation varied over 100‐fold in the human livers investigated. 3. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to the 7‐hydroxylation of granisetron, one of which was a high affinity component with a Km of 4 microM. A single, low affinity, enzyme was responsible for the 9'‐ desmethylation of granisetron. 4. Granisetron caused no inhibition of any of the cytochrome P450 activities investigated (CYP1A2, CYP2A6, CYP2B6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E1 and CYP3A), at concentrations up to 250 microM. 5. Studies using chemical inhibitors selective for individual P450 enzymes indicated the involvement of cytochrome P450 3A (CYP3A), both pathways of granisetron metabolism being very sensitive to ketoconazole inhibition. Correlation data were consistent with the role of CYP3A3/4 in granisetron 9'‐desmethylation but indicated that a different enzyme was involved in the 7‐hydroxylation.
Monoamine oxidase‐A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor.
Authors: Holford NH , Guentert TW , Dingemanse J. , Banken L.
Published: July 2012

1. Single oral doses of 300, 450 and 600 mg moclobemide, a monoamine oxidase type A inhibitor, were administered in a cross‐over design to eight healthy male volunteers. Plasma concentrations of the parent drug and of two monoamine metabolites (3,4‐dihydroxyphenylglycol DHPG from noradrenaline; 5‐hydroxy‐indoleacetic acid 5HIAA from serotonin) were measured over time. 2. A physiological pharmacokinetic‐pharmacodynamic model was used to describe MAO‐A inhibition as reflected in the alterations of monoamine metabolites. Population values for the model parameters were obtained by a two‐stage method allowing for repeated dosing per subject. 3. Even at the lowest dose an effect of moclobemide on plasma DHPG and 5HIAA concentrations was detectable in most subjects for up to 24 h. In contrast to DHPG, 5HIAA formation was only partially suppressed by moclobemide (maximum fractional extent of enzyme inhibition Imax: 0.57, CV 26%) suggesting the existence of 5HIAA formation pathways independent of those inhibitable by moclobemide. 4. Plasma moclobemide concentrations associated with 50% of maximum enzyme inhibition (IC50) were in the range of 100 (IC50,5HIAA at 300 mg) to 400 micrograms l‐1 (IC50,DHPG at 600 mg).
Effects of gemfibrozil on the oxygen transport properties of erythrocytes.
Authors: Scatena R , Nocca G , Messana I , de Sole P , Baroni S , Zuppi C , Castagnola M , Giardina B
Published: July 2012

1. In the present study we have investigated the effects of the relatively low plasma concentrations of gemfibrozil (GFZ) found in clinical practice on the oxygen dissociation curve (ODC) of erythrocytes. 2. ODCs were measured at 30 degrees C and 37 degrees C and at pH 7.4: a) both on HbA solution and erythrocytes incubated in vitro with gemfibrozil and clofibric acid; b) on erythrocytes from healthy volunteers treated with a single oral dose of gemfibrozil. 3. These experiments showed a significant drug‐induced shift of the ODC towards lower O2 affinity values without any significant modification of metabolic parameters of erythrocytes such as intracellular pH and intraerythrocytic levels of ATP and DPG. 4. In our experimental conditions gemfibrozil appears to lower both in vitro and in vivo, the partial pressure of oxygen required to give 50% of the haemes saturated with oxygen (P50) of erythrocytes from the control value of 24 +/‐ 0.5 mm Hg to 29 +/‐ 0.5 mm Hg (mean +/‐ s.d.; P < 0.02 by ANOVA). 5. These data clearly indicate that therapeutic doses of gemfibrozil may influence the oxygen transport properties of red cells. This effect could have relevant pharmacological and toxicological implications.
Pharmacokinetics of physostigmine in man following a single application of a transdermal system.
Authors: Walter K , Muller M , Barkworth MF , Nieciecki AV , Stanislaus F
Published: July 2012

1. The pharmacokinetics of physostigmine were investigated in a three‐ way cross‐over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag‐time of 4 h. Thereafter, the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h. 3. A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution. In comparison with the oral solution, interindividual variability of pharmacokinetics was less with the PTS. 4. The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg. Because of extensive metabolism, only 2.2 mg of physostigmine were detected systemically. 5. After removing the PTS, the mean apparent half‐life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion. This indicates continued drug absorption from a skin depot. 6. Physostigmine was well tolerated by the volunteers. With the PTS, a mild erythema was observed at the area of application, disappearing within a few hours.
Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism.
Authors: Liu Z , Mortimer O , Smith CA , Wolf CR , Rane A
Published: July 2012

Ethylmorphine is metabolised by N‐demethylation (to norethylmorphine) and by O‐deethylation (to morphine). The O‐deethylation reaction was previously shown in vivo to co‐segregate with the O‐demethylation of dextromethorphan indicating that ethylmorphine is a substrate of polymorphic cytochrome P450(CYP)2D6. To study further the features of ethylmorphine metabolism we investigated its N‐demethylation and O‐ deethylation in human liver microsomes from eight extensive (EM) and one poor metaboliser (PM) of dextromethorphan. Whereas N‐demethylation varied only two‐fold there was a 4.3‐fold variation in the O‐ deethylation of ethylmorphine, the lowest rate being observed in the PM. Quinidine, at a concentration of 1 microM, inhibited O‐deethylation in microsomes from an EM, but was unable to do so in microsomes from the PM. The immunoidentified CYP2D6 and CYP3A4 correlated with the rates of O‐deethylation (r = 0.972) and N‐demethylation (r = 0.969), respectively. We conclude that the O‐deethylation of ethylmorphine is catalysed by the CYP2D6 in human liver microsomes consistent with previous findings in healthy volunteers.
The N‐oxidation of trimethylamine in a Jordanian population.
Authors: Hadidi HF , Cholerton S , Atkinson S , Irshaid YM , Rawashdeh NM , Idle JR
Published: July 2012

The ability to oxidise trimethylamine (TMA) to trimethylamine N‐oxide (TMAO) is distributed polymorphically within a British white population with the majority of individuals excreting greater than 90% of total urinary TMA as TMAO. The opposite extreme is characterised by a rare inborn error of TMA N‐oxidation known as the fish‐odour syndrome. However there is a lack of information regarding inter‐individual variability in the N‐oxidation of TMA in other ethnic groups. In this study the urinary excretion of TMA and TMAO was determined over a period of 24 h in 82 Jordanian subjects. A frequency distribution histogram of % of total urinary TMA excreted as TMAO revealed that the majority of subjects excreted greater than 80% of the total urinary TMA as TMAO, however eight subjects (9.7%) excreted less than 80% of the total TMA as TMAO. In a previous study of 169 white British subjects only one (0.6%) excreted less than 80% of the total TMA as TMAO. The results suggest that the prevalence of compromised ability to N‐oxidise TMA may be higher in a Jordanian population than in a British population.
Patient‐controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan.
Authors: Persson K , Sjostrom S , Sigurdardottir I , Molnar V , Hammarlund‐Udenaes M , Rane A
Published: July 2012

Postoperative pain relief with codeine was evaluated in 11 women undergoing hysterectomy. Patient‐controlled analgesia (PCA) was used to administer codeine. After the study the patients were phenotyped with respect to the O‐demethylation of dextromethorphan (cytochrome P4502D6 polymorphism). Ten were extensive metabolisers and one a poor metaboliser. There was a nine‐fold variation in the minimum plasma concentration of codeine consistent with pain relief (40‐350 ng ml‐1). Two patients did not experience any effect of codeine, one of whom was a poor metaboliser of dextromethorphan, confirmed by genotyping. In the other nine patients the effective dose of codeine varied from 4.8‐25.3 mg h‐1.
Effects of milk and food on the absorption of enoxacin.
Authors: Lehto P , Kivisto KT
Published: July 2012

The effects of milk and a standard breakfast on the oral absorption of enoxacin were evaluated in eight healthy volunteers in a randomized, balanced, four‐way crossover study. After an overnight fast, 400 mg enoxacin was given with water, milk, a breakfast or with a breakfast and milk. The extent of enoxacin absorption was not affected by any of the three treatments, and no statistically significant changes were found with respect to peak plasma enoxacin concentration or time to peak. We conclude that enoxacin can be taken together with food and dairy products.
Effects of in vitro addition of captopril on copper‐induced low density lipoprotein oxidation.
Authors: Zieden B , Wuttge DM , Karlberg BE , Olsson AG
Published: July 2012

Low density lipoprotein (LDL) was incubated with 20 microM of the angiotensin converting enzyme (ACE) inhibitors captopril, fosinopril and quinapril or ethanol. Oxidation of LDL was initiated by addition of CuSO4 and monitored for production of conjugated dienes, thiobarbituric acid reactive substances (TBARS) and lipid peroxides. The inhibition of production of conjugated dienes was expressed as the lag phase in minutes. The lag phase for control samples was 55.2 +/‐ 6.1 (mean +/‐ s.e. mean) min and for captopril 86.4 +/‐ 7.0 min (P = 0.0058). Quinapril had a small but nonsignificant effect, fosinopril and ethanol had no effect. LDL incubated with captopril showed only 13.8% of TBARS and 22.7% of lipid peroxides produced by control (100%) after 1 h. Increasing concentrations of captopril showed a linear increase in the lag phase. We conclude that captopril increases the resistance of LDL to copper‐induced oxidation.
Evaluation of the alpha 2‐adrenoceptor blocking properties of buspirone and ipsapirone in healthy subjects. Relationship with the plasma concentration of the common metabolite 1‐(2‐pyrimidinyl)‐piperazine.
Authors: Berlin I , Chalon S , Payan C , Schollnhammer G , Cesselin F , Varoquaux O , Puech AJ
Published: July 2012

1. Because the 5‐HT1A agonist anxiolytic azapirones have a common alpha 2‐adrenoceptor antagonist metabolite, 1‐(2‐pyrimidinyl)‐piperazine (1PP), we measured central and peripheral alpha 2‐adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day‐1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day‐1 for 4 days and 5 mg on day 5) or placebo. 2. Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4‐dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C‐peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3. The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4. Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma 1PP concentration which was higher on buspirone than on ipsapirone (2.76 micrograms l‐1, 95% CI:1.3‐4.22 vs 0.65 microgram l‐1, 95% CI: 0.32‐0.98, P = 0.006). 5. Mean AUC of the 1PP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC 1PP ratio was 6.45 and the AUC buspirone/AUC 1PP ratio was 0.076.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of reboxetine and desipramine on the kinetics of the pupillary light reflex.
Authors: Theofilopoulos N , McDade G , Szabadi E , Bradshaw CM
Published: July 2012

1. The aim of the study was to examine the effects of single doses of two antidepressants (desipramine and reboxetine) on three kinetic parameters (latency, amplitude, 75% recovery time) of the pupillary light reflex response. 2. Six healthy male volunteers participated in three experimental sessions at biweekly intervals. Each session was associated with one of three treatment conditions (placebo, desipramine 100 mg, reboxetine 4 mg). Subjects were allocated to sessions and treatments double‐blind according to a Latin Square design. 3. Pupil diameter was measured in the dark with binocular television pupillometry. Reflex responses were evoked by 12 light stimuli (5.3 × 10(‐5)‐3.5 mW cm‐2; 500 ms), and the kinetic parameters of each response were recorded. 4. The amplitude and 75% recovery time were positively, and latency was negatively correlated with the logarithm of light stimulus intensity. In the presence of the antidepressants the latency was prolonged, the amplitude was reduced and the 75% recovery time was shortened. There was a positive linear relationship between reflex amplitude and recovery time under all three treatment conditions; this relationship was not significantly affected by the antidepressants. 5. The effects of the antidepressants on latency and amplitude are consistent with the blockade of muscarinic cholinoceptors in the iris, whereas the shortening of the recovery time appears to be secondary to the reduction in amplitude.
Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.
Authors: Bronner U , Gustafsson LL , Doua F , Ericsson O , Miezan T , Rais M , Rombo L
Published: July 2012

1. Plasma concentrations of pentamidine were measured up to 1‐8 months after a single 2 h i.v. infusion of 3.0 to 4.8 mg kg‐1 pentamidine isethionate in 11 patients with late stage Trypanosoma gambiense sleeping sickness. 2. Maximum plasma drug concentrations varied between 713 and 2461 nmol 1‐1. After termination of infusion, a rapid distribution phase over 10 min was followed by a slower distribution phase and an elimination phase prolonged over weeks to months. 3. The 'terminal' elimination rate constant could be determined in six patients and subsequent kinetic calculations showed a three to fourfold variation in plasma clearance and 'terminal' half‐life (median 1126 (range 553‐2036) ml min‐1 and 265 (107‐446) h, respectively). The median apparent volume of distribution (Vss) was 11,850 1. Renal clearance accounted for a median of 11% of total plasma clearance, indicating that metabolism is a major route of pentamidine elimination in man. 4. Side effects were few and mild and a slight or moderate decrease in blood pressure was the most common registered adverse reaction observed in four subjects. 5. The prolonged elimination of pentamidine seems inconsistent with the present recommended dosage regimen of pentamidine for treatment of trypanosomiasis of 7 to 10 parenteral doses given once daily or every second day.
Blood and urine 5‐hydroxytryptophan and 5‐hydroxytryptamine levels after administration of two 5‐hydroxytryptamine precursors in normal man.
Authors: Wa TC , Burns NJ , Williams BC , Freestone S , Lee MR
Published: July 2012

Six healthy male subjects received equimolar amounts of two 5‐ hydroxytryptamine (5‐HT) precursors, 5‐hydroxy‐L‐tryptophan (5‐HTP) and gamma‐L‐glutamyl‐5‐hydroxy‐L‐tryptophan (glu‐5‐HTP), on two occasions in a randomised cross‐over study. There were marked increases in urinary 5‐HTP and 5‐HT excretion after infusion of both compounds. Mean urinary excretion rate of 5‐HT, which was < 0.7 nmol min‐1 before dosing, rose to a peak value of 412 +/‐ 92 nmol min‐1 at the end of 5‐ HTP infusion and 303 +/‐ 29 nmol min‐1 after administration of glu‐5‐ HTP. This occurred without significant changes in blood 5‐HT levels measured in platelet‐rich plasma. These findings provide further evidence that the increase in urine 5‐HT after administration of both 5‐ HT precursors is largely due to 5‐HT synthesised within the kidney.
The effects of pharmaceutical excipients on small intestinal transit.
Authors: Adkin DA , Davis SS , Sparrow RA , Huckle PD , Phillips AJ , Wilding IR
Published: July 2012

1. The effect of three iso‐osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non‐disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11‐ 14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39‐ 94‐149 min, and 40‐82‐124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non‐disintegrating tablet preparations, when co‐administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)
Sensation seeking amongst healthy volunteers participating in phase I clinical trials.
Authors: Farre M , Lamas X , Cami J
Published: July 2012

1. Phase I clinical trials are usually carried out in healthy volunteers. In addition to economic gain, factors that may influence willingness to participate include scientific interest, curiosity and choice for risky activities. 2. We assessed the relationship between personality variables and volunteering for clinical pharmacology research. Two personality questionnaires, the Sensation Seeking Scale (SSS, form V) and the Eysenck Personality Questionnaire (EPQ), were administered to 48 male healthy university students who volunteered to participate in a phase I clinical trial and to 43 male university students who were not willing to participate in phase I clinical trials. General norm data were also used for the comparison of results. 3. When healthy volunteers were compared with unwilling subjects, significant differences were found in thrill‐and‐adventure seeking (7.9 vs 6.7, P = 0.0034), experience seeking (6.4 vs 5.2, P = 0.0012), disinhibition (6.2 vs 4.3, P < 0.0001), boredom susceptibility (3.9 vs 2.8, P = 0.0073), total sensation seeking trait (24.3 vs 19.0, P < 0.0001), extraversion (15.1 vs 13.3, P = 0.0490), and psychoticism (4.4 vs 3.5, P = 0.0086). When healthy volunteers were compared with general norm data similar statistically significant differences were found in all these scales, except for boredom susceptibility and psychoticism. 4. The personality profile of healthy volunteers was characterized by a higher sensation seeking trait and extraversion as compared with individuals who were not willing to participate in phase I clinical trials and general norm data.
Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers—N‐desisopropylation is mediated mainly by CYP1A2.
Authors: Yoshimoto K , Echizen H , Chiba K , Tani M , Ishizaki T
Published: July 2012

1. Studies using human liver microsomes and six recombinant human CYP isoforms (i.e. CYP1A2, 2A6, 2B6, 2D6, 2E1 and 3A4) were performed to identify the cytochrome P450 (CYP) isoform(s) involved in the ring 4‐ hydroxylation and side‐chain N‐desisopropylation of propranolol enantiomers in humans. 2. alpha‐Naphthoflavone and 7‐ethoxyresorufin (selective inhibitors of CYP1A1/2) inhibited the N‐desisopropylation of R‐ and S‐propranolol by human liver microsomes by 20 and 40%, respectively, while quinidine (a selective inhibitor of CYP2D6) abolished the 4‐hydroxylation of both propranolol enantiomers almost completely. In contrast, sulphaphenazole (CYP2C8/9 inhibitor), S‐ mephenytoin (CYP2C19 inhibitor), troleandomycin (CYP3A3/4 inhibitor) and diethyldithiocarbamate (CYP2E1 inhibitor) elicited only weak inhibitory effects on propranolol metabolism via the two measured metabolic pathways. 3. Significant (P < 0.01) correlations were observed between the microsomal N‐desisopropylation of both propranolol enantiomers and that for the O‐deethylation of phenacetin among the 11 different human liver microsome samples (r = 0.98 and 0.77 for R‐ and S‐ propranolol, respectively). A marginally significant (r = 0.60, P congruent to 0.05) correlation was also observed between N‐ desisopropylation of S‐, but not of R‐propranolol and the 4'‐ hydroxylation of S‐mephenytoin. No significant correlations were observed between the N‐desisopropylation of propranolol enantiomers and the 2‐hydroxylation of desipramine, the hydroxylation of tolbutamide or the 6 beta‐hydroxylation of testosterone. 4. Significant (P < 0.01) correlations were observed between the microsomal 4‐hydroxylation of R‐ and S‐propranolol and the 2‐hydroxylation of desipramine (r = 0.85 and 0.98, respectively). A weak (r = 0.66), albeit significant (P < 0.05) correlation was observed between the 4‐hydroxylation of R‐, but not of S‐propranolol and the hydroxylation of tolbutamide. No significant correlations were observed between the 4‐hydroxylation of propranolol enantiomers and the oxidation of other substrates for CYP1A2, 2C19, and 3A3/4. 5. Recombinant human CYP1A2 and CYP2D6 exhibited comparable catalytic activity with respect to the N‐desisopropylation of both propranolol enantiomers; only expressed CYP2D6 exhibited a marked catalytic activity with respect to the 4‐hydroxylation of both propranolol enantiomers.(ABSTRACT TRUNCATED AT 400 WORDS)
Interphenotype differences in disposition and effect on gastrin levels of omeprazole—suitability of omeprazole as a probe for CYP2C19.
Authors: Chang M , Tybring G , Dahl ML , Gotharson E , Sagar M , Seensalu R , Bertilsson L
Published: July 2012

1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S‐mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S‐mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).
A survey of the administration of drugs to young infants. The Alspac Survey Team. Avon Longitudinal Study of Pregnancy and Childhood.
Authors: Hawkins N , Golding J
Published: July 2012

Medication which is given to young infants during the first months of life, an important period of development, may have effects on development which would not be observed in adults receiving the same drugs. The aim of this study was to estimate the numbers of children receiving various types of medication, including both prescription and non‐prescription drugs, during the first 6 months of life. Self‐ completion questionnaires were posted to mothers participating in the Avon Longitudinal Study of Pregnancy & Childhood (ALSPAC) when their children were 6 months of age. These questionnaires included enquiries about the administration of drugs to the study children. The study was based in the three Bristol‐based health districts of Avon in the United Kingdom. The study population comprised of 6973 children born in the 12 month period between the 1st July 1991 and the 30th June 1992. The majority of mothers, 96%, reported that their children had received medication, excluding vaccines, during the first 6 months of life. 35% had been given drugs from four or more different classes. Paracetamol had been given to 84% of the children, antibiotics to 30%. In view of potential effects of drug exposure on long term development, it is important that drugs which are administered to children are carefully assessed to ensure that they are not harmful.
The acceptability of resin therapy to patients attending a hospital lipid clinic.
Authors: Iversen SA , Davidson D , Davidson C
Published: July 2012

Low dose cholestyramine ('Questran A') and colestipol ('Colestid Orange') were compared in a blinded two period crossover study of 55 patients attending a hospital lipid clinic. Colestipol was rated higher on a combined acceptability/palatability score. Both treatments reduced low density lipoprotein (LDL) cholesterol to a similar extent.
Intradermal actions of hypertonic saline involve neural and vascular mechanisms.
Authors: Sharara AM , Higham MA , Iredale MJ , Ind PW
Published: July 2012

The aim of this study was to investigate whether the wheal and flare responses to intradermal injection of hypertonic (4.5%) saline (HTS) were inhibited by local injection of 1% lignocaine. Eight normal subjects were studied on one occasion. Lignocaine (0.125 ml) was infiltrated at four sites on one forearm and normal saline on the other. Five minutes later, duplicate intradermal injections of 30 microliters of histamine (22.5 nmol ml‐1), substance P (1 nmol ml‐1), HTS and normal saline were given coded and in random order, one of each pair to each forearm. Lignocaine inhibited flare responses to histamine, substance P and HTS by 56% (P < 0.01), 78% (P < 0.01) and 77% (P < 0.05) respectively suggesting similar involvement of an axon reflex. Wheal to histamine was inhibited by 31% (P < 0.02) and to substance P by 33% (P < 0.05) but not to HTS. This suggests that the mechanism of wheal response to HTS differs from that of histamine and substance P.
Effects of flurbiprofen enantiomers on pain‐related chemo‐somatosensory evoked potentials in human subjects.
Authors: Lotsch J , Geisslinger G , Mohammadian P , Brune K , Kobal G
Published: July 2012

1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo‐somatosensory event‐related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23‐36 years) participated in a placebo‐controlled, randomised, double‐blind, four‐ way crossover study. Single doses of (S)‐flurbiprofen (50 mg), (R)‐ flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2‐ stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP‐amplitude P2, a measure of analgesic effect, decreased after administration of both (R)‐ and (S)‐ flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia‐related decreases in evoked potential produced by (R)‐ flurbiprofen were dose‐dependent. Comparing similar doses of (R)‐ and (S)‐flurbiprofen, the decrease in CSSERP‐amplitudes produced by the (S)‐ enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)‐flurbiprofen caused only little toxicity in rats as compared with the (S)‐enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)‐flurbiprofen in pain therapy.
Inter‐individual and intra‐individual variability of ethanol concentration‐time profiles: comparison of ethanol ingestion before or after an evening meal.
Authors: Fraser AG , Rosalki SB , Gamble GD , Pounder RE
Published: July 2012

1. The magnitude of the variability of ethanol absorption is an important factor for studies that seek to determine the significance of potential interactions between ethanol and drugs. The aim of this study was to determine the extent of inter‐ and intra‐individual variability of ethanol concentration‐time profiles in fasted and fed subjects. 2. Twenty‐four healthy male subjects were randomized to receive ethanol 0.3 g kg‐1 before an evening meal on two study days and ethanol 0.3 g kg‐1 after an evening meal on two study days. Plasma ethanol concentrations were measured at intervals from 0‐240 min. 3. There were significant differences in the mean area under the ethanol concentration‐time curve (AUC), the mean peak ethanol concentration (Cmax), the mean ethanol elimination slope and the time to peak ethanol concentration between the fed and fasted subjects. There were no significant differences between the first and second study days for either fed or fasting subjects for all parameters. 4. There was no statistically significant difference in inter‐ or intra‐subject variance between fed and fasted studies although the coefficients of variation (standard deviation expressed as a percentage of the mean) for the differences between the first and second study day were higher for fed studies. 5. The large inter‐ and intra‐individual variability of alcohol absorption for both fasted and fed subjects must be considered in the design of alcohol‐drug interaction studies.
Differential actions of desipramine on sympathoadrenal release of noradrenaline and adrenaline.
Authors: Eisenhofer G. , Friberg P. , Goldstein DS , Esler M.
Published: July 2012

Spillovers noradrenaline (NA) and adrenaline (A) into plasma were examined before and after i.v. administration of 0.3‐0.5 mg kg‐1 desipramine (DMI) in 19 normal volunteers. DMI decreased the total body spillover of NA by 20 +/‐ 4%, but increased that of A by 45 +/‐ 10%. The results indicate differential sympathoadrenal actions of DMI, characterized by inhibition of NA release from sympathetic nerves and stimulation of A secretion from the adrenals. These effects of DMI provide an explanation for some of the cardiovascular complications of tricyclic antidepressant therapy and may also help to explain how sympathoadrenal function is differentially regulated.
Determination of the minimum dose of lactose drug carrier that can be sensed during inhalation.
Authors: Higham MA , Sharara AM , Magee RP , Ind PW
Published: July 2012

Lactose is commonly used as a carrier for inhaled drugs. Twenty healthy volunteers without respiratory symptoms inhaled seven different doses of lactose and a placebo (empty) dose through the four place Diskhaler device, in order to determine the lowest dose that could be reliably sensed. The minimum dose for which all subjects reported taste or feel sensations was 10 mg. This has implications regarding the amount of carrier used in future drug delivery systems.
The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.
Authors: Kivisto KT , Kroemer HK , Eichelbaum M.
Published: July 2012

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P‐glycoprotein inhibitors inhibit P‐glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P‐glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.
N‐Hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity.
Authors: Gill HJ , Tingle MD , Park BK
Published: July 2012

1. The adverse reactions associated with the administration of dapsone are believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1]. 2. Data presented in this paper illustrate the involvement of more than one cytochrome P450 enzyme in dapsone hydroxylamine formation using human liver microsomes. Eadie‐Hofstee plots demonstrated bi‐ phasic kinetics in several livers. No correlation could be established between hydroxylamine formation and CYP3A concentrations in six human livers (r = ‐0.47; P = 0.34). 3. Studies with low molecular weight inhibitors illustrate the importance of CYP2C9 and CYP3A in dapsone N‐ hydroxylation. 4. Differential sensitivity of dapsone N‐hydroxylation to selective CYP inhibitors indicated that the contribution of individual CYP enzymes varies between livers. Selective inhibition ranged from 6.8 to 44.1% by 5 microM ketoconazole, and from 24.0 to 68.4% by 100 microM sulphaphenazole. The extent of inhibition, by either ketoconazole or sulphaphenazole was dependent on the CYP3A content of the liver. 5. The levels of expression of these cytochrome P450 enzymes may be an important determinant of individual susceptibility to the toxic effects of dapsone, and may influence the ability of an enzyme inhibitor to block dapsone toxicity in vivo. Because of the inability to produce complete inhibition, selective CYP inhibitors are unlikely to offer any clinical advantage over cimetidine in decreasing dapsone hydroxylamine formation in vivo.